当前期刊: Life Science Alliance Go to current issue    加入关注   
显示样式:        排序: IF: - GO 导出
  • Wnt10b-GSK3β-dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-30
    Yu-Chih Lin; Alexander Haas; Anja Bufe; Sabnam Parbin; Magdalena Hennecke; Oksana Voloshanenko; Julia Gross; Michael Boutros; Sergio P Acebron; Holger Bastians

    Wnt signaling is crucial for proper development, tissue homeostasis and cell cycle regulation. A key role of Wnt signaling is the GSK3β-mediated stabilization of β-catenin, which mediates many of the critical roles of Wnt signaling. In addition, it was recently revealed that Wnt signaling can also act independently of β-catenin. In fact, Wnt mediated stabilization of proteins (Wnt/STOP) that involves

  • Scratch-induced partial skin wounds re-epithelialize by sheets of independently migrating keratinocytes.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-30
    Laura Bornes; Reinhard Windoffer; Rudolf E Leube; Jessica Morgner; Jacco van Rheenen

    Re-epithelialization is a crucial process to reestablish the protective barrier upon wounding of the skin. Although this process is well described for wounds where the complete epidermis and dermis is damaged, little is known about the re-epithelialization strategy in more frequently occurring smaller scratch wounds in which structures such as the hair follicles and sweat glands stay intact. To study

  • Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-30
    Ruth Karlina; Dominik Lutter; Viktorian Miok; David Fischer; Irem Altun; Theresa Schöttl; Kenji Schorpp; Andreas Israel; Cheryl Cero; James W Johnson; Ingrid Kapser-Fischer; Anika Böttcher; Susanne Keipert; Annette Feuchtinger; Elisabeth Graf; Tim Strom; Axel Walch; Heiko Lickert; Thomas Walzthoeni; Matthias Heinig; Fabian J Theis; Cristina García-Cáceres; Aaron M Cypess; Siegfried Ussar

    Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights

  • BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-24
    Hongtao Shen; Jing Li; Xiujie Xie; Huan Yang; Mengxue Zhang; Bowen Wang; K Craig Kent; Jorge Plutzky; Lian-Wang Guo

    The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation. Cholesterol

  • G-CSF shifts erythropoiesis from bone marrow into spleen in the setting of systemic inflammation.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-24
    Weiqiang Jing; Xing Guo; Fei Qin; Yue Li; Ganyu Wang; Yuxuan Bi; Xing Jin; Lihui Han; Xiaoyuan Dong; Yunxue Zhao

    The anemia of inflammation is related in part to abnormal erythropoiesis in bone marrow. G-CSF regulates granulopoiesis and is increased during systemic inflammation. Here, we have showed that high levels of G-CSF are associated with repression of bone marrow erythropoiesis and expansion of splenic erythropoiesis in Escherichia coli-infected mice and lipopolysaccharide-treated mice. Under lipopolysaccharide-induced

  • Inhibiting the reproduction of SARS-CoV-2 through perturbations in human lung cell metabolic network.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-24
    Hadrien Delattre; Kalesh Sasidharan; Orkun S Soyer

    Viruses rely on their host for reproduction. Here, we made use of genomic and structural information to create a biomass function capturing the amino and nucleic acid requirements of SARS-CoV-2. Incorporating this biomass function into a stoichiometric metabolic model of the human lung cell and applying metabolic flux balance analysis, we identified host-based metabolic perturbations inhibiting SARS-CoV-2

  • Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-24
    Anne Rietz; Kevin J Hodgetts; Hrvoje Lusic; Kevin M Quist; Erkan Y Osman; Christian L Lorson; Elliot J Androphy

    Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. SMA results from insufficient survival motor neuron (SMN) protein due to alternative splicing. Antisense oligonucleotides, gene therapy and splicing modifiers recently received FDA approval. Although severe SMA transgenic mouse models have been beneficial for testing therapeutic efficacy, models

  • Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-16
    Joseph A Newman; Angeline E Gavard; Simone Lieb; Madhwesh C Ravichandran; Katja Hauer; Patrick Werni; Leonhard Geist; Jark Böttcher; John R Engen; Klaus Rumpel; Matthias Samwer; Mark Petronczki; Opher Gileadi

    Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2-Å crystal structure of the WRN helicase core (517-1,093), comprising the two helicase subdomains and winged helix domain

  • Characterization of ori and parS-like functions in secondary genome replicons in Deinococcus radiodurans.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-16
    Ganesh K Maurya; Hari S Misra

    The mechanisms underlying multipartite genome maintenance and its functional significance in extraordinary radioresistance of Deinococcus radiodurans are not well understood. The sequences upstream to parAB operons in chrII (cisII) and MP (cisMP) could stabilize an otherwise, non-replicative colE1 plasmid, in D. radiodurans DnaA and cognate ParB proteins bound specifically with cisII and cisMP elements

  • The actin regulator profilin 1 is functionally associated with the mammalian centrosome.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-12
    Michaela Nejedlá; Anastasiya Klebanovych; Vadym Sulimenko; Tetyana Sulimenko; Eduarda Dráberová; Pavel Dráber; Roger Karlsson

    Profilin 1 is a crucial actin regulator, interacting with monomeric actin and several actin-binding proteins controlling actin polymerization. Recently, it has become evident that this profilin isoform associates with microtubules via formins and interferes with microtubule elongation at the cell periphery. Recruitment of microtubule-associated profilin upon extensive actin polymerizations, for example

  • Interferon lambda 4 can directly activate human CD19+ B cells and CD8+ T cells.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-06
    Mairene Coto-Llerena; Marco Lepore; Julian Spagnuolo; Daniela Di Blasi; Diego Calabrese; Aleksei Suslov; Glenn Bantug; Francois Ht Duong; Luigi M Terracciano; Gennaro De Libero; Markus H Heim

    Compared with the ubiquitous expression of type I (IFNα and IFNβ) interferon receptors, type III (IFNλ) interferon receptors are mainly expressed in epithelial cells of mucosal barriers of the of the intestine and respiratory tract. Consequently, IFNλs are important for innate pathogen defense in the lung and intestine. IFNλs also determine the outcome of hepatitis C virus (HCV) infections, with IFNλ4

  • Myeloid transformation by MLL-ENL depends strictly on C/EBP.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-11-03
    Radoslaw Wesolowski; Elisabeth Kowenz-Leutz; Karin Zimmermann; Dorothea Dörr; Maria Hofstätter; Robert K Slany; Alexander Mildner; Achim Leutz

    Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription

  • Leishmania-infected macrophages release extracellular vesicles that can promote lesion development.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-29
    Anna Gioseffi; Tim Hamerly; Kha Van; Naixin Zhang; Rhoel R Dinglasan; Phillip A Yates; Peter E Kima

    Leishmania donovani infection of macrophages results in quantitative and qualitative changes in the protein profile of extracellular vesicles (EVs) released by the infected host cells. We confirmed mass spectrometry results orthogonally by performing Western blots for several Leishmania-infected macrophage-enriched EVs (LieEVs) molecules. Several host cell proteins in LieEVs have been implicated in

  • Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-27
    Hongwei Shao; Yan Li; Irena Pastar; Min Xiao; Rochelle Prokupets; Sophia Liu; Kerstin Yu; Roberto I Vazquez-Padron; Marjana Tomic-Canic; Omaida C Velazquez; Zhao-Jun Liu

    Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin

  • Aberrant autophagosome formation occurs upon small molecule inhibition of ULK1 kinase activity.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-27
    Maria Zachari; Marianna Longo; Ian G Ganley

    Autophagy is a crucial homeostatic mechanism that mediates the degradation of damaged or excess intracellular components. Such components are engulfed and sequestered into double membrane autophagosomes, which deliver their contents to lysosomes for degradation. Autophagy plays a role in numerous human disorders and its pharmacological targeting by small molecules offers therapeutic potential. The

  • Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-26
    Francesca Sardina; Alessandra Pisciottani; Manuela Ferrara; Davide Valente; Marialuisa Casella; Marco Crescenzi; Angelo Peschiaroli; Carlo Casali; Silvia Soddu; Andrew J Grierson; Cinzia Rinaldo

    Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule-severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy

  • Plasmodium DEH is ER-localized and crucial for oocyst mitotic division during malaria transmission.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-26
    David S Guttery; Rajan Pandey; David Jp Ferguson; Richard J Wall; Declan Brady; Dinesh Gupta; Anthony A Holder; Rita Tewari

