32 results on '"Beibel, Martin"'
Search Results
2. Transcriptional profiling of hepatocytes infected with the replicative form of the malaria parasite Plasmodium cynomolgi
- Author
-
Mitchell, Gabriel, Roma, Guglielmo, Voorberg-van der Wel, Annemarie, Beibel, Martin, Zeeman, Anne-Marie, Schuierer, Sven, Torres, Laura, Flannery, Erika L., Kocken, Clemens H. M., Mikolajczak, Sebastian A., and Diagana, Thierry T.
- Published
- 2022
- Full Text
- View/download PDF
3. mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level
- Author
-
Zeng, Hao, Lu, Bo, Zamponi, Raffaella, Yang, Zinger, Wetzel, Kristie, Loureiro, Joseph, Mohammadi, Sina, Beibel, Martin, Bergling, Sebastian, Reece-Hoyes, John, Russ, Carsten, Roma, Guglielmo, Tchorz, Jan S., Capodieci, Paola, and Cong, Feng
- Published
- 2018
4. Screening of Intestinal Crypt Organoids: A Simple Readout for Complex Biology
- Author
-
Ley, Svenja, Galuba, Olaf, Salathe, Adrian, Melin, Nicolas, Aebi, Alexandra, Pikiolek, Monika, Knehr, Judith, Carbone, Walter, Beibel, Martin, Nigsch, Florian, Roma, Guglielmo, d’Ario, Giovanni, Kirkland, Susan, Bouchez, Laure C., Gubser Keller, Caroline, Bouwmeester, Tewis, Parker, Christian N., and Ruffner, Heinz
- Published
- 2017
- Full Text
- View/download PDF
5. Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients
- Author
-
Crick, Peter J., Griffiths, William J., Zhang, Juan, Beibel, Martin, Abdel-Khalik, Jonas, Kuhle, Jens, Sailer, Andreas W., and Wang, Yuqin
- Published
- 2016
- Full Text
- View/download PDF
6. Comparison of Multivariate Data Analysis Strategies for High-Content Screening
- Author
-
Kümmel, Anne, Selzer, Paul, Beibel, Martin, Gubler, Hanspeter, Parker, Christian N., and Gabriel, Daniela
- Published
- 2011
- Full Text
- View/download PDF
7. Integration of Multiple Readouts into the Z′ Factor for Assay Quality Assessment
- Author
-
Kümmel, Anne, Gubler, Hanspeter, Gehin, Patricia, Beibel, Martin, Gabriel, Daniela, and Parker, Christian N.
- Published
- 2010
- Full Text
- View/download PDF
8. An iron-dependent metabolic vulnerability underlies VPS34-dependence in RKO cancer cells.
- Author
-
Kobylarz, Marek J., Goodwin, Jonathan M., Kang, Zhao B., Annand, John W., Hevi, Sarah, O'Mahony, Ellen, McAllister, Gregory, Reece-Hoyes, John, Wang, Qiong, Alford, John, Russ, Carsten, Lindeman, Alicia, Beibel, Martin, Roma, Guglielmo, Carbone, Walter, Knehr, Judith, Loureiro, Joseph, Antczak, Christophe, Wiederschain, Dmitri, and Murphy, Leon O.
- Subjects
CANCER cells ,CELL respiration ,LIPOPROTEIN receptors ,TRANSFERRIN receptors ,TRANSFERRIN ,CELL growth - Abstract
VPS34 is a key regulator of endomembrane dynamics and cargo trafficking, and is essential in cultured cell lines and in mice. To better characterize the role of VPS34 in cell growth, we performed unbiased cell line profiling studies with the selective VPS34 inhibitor PIK-III and identified RKO as a VPS34-dependent cellular model. Pooled CRISPR screen in the presence of PIK-III revealed endolysosomal genes as genetic suppressors. Dissecting VPS34-dependent alterations with transcriptional profiling, we found the induction of hypoxia response and cholesterol biosynthesis as key signatures. Mechanistically, acute VPS34 inhibition enhanced lysosomal degradation of transferrin and low-density lipoprotein receptors leading to impaired iron and cholesterol uptake. Excess soluble iron, but not cholesterol, was sufficient to partially rescue the effects of VPS34 inhibition on mitochondrial respiration and cell growth, indicating that iron limitation is the primary driver of VPS34-dependency in RKO cells. Loss of RAB7A, an endolysosomal marker and top suppressor in our genetic screen, blocked transferrin receptor degradation, restored iron homeostasis and reversed the growth defect as well as metabolic alterations due to VPS34 inhibition. Altogether, our findings suggest that impaired iron mobilization via the VPS34-RAB7A axis drive VPS34-dependence in certain cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
