Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here we reveal that the direct effects of ... More
Comprehensive structure and functional adaptations of the yeast nuclear pore complex.
AuthorsAkey CW, Singh D, Ouch C, Echeverria I, Nudelman I, Varberg JM, Yu Z, Fang F, Shi Y, Wang J, Salzberg D, Song K, Xu C, Gumbart JC, Suslov S, Unruh J, Jaspersen SL, Chait BT, Sali A, Fernandez-Martinez J, Ludtke SJ, Villa E, Rout MP
JournalCell
PubMed ID34982960
Nuclear pore complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the isolated yeast NPC in which the inner ring is resolved by cryo-EM at sub-nanometer resolution to show how flexible connectors tie together different structural and functional layers. These connectors may be targets for ... More
Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity.
AuthorsRingel AE, Drijvers JM, Baker GJ, Catozzi A, García-Cañaveras JC, Gassaway BM, Miller BC, Juneja VR, Nguyen TH, Joshi S, Yao CH, Yoon H, Sage PT, LaFleur MW, Trombley JD, Jacobson CA, Maliga Z, Gygi SP, Sorger PK, Rabinowitz JD, Sharpe AH, Haigis MC
JournalCell
PubMed ID33301708
Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8(+) T cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution ... More
Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions.
AuthorsHansen JM, de Jong MF, Wu Q, Zhang LS, Heisler DB, Alto LT, Alto NM
JournalCell
PubMed ID34022140
Gasdermin B (GSDMB) belongs to a large family of pore forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the ... More
WNK kinases sense molecular crowding and rescue cell volume via phase separation.
AuthorsBoyd-Shiwarski CR, Shiwarski DJ, Griffiths SE, Beacham RT, Norrell L, Morrison DE, Wang J, Mann J, Tennant W, Anderson EN, Franks J, Calderon M, Connolly KA, Cheema MU, Weaver CJ, Nkashama LJ, Weckerly CC, Querry KE, Pandey UB, Donnelly CJ, Sun D, Rodan AR, Subramanya AR
JournalCell
PubMed ID36318922
When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating ... More
Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.
AuthorsNava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, Vihinen H, Jokitalo E, Li X, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Dahl KN, Wickström SA
JournalCell
PubMed ID32302590
Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a ... More
Thermus thermophilus Argonaute Functions in the Completion of DNA Replication.
AuthorsJolly SM, Gainetdinov I, Jouravleva K, Zhang H, Strittmatter L, Bailey SM, Hendricks GM, Dhabaria A, Ueberheide B, Zamore PD
JournalCell
PubMed ID32846159
In many eukaryotes, Argonaute proteins, guided by short RNA sequences, defend cells against transposons and viruses. In the eubacterium Thermus thermophilus, the DNA-guided Argonaute TtAgo defends against transformation by DNA plasmids. Here, we report that TtAgo also participates in DNA replication. In vivo, TtAgo binds 15â18 nt DNA guides derived ... More
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.
AuthorsLogan T, Simon MJ, Rana A, Cherf GM, Srivastava A, Davis SS, Low RLY, Chiu CL, Fang M, Huang F, Bhalla A, Llapashtica C, Prorok R, Pizzo ME, Calvert MEK, Sun EW, Hsiao-Nakamoto J, Rajendra Y, Lexa KW, Srivastava DB, van Lengerich B, Wang J, Robles-Colmenares Y, Kim DJ, Duque J, Lenser M, Earr TK, Nguyen H, Chau R, Tsogtbaatar B, Ravi R, Skuja LL, Solanoy H, Rosen HJ, Boeve BF, Boxer AL, Heuer HW, Dennis MS, Kariolis MS, Monroe KM, Przybyla L, Sanchez PE, Meisner R, Diaz D, Henne KR, Watts RJ, Henry AG, Gunasekaran K, Astarita G, Suh JH, Lewcock JW, DeVos SL, Di Paolo G
JournalCell
PubMed ID34450028
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn(â/â) mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of ... More
Pyramidal neurons form active, transient, multilayered circuits perturbed by autism-associated mutations at the inception of neocortex.
AuthorsMunz M, Bharioke A, Kosche G, Moreno-Juan V, Brignall A, Rodrigues TM, Graff-Meyer A, Ulmer T, Haeuselmann S, Pavlinic D, Ledergerber N, Gross-Scherf B, Rózsa B, Krol J, Picelli S, Cowan CS, Roska B
JournalCell
PubMed ID37071993
Cortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that mouse embryonic Rbp4-Cre cortical neurons, transcriptomically closest to layer 5 pyramidal neurons, display two phases of circuit assembly in vivo. At E14.5, they form a multi-layered circuit motif, composed ... More
Non-canonical β-adrenergic activation of ERK at endosomes.