    Cells use fatty acids (FAs) for membrane biosynthesis, energy storage, and the generation of signaling molecules. 3-hydroxyacyl-CoA dehydratase-DEH-is a key component of very long chain fatty acid synthesis. Here, we further characterized in-depth the location and function of DEH, applying in silico analysis, live cell imaging, reverse genetics, and ultrastructure analysis using the mouse malaria model

  • Chromosome instability induced by a single defined sister chromatid fusion.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-26
    Katsushi Kagaya; Naoto Noma-Takayasu; Io Yamamoto; Sanki Tashiro; Fuyuki Ishikawa; Makoto T Hayashi

    Chromosome fusion is a frequent intermediate in oncogenic chromosome rearrangements and has been proposed to cause multiple tumor-driving abnormalities. In conventional experimental systems, however, these abnormalities were often induced by randomly induced chromosome fusions involving multiple different chromosomes. It was therefore not well understood whether a single defined type of chromosome

  • Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-23
    Tania Martins-Marques; Teresa Ribeiro-Rodrigues; Saskia C de Jager; Monica Zuzarte; Cátia Ferreira; Pedro Cruz; Liliana Reis; Rui Baptista; Lino Gonçalves; Joost Pg Sluijter; Henrique Girao

    Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy

  • Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-21
    Yoko Nakano; Susan Wiechert; Bernd Fritzsch; Botond Bánfi

    In mechanosensory hair cells (HCs) of the ear, the transcriptional repressor REST is continuously inactivated by alternative splicing of its pre-mRNA. This mechanism of REST inactivation is crucial for hearing in humans and mice. Rest is one of many pre-mRNAs whose alternative splicing is regulated by the splicing factor SRRM4; Srrm4 loss-of-function mutation in mice (Srrm4 bv/bv ) causes deafness

  • Brain is an endocrine organ through secretion and nuclear transfer of parathymosin.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-21
    Bin Yu; Yizhe Tang; Dongsheng Cai

    This study reports that parathymosin (PTMS) is secreted by hypothalamic stem/progenitor cells (htNSC) to inhibit senescence of recipient cells such as fibroblasts. Upon release, PTMS is rapidly transferred into the nuclei of various cell types, including neuronal GT1-7 cells and different peripheral cells, and it is effectively transferred into neuronal nuclei in various brain regions in vivo. Notably

  • Incipient sympatric speciation in wild barley caused by geological-edaphic divergence.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-20
    Kexin Li; Xifeng Ren; Xiaoying Song; Xiujuan Li; Yu Zhou; Eli Harlev; Dongfa Sun; Eviatar Nevo

    Sympatric speciation (SS) has been contentious since the idea was suggested by Darwin. Here, we show in wild barley SS due to geologic and edaphic divergence in "Evolution Plateau," Upper Galilee, Israel. Our whole genome resequencing data showed SS separating between the progenitor old Senonian chalk and abutting derivative young Pleistocene basalt wild barley populations. The basalt wild barley species

  • Role of opioid signaling in kidney damage during the development of salt-induced hypertension.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-12
    Daria Golosova; Oleg Palygin; Ruslan Bohovyk; Christine A Klemens; Vladislav Levchenko; Denisha R Spires; Elena Isaeva; Ashraf El-Meanawy; Alexander Staruschenko

    Opioid use is associated with predictors of poor cardiorenal outcomes. However, little is known about the direct impact of opioids on podocytes and renal function, especially in the context of hypertension and CKD. We hypothesize that stimulation of opioid receptors (ORs) contributes to dysregulation of intracellular calcium ([Ca2+]i) homeostasis in podocytes, thus aggravating the development of renal

  • A double role of the Gal80 N terminus in activation of transcription by Gal4p.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-09
    Annekathrin Reinhardt-Tews; Rościsław Krutyhołowa; Christian Günzel; Constance Roehl; Sebastian Glatt; Karin D Breunig