9. UTS2B Defines a Novel Enteroendocrine Cell Population and Regulates GLP-1 Secretion Through SSTR5 in Male Mice.
- Author
-
Tang, Cong, Ksiazek, Iwona, Siccardi, Noemie, Gapp, Berangere, Weber, Delphine, Wirsching, Johann, Beck, Valerie, Reist, Matthias, Gaudet, Laurent, Stuber, Nathalie, Surber, Sabrina Silvia, Mao, Xiaohong, Nicholson, Thomas B, Carbone, Walter, Beibel, Martin, Roma, Guglielmo, Keller, Caroline Gubser, and Bassilana, Frederic
- Published
- 2019
- Full Text
- View/download PDF
10. mTORC1 signaling suppresses Wnt/β-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level.
- Author
-
Hao Zeng, Bo Lu, Zamponi, Raffaella, Zinger Yang, Wetzel, Kristie, Loureiro, Joseph, Mohammadi, Sina, Beibel, Martin, Bergling, Sebastian, Reece-Hoyes, John, Russ, Carsten, Roma, Guglielmo, Tchorz, Jan S., Capodieci, Paola, and Feng Cong
- Subjects
CATENINS ,CELL proliferation ,STEM cells ,RAPAMYCIN ,MTOR protein - Abstract
Wnt/β-catenin signaling plays pivotal roles in cell proliferation and tissue homeostasis by maintaining somatic stem cell functions. The mammalian target of rapamycin (mTOR) signaling functions as an integrative rheostat that orchestrates various cellular and metabolic activities that shape tissue homeostasis. Whether these two fundamental signaling pathways couple to exert physiological functions still remains mysterious. Using a genome-wide CRISPRCas9 screening, we discover that mTOR complex 1 (mTORC1) signaling suppresses canonical Wnt/β-catenin signaling. Deficiency in tuberous sclerosis complex 1/2 (TSC1/2), core negative regulators of mTORC1 activity, represses Wnt/β-catenin target gene expression, which can be rescued by RAD001. Mechanistically, mTORC1 signaling regulates the cell surface level of Wnt receptor Frizzled (FZD) in a Dishevelled (DVL)-dependent manner by influencing the association of DVL and clathrin AP-2 adaptor. Sustained mTORC1 activation impairs Wnt/β-catenin signaling and causes loss of stemness in intestinal organoids ex vivo and primitive intestinal progenitors in vivo. Wnt/β-catenin-dependent liver metabolic zonation gene expression program is also down-regulated by mTORC1 activation. Our study provides a paradigm that mTORC1 signaling cell autonomously regulates Wnt/β-catenin pathway to influence stem cell maintenance. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
11. TORC1 inhibition enhances immune function and reduces infections in the elderly.
- Author
-
Mannick, Joan B., Morris, Melody, Hockey, Hans-Ulrich P., Roma, Guglielmo, Beibel, Martin, Kulmatycki, Kenneth, Watkins, Mollie, Shavlakadze, Tea, Zhou, Weihua, Quinn, Dean, Glass, David J., and Klickstein, Lloyd B.
- Subjects
RAPAMYCIN ,IMMUNOSUPPRESSIVE agents ,HEALTH of older people ,IMMUNE response ,QUALITY of life - Abstract
Treating elderly subjects with two low-dose mTOR inhibitors that selectively block TORC1 led to a decrease in infection rates. Dialing down TORC1 dials up immunity: Aging may be regulated by a discrete set of intracellular proteins including the mechanistic target of rapamycin (mTOR) kinase. mTOR functions within two multiprotein complexes called TORC1 and TORC2. Inhibition of TORC1 has extended life span in every species studied to date and ameliorated multiple aging-related pathologies including declining immune function. Mannick et al. now show that low-dose TORC1 inhibitor therapy in elderly humans decreased the incidence of all infections, improved influenza vaccination responses, and up-regulated antiviral immunity. Thus, targeting the TORC1 pathway that regulates aging may have clinical benefits for elderly humans including improvement in immune function and decreased infection rates. Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