AuthorsKwon Y, Mehta S, Clark M, Walters G, Zhong Y, Lee HN, Sunahara RK, Zhang J
JournalNature
PubMed ID36289326
G protein-coupled receptors (GPCRs), the largest family of signaling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK), a master regulator of cell proliferation and survival(1). However, the precise mechanisms underlying GPCR-mediated ERK activation are not clearly understood(2â4). Here we investigated how spatially organized β(2)-adrenergic ... More
Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner.
AuthorsGwon Y, Maxwell BA, Kolaitis RM, Zhang P, Kim HJ, Taylor JP
JournalScience (New York, N.Y.)
PubMed ID34739333
Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern ... More
Hand2 Selectively Reorganizes Chromatin Accessibility to Induce Pacemaker-like Transcriptional Reprogramming.
AuthorsFernandez-Perez A, Sathe AA, Bhakta M, Leggett K, Xing C, Munshi NV
JournalCell Rep
PubMed ID31116981
'Gata4, Hand2, Mef2c, and Tbx5 (GHMT) can reprogram transduced fibroblasts into induced pacemaker-like myocytes (iPMs), but the underlying mechanisms remain obscure. Here, we explore the role of Hand2 in iPM formation by using a combination of transcriptome, genome, and biochemical assays. We found many shared transcriptional signatures between iPMs and ... More
PTBP1 contributes to spermatogenesis through regulation of proliferation in spermatogonia.
AuthorsSenoo M, Takijiri T, Yoshida N, Ozawa M, Ikawa M
JournalJ Reprod Dev
PubMed ID30416150
'Polypyrimidine tract-binding protein 1 (PTBP1) is a highly conserved RNA-binding protein that is a well-known regulator of alternative splicing. Testicular tissue is one of the richest tissues with respect to the number of alternative splicing mRNA isoforms, but the molecular role(s) of PTBP1 in the regulation of these isoforms during ... More
Transferrin receptor 1 is required for enucleation of mouse erythroblasts during terminal differentiation.
AuthorsAoto M, Iwashita A, Mita K, Ohkubo N, Tsujimoto Y, Mitsuda N,
JournalFEBS Open Bio
PubMed ID30761254
'Enucleation is the process whereby the nucleus is extruded from the erythroblast during late stage mammalian erythropoiesis. However, the specific signaling pathways involved in this process remain unclear. To better understand the mechanisms underlying erythroblast enucleation, we investigated erythroblast enucleation using both the spleens of adult mice with phenylhydrazine-induced anemia ... More
Rapid liquid biopsy for Mohs surgery: rare target cell separation from surgical margin lavage fluid with a high recovery rate and selectivity.
AuthorsZhou W, Liu Y, Ran M, Zhao X, Li H, Li H, Wang W
JournalLab Chip
PubMed ID30694285
'In melanoma surgery, it is difficult to identify residual scattered tumor cells at the surgical margin because of invasive growth. Mohs surgery, widely applied to increase the cure rate and decrease the recurrence rate of melanoma, involves examination of the tissue for tumor cells after tissue removal. Here, we established ... More
A case report of multiple primary prostate tumors with differential drug sensitivity.
AuthorsWilkinson S, Harmon SA, Terrigino NT, Karzai F, Pinto PA, Madan RA, VanderWeele DJ, Lake R, Atway R, Bright JR, Carrabba NV, Trostel SY, Lis RT, Chun G, Gulley JL, Merino MJ, Choyke PL, Ye H, Dahut WL, Turkbey B, Sowalsky AG
JournalNat Commun
PubMed ID32054861
'Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen ... More
Assembly of Peripheral Actomyosin Bundles in Epithelial Cells Is Dependent on the CaMKK2/AMPK Pathway.
AuthorsRajakylä EK, Lehtimäki JI, Acheva A, Schaible N, Lappalainen P, Krishnan R, Tojkander S
JournalCell Rep
PubMed ID32209483
'Defects in the maintenance of intercellular junctions are associated with loss of epithelial barrier function and consequent pathological conditions, including invasive cancers. Epithelial integrity is dependent on actomyosin bundles at adherens junctions, but the origin of these junctional bundles is incompletely understood. Here we show that peripheral actomyosin bundles can ... More
Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage.