    The yeast galactose switch operated by the Gal4p-Gal80p-Gal3p regulatory module is a textbook model of transcription regulation in eukaryotes. The Gal80 protein inhibits Gal4p-mediated transcription activation by binding to the transcription activation domain. In Saccharomyces cerevisiae, inhibition is relieved by formation of an alternative Gal80-Gal3 complex. In yeasts lacking a Gal3p ortholog, such

  • In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-08
    Linda K Rushworth; Victoria Harle; Peter Repiscak; William Clark; Robin Shaw; Holly Hall; Martin Bushell; Hing Y Leung; Rachana Patel

    Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may

  • Neurturin regulates the lung-resident macrophage inflammatory response to viral infection.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-10-05
    Emma Connolly; David J Morgan; Miriam Franklin; Angela Simpson; Rajesh Shah; Oliver J Brand; Christopher P Jagger; Joshua Casulli; Karishma Mohamed; Aleksander M Grabiec; Tracy Hussell

    Lung-resident macrophages are crucial to the maintenance of health and in the defence against lower respiratory tract infections. Macrophages adapt to local environmental cues that drive their appropriate function; however, this is often dysregulated in many inflammatory lung pathologies. In mucosal tissues, neuro-immune interactions enable quick and efficient inflammatory responses to pathogenic threats

  • Gene selection for optimal prediction of cell position in tissues from single-cell transcriptomics data.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-24
    Jovan Tanevski; Thin Nguyen; Buu Truong; Nikos Karaiskos; Mehmet Eren Ahsen; Xinyu Zhang; Chang Shu; Ke Xu; Xiaoyu Liang; Ying Hu; Hoang Vv Pham; Li Xiaomei; Thuc D Le; Adi L Tarca; Gaurav Bhatti; Roberto Romero; Nestoras Karathanasis; Phillipe Loher; Yang Chen; Zhengqing Ouyang; Disheng Mao; Yuping Zhang; Maryam Zand; Jianhua Ruan; Christoph Hafemeister; Peng Qiu; Duc Tran; Tin Nguyen; Attila Gabor;

    Single-cell RNA-sequencing (scRNAseq) technologies are rapidly evolving. Although very informative, in standard scRNAseq experiments, the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to maintain cell localization have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while

  • Mps2 links Csm4 and Mps3 to form a telomere-associated LINC complex in budding yeast.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-23
    Jinbo Fan,Hui Jin,Bailey A Koch,Hong-Guo Yu

    The linker of the nucleoskeleton and cytoskeleton (LINC) complex is composed of two transmembrane proteins: the KASH domain protein localized to the outer nuclear membrane and the SUN domain protein to the inner nuclear membrane. In budding yeast, the sole SUN domain protein, Mps3, is thought to pair with either Csm4 or Mps2, two KASH-like proteins, to form two separate LINC complexes. Here, we show

  • Fungal mycelia and bacterial thiamine establish a mutualistic growth mechanism.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-22
    Gayan Abeysinghe,Momoka Kuchira,Gamon Kudo,Shunsuke Masuo,Akihiro Ninomiya,Kohei Takahashi,Andrew S Utada,Daisuke Hagiwara,Nobuhiko Nomura,Naoki Takaya,Nozomu Obana,Norio Takeshita

    Exclusivity in physical spaces and nutrients is a prerequisite for survival of organisms, but a few species have been able to develop mutually beneficial strategies that allow them to co-habit. Here, we discovered a mutualistic mechanism between filamentous fungus, Aspergillus nidulans, and bacterium, Bacillus subtilis The bacterial cells co-cultured with the fungus traveled along mycelia using their

  • Predicting gene regulatory networks from cell atlases.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-21
    Andreas Fønss Møller,Kedar Nath Natarajan

    Recent single-cell RNA-sequencing atlases have surveyed and identified major cell types across different mouse tissues. Here, we computationally reconstruct gene regulatory networks from three major mouse cell atlases to capture functional regulators critical for cell identity, while accounting for a variety of technical differences, including sampled tissues, sequencing depth, and author assigned

  • Implications for tetraspanin-enriched microdomain assembly based on structures of CD9 with EWI-F.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-21
    Wout Oosterheert,Katerina T Xenaki,Viviana Neviani,Wouter Pos,Sofia Doulkeridou,Jip Manshande,Nicholas M Pearce,Loes Mj Kroon-Batenburg,Martin Lutz,Paul Mp van Bergen En Henegouwen,Piet Gros