12. An Activating Janus Kinase-3 Mutation is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome.
- Author
-
Sic, Heiko, Speletas, Matthaios, Cornacchione, Vanessa, Seidl, Maximillian, Beibel, Martin, Linghu, Bolan, Fan Yang, Sevdali, Eirini, Germenis, Anastasios E., Oakeley, Edward J., Vangrevelinghe, Eric, Sailer, Andreas W., Traggiai, Elisabetta, Gram, Hermann, and Eibel, Hermann
- Subjects
CYTOTOXIC T lymphocyte-associated molecule-4 ,JANUS kinases ,IMMUNOLOGIC diseases - Abstract
Heterozygous mutations in the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated with lymphadenopathy, autoimmunity, immune dysregulation, and hypogammaglob- ulinemia in about 70% of the carriers. So far, the incomplete penetrance of CTLA-4 haploinsufficiency has been attributed to unknown genetic modifiers, epigenetic changes, or environmental effects. We sought to identify potential genetic modifiers in a family with differential clinical penetrance of CTLA-4 haploinsufficiency. Here, we report on a rare heterozygous gain-of-function mutation in Janus kinase-3 (JAK3) (p.R840C), which is associated with the clinical manifestation of CTLA-4 haploinsufficiency in a patient carrying a novel loss-of-function mutation in CTLA-4 (p.Y139C). While the asymptomatic parents carry either the CTLA-4 mutation or the JAK3 variant, their son has inherited both heterozygous mutations and suffers from hypogammaglobulinemia combined with autoimmunity and lymphoid hyperplasia. Although the patient's lymph node and spleen contained many hyperplastic germinal centers with follicular helper T (TFH) cells and immunoglobulin (Ig) G-positive B cells, plasma cell, and memory B cell development was impaired. CXCR5+PD-1+TIGIT+ TFH cells contributed to a large part of circulating T cells, but they produced only very low amounts of interleukin (IL)-4, IL-10, and IL-21 required for the development of memory B cells and plasma cells. We, therefore, suggest that the combination of the loss-of-function mutation in CTLA-4 with the gain-of-function mutation in JAK3 directs the differentiation of CD4 T cells into dysfunctional TFH cells supporting the development of lymphadenopathy, hypogammaglobulinemia, and immu- nodeficiency. Thus, the combination of rare genetic heterozygous variants that remain clinically unnoticed individually may lead to T cell hyperactivity, impaired memory B cell, and plasma cell development resulting finally in combined immunodeficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
13. Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients.
- Author
-
Crick, Peter, Griffiths, William, Zhang, Juan, Beibel, Martin, Abdel-Khalik, Jonas, Kuhle, Jens, Sailer, Andreas, and Wang, Yuqin
- Abstract
Multiple sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system (CNS). We have measured the levels of over 20 non-esterified sterols in plasma and cerebrospinal fluid (CSF) from patients suffering from MS, inflammatory CNS disease, neurodegenerative disease and control patients. Analysis was performed following enzyme-assisted derivatisation by liquid chromatography-mass spectrometry (LC- MS) exploiting multistage fragmentation ( MS ). We found increased concentrations of bile acid precursors in CSF from each of the disease states and that patients with inflammatory CNS disease classified as suspected autoimmune disease or of unknown aetiology also showed elevated concentrations of 25-hydroxycholestertol (25-HC, P < 0.05) in CSF. Cholesterol concentrations in CSF were not changed except for patients diagnosed with amyotrophic lateral sclerosis ( P < 0.01) or pathogen-based infections of the CNS ( P < 0.05) where they were elevated. In plasma, we found that 25-HC ( P < 0.01), (25R)26-hydroxycholesterol ((25R)26-HC, P < 0.05) and 7α-hydroxy-3-oxocholest-4-enoic acid (7αH,3O-CA, P < 0.05) were reduced in relapsing-remitting MS (RRMS) patients compared to controls. The pattern of reduced plasma levels of 25-HC, (25R)26-HC and 7αH,3O-CA was unique to RRMS. In summary, in plasma, we find that the concentration of 25-HC in RRMS patients is significantly lower than in controls. This is consistent with the hypothesis that a lower propensity of macrophages to synthesise 25-HC will result in reduced negative feedback by 25-HC on IL-1 family cytokine production and exacerbated MS. In CSF, we find that the dominating metabolites reflect the acidic pathway of bile acid biosynthesis and the elevated levels of these in CNS disease is likely to reflect cholesterol release as a result of demyelination or neuronal death. 25-HC is elevated in patients with inflammatory CNS disease probably as a consequence of up-regulation of the type 1 interferon-stimulated gene cholesterol 25-hydroxylase in macrophages. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