AuthorsNava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, Vihinen H, Jokitalo E, Li X, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Dahl KN, Wickström SA
JournalCell
PubMed ID32302590
'Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a ... More
Visualization of a blue light transmission area in living animals using light-induced nuclear translocation of fluorescent proteins.
AuthorsInutsuka A, Kimizuka N, Takanohashi N, Yakabu H, Onaka T
JournalBiochem Biophys Res Commun
PubMed ID31757418
'Optical manipulations are widely used to analyze neuronal functions in vivo. Blue light is frequently used to activate channelrhodopsins or LOV domains, although the degrees of its absorption and scattering are higher than those of longer wavelength light. High spatial resolution of optical manipulation is easily achieved in vitro, while the light ... More
Quantitative Microscopy Reveals Stepwise Alteration of Chromatin Structure during Herpesvirus Infection.
AuthorsAho V, Mäntylä E, Ekman A, Hakanen S, Mattola S, Chen JH, Weinhardt V, Ruokolainen V, Sodeik B, Larabell C, Vihinen-Ranta M
JournalViruses
PubMed ID31614678
'During lytic herpes simplex virus 1 (HSV-1) infection, the expansion of the viral replication compartments leads to an enrichment of the host chromatin in the peripheral nucleoplasm. We have shown previously that HSV-1 infection induces the formation of channels through the compacted peripheral chromatin. Here, we used three-dimensional confocal and ... More
Meta-Analysis and Experimental Validation Identified FREM2 and SPRY1 as New Glioblastoma Marker Candidates.
AuthorsVidak M, Jovcevska I, Samec N, Zottel A, Liovic M, Rozman D, Dzeroski S, Juvan P, Komel R,
JournalInt J Mol Sci
PubMed ID29734672
'Glioblastoma (GB) is the most aggressive brain malignancy. Although some potential glioblastoma biomarkers have already been identified, there is a lack of cell membrane-bound biomarkers capable of distinguishing brain tissue from glioblastoma and/or glioblastoma stem cells (GSC), which are responsible for the rapid post-operative tumor reoccurrence. In order to find ... More
Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson's Disease.
AuthorsHan X, Zhu J, Zhang X, Song Q, Ding J, Lu M, Sun S, Hu G
JournalFront Neurosci
PubMed ID29967574
Epidemiological studies have shown that both lipid metabolism disorder and mitochondrial dysfunction are correlated with the pathogenesis of neurodegenerative diseases (NDDs), including Parkinson's disease (PD). Emerging evidence suggests that deposition of intracellular lipid droplets (LDs) participates in lipotoxicity and precedes neurodegeneration. Perilipin family members were recognized to facilitate LD movement ... More
Cholesterol and phosphatidylserine are engaged in adenoviral dodecahedron endocytosis.
AuthorsJedynak M, Worch R, Podsiadla-Bialoskórska M, Chroboczek J, Szolajska E
JournalBiochim Biophys Acta Biomembr
PubMed ID30409517
Adenoviral dodecahedron is a virus-like particle composed of twelve penton base proteins, derived from the capsid of human adenovirus type 3. Due to the high cell penetration capacity, it was used as a vector for protein, peptide and drug delivery. Two receptors are known to be involved in the endocytic ... More
Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation.
AuthorsLeBlanc L, Lee BK, Yu AC, Kim M, Kambhampati AV, Dupont SM, Seruggia D, Ryu BU, Orkin SH, Kim J,
JournalElife
PubMed ID30561326
Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking ... More
Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.
AuthorsPoli MC, Ebstein F, Nicholas SK, de Guzman MM, Forbes LR, Chinn IK, Mace EM, Vogel TP, Carisey AF, Benavides F, Coban-Akdemir ZH, Gibbs RA, Jhangiani SN, Muzny DM, Carvalho CMB, Schady DA, Jain M, Rosenfeld JA, Emrick L, Lewis RA, Lee B, Zieba BA, Küry S, Krüger E, Lupski JR, Bostwick BL, Orange JS,
JournalAm J Hum Genet
PubMed ID29805043
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency ... More
Expression of Neuropeptide FF Defines a Population of Excitatory Interneurons in the Superficial Dorsal Horn of the Mouse Spinal Cord that Respond to Noxious and Pruritic Stimuli.