    Tetraspanins are eukaryotic membrane proteins that contribute to a variety of signaling processes by organizing partner-receptor molecules in the plasma membrane. How tetraspanins bind and cluster partner receptors into tetraspanin-enriched microdomains is unknown. Here, we present crystal structures of the large extracellular loop of CD9 bound to nanobodies 4C8 and 4E8 and, the cryo-EM structure of

  • Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-21
    Meliha Mehmeti-Ajradini,Caroline Bergenfelz,Anna-Maria Larsson,Robert Carlsson,Kristian Riesbeck,Jonas Ahl,Helena Janols,Marlene Wullt,Anders Bredberg,Eva Källberg,Frida Björk Gunnarsdottir,Camilla Rydberg Millrud,Lisa Rydén,Gesine Paul,Niklas Loman,Jörgen Adolfsson,Ana Carneiro,Karin Jirström,Fredrika Killander,Daniel Bexell,Karin Leandersson

    Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs

  • Stoichiometry of Rtt109 complexes with Vps75 and histones H3-H4.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-10
    Noushin Akhavantabib,Daniel D Krzizike,Victoria Neumann,Sheena D'Arcy

    Histone acetylation is one of many posttranslational modifications that affect nucleosome accessibility. Vps75 is a histone chaperone that stimulates Rtt109 acetyltransferase activity toward histones H3-H4 in yeast. In this study, we use sedimentation velocity and light scattering to characterize various Vps75-Rtt109 complexes, both with and without H3-H4. These complexes were previously ill-defined

  • multicrispr: gRNA design for prime editing and parallel targeting of thousands of targets.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-09
    Aditya M Bhagwat,Johannes Graumann,Rene Wiegandt,Mette Bentsen,Jordan Welker,Carsten Kuenne,Jens Preussner,Thomas Braun,Mario Looso

    Targeting the coding genome to introduce nucleotide deletions/insertions via the CRISPR/Cas9 technology has become a standard procedure. It has quickly spawned a multitude of methods such as prime editing, APEX proximity labeling, or homology directed repair, for which supporting bioinformatics tools are, however, lagging behind. New CRISPR/Cas9 applications often require specific gRNA design functionality

  • MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-09
    Sarbani Saha,Rupasri Ain

    Proper placentation is fundamental to successful pregnancy. Placenta arises from differentiation of trophoblast stem (TS) cells during development. Despite being recognized as the counterpart of ES cells in placental development, the role of regulatory miRNAs in TS cell differentiation remains inadequately explored. Here, we have identified complete repertoire of microRNAs present in mouse trophoblast

  • Multiplexed chemogenetics in astrocytes and motoneurons restore blood-spinal cord barrier in ALS.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-09-08
    Najwa Ouali Alami,Linyun Tang,Diana Wiesner,Barbara Commisso,David Bayer,Jochen Weishaupt,Luc Dupuis,Phillip Wong,Bernd Baumann,Thomas Wirth,Tobias M Boeckers,Deniz Yilmazer-Hanke,Albert Ludolph,Francesco Roselli

    Blood-spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1 G93A , FUSΔNLS , TDP43 G298S , and Tbk1 +/- ALS mouse models commonly shared alterations

  • An atlas of human proximal epididymis reveals cell-specific functions and distinct roles for CFTR.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-27
    Shih-Hsing Leir,Shiyi Yin,Jenny L Kerschner,Wilmel Cosme,Ann Harris

    Spermatozoa released from the testis are unable to fertilize an egg without a coordinated process of maturation in the lumen of the epididymis. Relatively little is known about the molecular events that integrate this critical progression along the male genital ducts in man. Here, we use single cell RNA-sequencing to construct an atlas of the human proximal epididymis. We find that the CFTR, which

  • A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-25
    Mario Cocco,Matthew A Care,Amel Saadi,Muna Al-Maskari,Gina Doody,Reuben Tooze

    The activated B-cell (ABC) to plasmablast transition encompasses the cusp of antibody-secreting cell (ASC) differentiation. We explore this transition with integrated analysis in human cells, focusing on changes that follow removal from CD40-mediated signals. Within hours of input signal loss, cell growth programs shift toward enhanced proliferation, accompanied by ER-stress response, and up-regulation