14. Identification of oncogenic driver mutations by genome-wide CRISPR-Cas9 dropout screening.
- Author
-
Kiessling, Michael K., Schuierer, Sven, Stertz, Silke, Beibel, Martin, Bergling, Sebastian, Knehr, Judith, Carbone, Walter, de Vallière, Cheryl, Tchinda, Joelle, Bouwmeester, Tewis, Seuwen, Klaus, Rogler, Gerhard, and Roma, Guglielmo
- Subjects
CRISPRS ,NEUROBLASTOMA ,CELL lines ,LUNG cancer ,CELL survival - Abstract
Background: Genome-wide CRISPR-Cas9 dropout screens can identify genes whose knockout affects cell viability. Recent CRISPR screens detected thousands of essential genes required for cellular survival and key cellular processes; however discovering novel lineage-specific genetic dependencies from the many hits still remains a challenge. Results: To assess whether CRISPR-Cas9 dropout screens can help identify cancer dependencies, we screened two human cancer cell lines carrying known and distinct oncogenic mutations using a genome-wide sgRNA library. We found that the gRNA targeting the driver mutation EGFR was one of the highest-ranking candidates in the EGFRmutant HCC-827 lung adenocarcinoma cell line. Likewise, sgRNAs for NRAS and MAP2K1 (MEK1), a downstream kinase of mutant NRAS, were identified among the top hits in the NRAS-mutant neuroblastoma cell line CHP-212. Depletion of these genes targeted by the sgRNAs strongly correlated with the sensitivity to specific kinase inhibitors of the EGFR or RAS pathway in cell viability assays. In addition, we describe other dependencies such as TBK1 in HCC-827 cells and TRIB2 in CHP-212 cells which merit further investigation. Conclusions: We show that genome-wide CRISPR dropout screens are suitable for the identification of oncogenic drivers and other essential genes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
15. Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62.
- Author
-
DeJesus, Rowena, Moretti, Francesca, McAllister, Gregory, Zuncai Wang, Bergman, Phil, Shanming Liu, Frias, Elizabeth, Alford, John, Reece-Hoyes, John S., Lindeman, Alicia, Kelliher, Jennifer, Russ, Carsten, Knehr, Judith, Carbone, Walter, Beibel, Martin, Roma, Guglielmo, Ng, Aylwin, Tallarico, John A., Porter, Jeffery A., and Xavier, Ramnik J.