AuthorsGutierrez-Mecinas M, Bell A, Polgár E, Watanabe M, Todd AJ
JournalNeuroscience
PubMed ID31421202
The great majority of neurons in the superficial dorsal horn of the spinal cord are excitatory interneurons, and these are required for the normal perception of pain and itch. We have previously identified 5 largely non-overlapping populations among these cells, based on the expression of four different neuropeptides (cholecystokinin, neurotensin, ... More
Wnt activator FOXB2 drives the neuroendocrine differentiation of prostate cancer.
AuthorsMoparthi L, Pizzolato G, Koch S
JournalProc Natl Acad Sci U S A
PubMed ID31611391
The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple ... More
Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma.
Glioblastoma harbors frequent alterations in receptor tyrosine kinases, phosphatidylinositol-3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) that dysregulate phospholipid signaling driven tumor proliferation and therapeutic resistance. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a 32 kDa intrinsically unstructured protein containing a polybasic (+13) effector domain (ED), which regulates its electrostatic sequestration of phospholipid phosphatidylinositol (4,5)-bisphosphate ... More
Optimized Ki-67 staining in murine cells: a tool to determine cell proliferation.
AuthorsGraefe C, Eichhorn L, Wurst P, Kleiner J, Heine A, Panetas I, Abdulla Z, Hoeft A, Frede S, Kurts C, Endl E, Weisheit CK
JournalMol Biol Rep
PubMed ID31093875
The reliable analysis of the cell cycle status has become increasingly relevant for scientific and clinical work, especially for the determination of tumor cell growth. One established method to characterize the proliferation activity of cells is the analysis of the Ki-67 protein. Ki-67 is expressed in the nucleus during the ... More
3D Electrophysiological Measurements on Cells Embedded within Fiber-Reinforced Matrigel.
AuthorsSchaefer N, Janzen D, Bakirci E, Hrynevich A, Dalton PD, Villmann C
JournalAdv Healthc Mater
PubMed ID30637979
2D electrophysiology is often used to determine the electrical properties of neurons. In the brain however, neurons form extensive 3D networks. Thus, performing electrophysiology in a 3D environment provides a closer situation to the physiological condition and serves as a useful tool for various applications in the field of neuroscience. ... More
Expression of cholecystokinin by neurons in mouse spinal dorsal horn.
AuthorsGutierrez-Mecinas M, Bell AM, Shepherd F, Polgár E, Watanabe M, Furuta T, Todd AJ
JournalJ Comp Neurol
PubMed ID30734936
Excitatory interneurons account for the majority of dorsal horn neurons, and are required for perception of normal and pathological pain. We have identified largely non-overlapping populations in laminae I-III, based on expression of substance P, gastrin-releasing peptide, neurokinin B, and neurotensin. Cholecystokinin (CCK) is expressed by many dorsal horn neurons, ... More
Solid Lipid Nanoparticles Surface Modification Modulates Cell Internalization and Improves Chemotoxic Treatment in an Oral Carcinoma Cell Line.
AuthorsArana L, Bayón-Cordero L, Sarasola LI, Berasategi M, Ruiz S, Alkorta I
JournalNanomaterials (Basel)
PubMed ID30897724
Solid lipid nanoparticles (SLN) present low toxicity, versatility to incorporate both lipophilic and hydrophilic drugs, controlled drug release and they are easy to scale-up. It is well known that the endocytosis pathway by which SLN are taken up and the subsequent subcellular distribution are crucial for the biological effect of ... More
Acute effects of milk polar lipids on intestinal tight junction expression: towards an impact of sphingomyelin through the regulation of IL-8 secretion?
AuthorsMilard M, Penhoat A, Durand A, Buisson C, Loizon E, Meugnier E, Bertrand K, Joffre F, Cheillan D, Garnier L, Viel S, Laugerette F, Michalski MC
JournalJ Nutr Biochem
PubMed ID30685581
Milk polar lipids (MPL) are specifically rich in milk sphingomyelin (MSM) which represents 24% of MPL. Beneficial effects of MPL or MSM have been reported on lipid metabolism, but information on gut physiology is scarce. Here we assessed whether MPL and MSM can impact tight junction expression. Human epithelial intestinal ... More
Endoplasmic reticulum contact sites regulate the dynamics of membraneless organelles.
AuthorsLee JE, Cathey PI, Wu H, Parker R, Voeltz GK
JournalScience
PubMed ID32001628
Tethered interactions between the endoplasmic reticulum (ER) and other membrane-bound organelles allow for efficient transfer of ions and/or macromolecules and provide a platform for organelle fission. Here, we describe an unconventional interface between membraneless ribonucleoprotein granules, such as processing bodies (P-bodies, or PBs) and stress granules, and the ER membrane. ... More