  • Biochemical and functional characterization of a meiosis-specific Pch2/ORC AAA+ assembly.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-21
    María Ascensión Villar-Fernández,Richard Cardoso da Silva,Magdalena Firlej,Dongqing Pan,Elisabeth Weir,Annika Sarembe,Vivek B Raina,Tanja Bange,John R Weir,Gerben Vader

    Pch2 is a meiosis-specific AAA+ protein that controls several important chromosomal processes. We previously demonstrated that Orc1, a subunit of the ORC, functionally interacts with budding yeast Pch2. The ORC (Orc1-6) AAA+ complex loads the AAA+ MCM helicase to origins of replication, but whether and how ORC collaborates with Pch2 remains unclear. Here, we show that a Pch2 hexamer directly associates

  • Plasma membrane phosphatidylinositol (4,5)-bisphosphate promotes Weibel-Palade body exocytosis.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-21
    Tu Thi Ngoc Nguyen,Sophia N Koerdt,Volker Gerke

    Weibel-Palade bodies (WPB) are specialized secretory organelles of endothelial cells that control vascular hemostasis by regulated, Ca2+-dependent exocytosis of the coagulation-promoting von-Willebrand factor. Some proteins of the WPB docking and fusion machinery have been identified but a role of membrane lipids in regulated WPB exocytosis has so far remained elusive. We show here that the plasma

  • PGE2 accounts for bidirectional changes in alveolar macrophage self-renewal with aging and smoking.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-20
    Loka R Penke,Jennifer M Speth,Christina Draijer,Zbigniew Zaslona,Judy Chen,Peter Mancuso,Christine M Freeman,Jeffrey L Curtis,Daniel R Goldstein,Marc Peters-Golden

    Alveolar macrophages (AMs) are resident immune cells of the lung that are critical for host defense. AMs are capable of proliferative renewal, yet their numbers are known to decrease with aging and increase with cigarette smoking. The mechanism by which AM proliferation is physiologically restrained, and whether dysregulation of this brake contributes to altered AM numbers in pathologic circumstances

  • The RECQL helicase prevents replication fork collapse during replication stress.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-20
    Bente Benedict,Marit Ae van Bueren,Frank Pa van Gemert,Cor Lieftink,Sergi Guerrero Llobet,Marcel Atm van Vugt,Roderick L Beijersbergen,Hein Te Riele

    Most tumors lack the G1/S phase checkpoint and are insensitive to antigrowth signals. Loss of G1/S control can severely perturb DNA replication as revealed by slow replication fork progression and frequent replication fork stalling. Cancer cells may thus rely on specific pathways that mitigate the deleterious consequences of replication stress. To identify vulnerabilities of cells suffering from replication

  • DDX5 promotes oncogene C3 and FABP1 expressions and drives intestinal inflammation and tumorigenesis.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-18
    Nazia Abbasi,Tianyun Long,Yuxin Li,Brian A Yee,Benjamin S Cho,Juan E Hernandez,Evelyn Ma,Parth R Patel,Debashis Sahoo,Ibrahim M Sayed,Nissi Varki,Soumita Das,Pradipta Ghosh,Gene W Yeo,Wendy Jia Men Huang

    Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different

  • Thymosin α1 protects from CTLA-4 intestinal immunopathology.
    Life Sci. Alliance (IF 2.622) Pub Date : 2020-08-14
    Giorgia Renga,Marina M Bellet,Marilena Pariano,Marco Gargaro,Claudia Stincardini,Fiorella D'Onofrio,Paolo Mosci,Stefano Brancorsini,Andrea Bartoli,Allan L Goldstein,Enrico Garaci,Luigina Romani,Claudio Costantini

    The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate

  • Robust repression of tRNA gene transcription during stress requires protein arginine methylation.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-06-03
    Richoo B Davis,Neah Likhite,Christopher A Jackson,Tao Liu,Michael C Yu

    Protein arginine methylation is an important means by which protein function can be regulated. In the budding yeast, this modification is catalyzed by the major protein arginine methyltransferase Hmt1. Here, we provide evidence that the Hmt1-mediated methylation of Rpc31, a subunit of RNA polymerase III, plays context-dependent roles in tRNA gene transcription: under conditions optimal for growth,