- Published
- 2016
- Full Text
- View/download PDF
16. MiR-210 promotes sensory hair cell formation in the organ of corti.
- Author
-
Riccardi, Sabrina, Bergling, Sebastian, Sigoillot, Frederic, Beibel, Martin, Werner, Annick, Leighton-Davies, Juliet, Knehr, Judith, Bouwmeester, Tewis, Parker, Christian N., Roma, Guglielmo, and Kinzel, Bernd
- Subjects
MICRORNA ,HAIR cells ,DEAFNESS ,INNER ear ,EPITHELIAL cells - Abstract
Background: Hearing loss is the most common sensory defect afflicting several hundred million people worldwide. In most cases, regardless of the original cause, hearing loss is related to the degeneration and death of hair cells and their associated spiral ganglion neurons. Despite this knowledge, relatively few studies have reported regeneration of the auditory system. Significant gaps remain in our understanding of the molecular mechanisms underpinning auditory function, including the factors required for sensory cell regeneration. Recently, the identification of transcriptional activators and repressors of hair cell fate has been augmented by the discovery of microRNAs (miRNAs) associated with hearing loss. As miRNAs are central players of differentiation and cell fate, identification of miRNAs and their gene targets may reveal new pathways for hair cell regeneration, thereby providing new avenues for the treatment of hearing loss. Results: In order to identify new genetic elements enabling regeneration of inner ear sensory hair cells, next-generation miRNA sequencing (miRSeq) was used to identify the most prominent miRNAs expressed in the mouse embryonic inner ear cell line UB/OC-1 during differentiation towards a hair cell like phenotype. Based on these miRSeq results eight most differentially expressed miRNAs were selected for further characterization. In UB/OC-1, miR-210 silencing in vitro resulted in hair cell marker expression, whereas ectopic expression of miR-210 resulted in new hair cell formation in cochlear explants. Using a lineage tracing mouse model, transdifferentiation of supporting epithelial cells was identified as the likely mechanism for this new hair cell formation. Potential miR-210 targets were predicted in silico and validated experimentally using a miR-trap approach. Conclusion: MiRSeq followed by ex vivo validation revealed miR-210 as a novel factor driving transdifferentiation of supporting epithelial cells to sensory hair cells suggesting that miR-210 might be a potential new factor for hearing loss therapy. In addition, identification of inner ear pathways regulated by miR-210 identified potential new drug targets for the treatment of hearing loss. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
17. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
- Author
-
Palacino, James, Swalley, Susanne E, Song, Cheng, Cheung, Atwood K, Shu, Lei, Zhang, Xiaolu, Van Hoosear, Mailin, Shin, Youngah, Chin, Donovan N, Keller, Caroline Gubser, Beibel, Martin, Renaud, Nicole A, Smith, Thomas M, Salcius, Michael, Shi, Xiaoying, Hild, Marc, Servais, Rebecca, Jain, Monish, Deng, Lin, and Bullock, Caroline
- Subjects
RNA splicing ,MOTOR neuron diseases ,SPINAL muscular atrophy ,CHEMICAL biology ,GENETICS - Abstract
Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5′ splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
18. Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon.
- Author
-
Junne, Tina, Wong, Joanne, Studer, Christian, Aust, Thomas, Bauer, Benedikt W., Beibel, Martin, Bhullar, Bhupinder, Bruccoleri, Robert, Eichenberger, Jürg, Estoppey, David, Hartmann, Nicole, Knapp, Britta, Krastel, Philipp, Melin, Nicolas, Oakeley, Edward J., Oberer, Lukas, Riedl, Ralph, Roma, Guglielmo, Schuierer, Sven, and Petersen, Frank
- Subjects
FUNGAL proteins ,CHROMOSOMAL translocation ,CHEMOGENOMICS ,MAMMAL cytology ,FUNGAL membranes - Abstract
A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon complex, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (including HUN-7293 and cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p (yeast) or Sec61α1 (mammals) that conferred resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and post-translationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 translocon homolog. We suggest 'decatransin' as the name for this new decadepsipeptide translocation inhibitor. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
19. Transmission and spreading of tauopathy in transgenic mouse brain.
- Author
-
Clavaguera, Florence, Bolmont, Tristan, Crowther, R. Anthony, Abramowski, Dorothee, Frank, Stephan, Probst, Alphonse, Fraser, Graham, Stalder, Anna K., Beibel, Martin, Staufenbiel, Matthias, Jucker, Mathias, Goedert, Michel, and Tolnay, Markus
- Subjects
NEURODEGENERATION ,ALZHEIMER'S disease ,NEOCORTEX ,NEURONS ,HIPPOCAMPUS (Brain) ,LABORATORY mice ,TRANSGENIC mice - Abstract