  • Molecular characterization of Chlamydomonas reinhardtii telomeres and telomerase mutants.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-06-03
    Stephan Eberhard,Sona Valuchova,Julie Ravat,Jaroslav Fulneček,Pascale Jolivet,Sandrine Bujaldon,Stéphane D Lemaire,Francis-André Wollman,Maria Teresa Teixeira,Karel Riha,Zhou Xu

    Telomeres are repeated sequences found at the end of the linear chromosomes of most eukaryotes and are required for chromosome integrity. Expression of the reverse-transcriptase telomerase allows for extension of telomeric repeats to counteract natural telomere shortening. Although Chlamydomonas reinhardtii, a photosynthetic unicellular green alga, is widely used as a model organism in photosynthesis

  • The m6A pathway protects the transcriptome integrity by restricting RNA chimera formation in plants.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-29
    Dominique Pontier,Claire Picart,Moaine El Baidouri,François Roudier,Tao Xu,Sylvie Lahmy,Christel Llauro,Jacinthe Azevedo,Michèle Laudié,Aurore Attina,Christophe Hirtz,Marie-Christine Carpentier,Lisha Shen,Thierry Lagrange

    Global, segmental, and gene duplication-related processes are driving genome size and complexity in plants. Despite their evolutionary potentials, those processes can also have adverse effects on genome regulation, thus implying the existence of specialized corrective mechanisms. Here, we report that an N6-methyladenosine (m6A)-assisted polyadenylation (m-ASP) pathway ensures transcriptome integrity

  • PKAc is not required for the preerythrocytic stages of Plasmodium berghei.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-29
    Hadi Hasan Choudhary,Roshni Gupta,Satish Mishra

    Plasmodium sporozoites invade hepatocytes to initiate infection in the mammalian host. In the infected hepatocytes, sporozoites undergo rapid expansion and differentiation, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Both sporozoites and merozoites invade their host cells by activation of a signaling cascade followed by discharge of micronemal content

  • The S. Typhi effector StoD is an E3/E4 ubiquitin ligase which binds K48- and K63-linked diubiquitin.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-29
    Melanie A McDowell,Alexander Mp Byrne,Elli Mylona,Rebecca Johnson,Agnes Sagfors,Valerie F Crepin,Susan Lea,Gad Frankel

    Salmonella enterica (e.g., serovars Typhi and Typhimurium) relies on translocation of effectors via type III secretion systems (T3SS). Specialization of typhoidal serovars is thought to be mediated via pseudogenesis. Here, we show that the Salmonella Typhi STY1076/t1865 protein, named StoD, a homologue of the enteropathogenic Escherichia coli/enterohemorrhagic E. coli/Citrobacter rodentium NleG, is

  • Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-27
    Bonnie L Bullock,Abigail K Kimball,Joanna M Poczobutt,Alexander J Neuwelt,Howard Y Li,Amber M Johnson,Jeff W Kwak,Emily K Kleczko,Rachael E Kaspar,Emily K Wagner,Katharina Hopp,Erin L Schenk,Mary Cm Weiser-Evans,Eric T Clambey,Raphael A Nemenoff

    Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras-mutant lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference

  • Molecular characterization of CHAD domains as inorganic polyphosphate-binding modules.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-27
    Laura Lorenzo-Orts,Ulrich Hohmann,Jinsheng Zhu,Michael Hothorn

    Inorganic polyphosphates (polyPs) are linear polymers of orthophosphate units linked by phosphoanhydride bonds. Here, we report that bacterial, archaeal, and eukaryotic conserved histidine α-helical (CHAD) domains are specific polyP-binding modules. Crystal structures reveal that CHAD domains are formed by two four-helix bundles, giving rise to a central pore surrounded by conserved basic surface patches

  • Rate of brain aging and APOE ε4 are synergistic risk factors for Alzheimer's disease.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-27
    Christin A Glorioso,Andreas R Pfenning,Sam S Lee,David A Bennett,Etienne L Sibille,Manolis Kellis,Leonard P Guarente

    Advanced age and the APOE ε4 allele are the two biggest risk factors for Alzheimer's disease (AD) and declining cognitive function. We describe a universal gauge to measure molecular brain age using transcriptome analysis of four human postmortem cohorts (n = 673, ages 25-97) free of neurological disease. In a fifth cohort of older subjects with or without neurological disease (n = 438, ages 67-108)

  • The hypoxia-response pathway modulates RAS/MAPK-mediated cell fate decisions in Caenorhabditis elegans.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-24
    Sabrina Maxeiner,Judith Grolleman,Tobias Schmid,Jan Kammenga,Alex Hajnal

    Animals need to adjust many cellular functions to oxygen availability to adapt to changing environmental conditions. We have used the nematode Caenorhabditis elegans as a model to investigate how variations in oxygen concentrations affect cell fate specification during development. Here, we show that several processes controlled by the conserved RTK/RAS/MAPK pathway are sensitive to changes in the

  • Loss of PGC-1α in RPE induces mesenchymal transition and promotes retinal degeneration.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-17
    Mariana Aparecida Brunini Rosales,Daisy Y Shu,Jared Iacovelli,Magali Saint-Geniez

    The retinal pigment epithelium (RPE) supports visual processing and photoreceptor homeostasis via energetically demanding cellular functions. Here, we describe the consequences of repressing peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), a master regulator of mitochondrial function and biogenesis, on RPE epithelial integrity. The sustained silencing of PGC-1α in differentiating

  • An N-terminal-truncated isoform of FAM134B (FAM134B-2) regulates starvation-induced hepatic selective ER-phagy.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-17
    Shohei Kohno,Yuji Shiozaki,Audrey L Keenan,Shinobu Miyazaki-Anzai,Makoto Miyazaki

    Autophagy is a conserved system that adapts to nutrient starvation, after which proteins and organelles are degraded to recycle amino acids in response to starvation. Recently, the ER was added to the list of targets of autophagic degradation. Autophagic degradation pathways of bulk ER and the specific proteins sorted through the ER are considered key mechanisms in maintaining ER homeostasis. Four

  • MicroRNA-155 is essential for the optimal proliferation and survival of plasmablast B cells.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-16
    Giuseppina Arbore,Tom Henley,Laura Biggins,Simon Andrews,Elena Vigorito,Martin Turner,Rebecca Leyland

    A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely

  • Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-13
    Chang-Min Lee,Chuan-Hua He,Jin Wook Park,Jae Hyun Lee,Suchita Kamle,Bing Ma,Bedia Akosman,Roberto Cotez,Emily Chen,Yang Zhou,Erica L Herzog,Changwan Ryu,Xueyan Peng,Ivan O Rosas,Sergio Poli,Carol Feghali Bostwick,Augustine M Choi,Jack A Elias,Chun Geun Lee

    TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1-mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1-stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects

  • Cellular response upon proliferation in the presence of an active mitotic checkpoint.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-08
    Andrea Corno,Elena Chiroli,Fridolin Gross,Claudio Vernieri,Vittoria Matafora,Stefano Maffini,Marco Cosentino Lagomarsino,Angela Bachi,Andrea Ciliberto

    Eukaryotic cells treated with microtubule-targeting agents activate the spindle assembly checkpoint to arrest in mitosis and prevent chromosome mis-segregation. A fraction of mitotically arrested cells overcomes the block and proliferates even under persistent checkpoint-activating conditions. Here, we asked what allows proliferation in such unfavourable conditions. We report that yeast cells are delayed

  • Development of a new monoclonal antibody specific to mouse Vγ6 chain.
    Life Sci. Alliance (IF 2.622) Pub Date : 2019-05-07
    Shinya Hatano,Xin Tun,Naoto Noguchi,Dan Yue,Hisakata Yamada,Xun Sun,Mitsuru Matsumoto,Yasunobu Yoshikai

    There are seven Vγ gene segments in the TCR γ chain loci of mice. We developed monoclonal antibodies (mAbs) specific to the Vγ6 chain (Heilig & Tonegawa nomenclature). By immunizing Vγ4/6 KO mice with complementarity-determining region peptides in Vγ6 chains, we generated three hybridomas. These hybridomas produced mAbs capable of cell surface staining of Vγ6/Vδ1 gene-transfected T-cell line lacking