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
20. Validation of Volume-Pressure Recording Tail-Cuff Blood Pressure Measurements.
- Author
-
Minjie Feng, Whitesall, Steven, Yunyu Zhang, Beibel, Martin, D’ Alecy, Louis, and DiPetrillo, Keith
- Subjects
BLOOD pressure measurement ,SPHYGMOMANOMETERS ,PHYSICAL diagnosis ,MUTAGENESIS ,LABORATORY rats ,MEDICAL research - Abstract
Background The American Heart Association has recommended tail-cuff blood pressure measurement for high-throughput experimental designs, including mutagenesis screens and genetic crosses. However, some tail-cuff methods show good agreement with radiotelemetry and others do not, indicating that each tail-cuff method requires independent validation. Methods We validated the volume-pressure recording (VPR) tail-cuff method by comparison to simultaneous radiotelemetry measurements. Results Bland-Altman analysis of 560 cycles from 26 independent measurement sessions showed good agreement between VPR and radiotelemetry measurements, with tail-cuff measurements being 0.25 mm Hg lower than telemetry measurements on average. However, the VPR method was less accurate, compared to radiotelemetry, at extreme high and low (i.e., <110 or >180 mm Hg) systolic blood pressures (SBPs). Conclusions We conclude that the VPR tail-cuff method provides accurate blood pressure measurements over the physiological range of blood pressure in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
21. Major shifts in genomic activity accompany progression through different stages of the hair cycle
- Author
-
Schlake, Thomas, Beibel, Martin, Weger, Nicole, and Boehm, Thomas
- Subjects
- *
HAIR follicles , *CELL proliferation , *CELL differentiation , *CELL migration , *EPITHELIUM , *GENOMICS - Abstract
Hair follicles display a unique pattern of cyclic growth and regression involving cell proliferation, differentiation and migration. The molecular details of these processes are largely unexplored. Global expression analyses on the basis of about 20,000 genes for each morphologically distinguishable stage of the hair cycle revealed unexpected complexities of and major temporal shifts in transcriptional programs involving about 13% of all genes. In particular, hundreds of genes characterise the pattern of genomic activity during regression and resting phases; selected genes can be used to monitor hair growth in mice. We demonstrate that temporal expression patterns predict gene expression domains within the hair follicle. Expression of insulin-like growth factor binding proteins and anti-angiogenic factors is associated with the regression phase of the hair cycle. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
22. Strong parenchymal amyloid reduction following CAD106 immunotherapy is associated with an increase in vascular Aβ but not microhemorrhages
- Author
-
Staufenbiel, Matthias, Beibel, Martin, Danner, Simone, Reichwald, Julia, and Wiederhold, Karl-Heinz
- Published
- 2009
- Full Text
- View/download PDF
23. Corrigendum: SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
- Author
-
Palacino, James, Swalley, Susanne E, Song, Cheng, Cheung, Atwood K, Shu, Lei, Zhang, Xiaolu, Van Hoosear, Mailin, Shin, Youngah, Chin, Donovan N, Keller, Caroline Gubser, Beibel, Martin, Renaud, Nicole A, Smith, Thomas M, Salcius, Michael, Shi, Xiaoying, Hild, Marc, Servais, Rebecca, Jain, Monish, Deng, Lin, and Bullock, Caroline
- Subjects
RNA splicing ,MESSENGER RNA - Abstract
A correction to the article "SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice" that was published in the previous issue is presented.
- Published
- 2015
- Full Text
- View/download PDF
24. Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived PeptideTLQP-21 in Rodent Cells.
- Author
-
Hannedouche, Sebastien, Beck, Valerie, Leighton-Davies, Juliet, Beibel, Martin, Roma, Guglielmo, Oakeley, Edward J., Lannoy, Vincent, Bernard, Jerome, Hamon, Jacques, Barbieri, Samuel, Preuss, Inga, Lasbennes, Marie-Christine, Sailer, Andreas W., Suply, Thomas, Seuwen, Klaus, Parker, Christian N., and Bassilana, Frederic
- Subjects
- *
PEPTIDE receptors , *ENERGY metabolism , *CELL differentiation , *ANIMAL models in research , *METABOLIC regulation , *G protein coupled receptors - Abstract
TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
25. Genome-wide screening in human kidney organoids identifies developmental and disease-related aspects of nephrogenesis.
- Author
-
Ungricht R, Guibbal L, Lasbennes MC, Orsini V, Beibel M, Waldt A, Cuttat R, Carbone W, Basler A, Roma G, Nigsch F, Tchorz JS, Hoepfner D, and Hoppe PS
- Subjects
- Gene Editing, Humans, Kidney, Organogenesis, Induced Pluripotent Stem Cells, Organoids
- Abstract
Human organoids allow the study of proliferation, lineage specification, and 3D tissue development. Here we present a genome-wide CRISPR screen in induced pluripotent stem cell (iPSC)-derived kidney organoids. The combination of inducible genome editing, longitudinal sampling, and endpoint sorting of tubular and stromal cells generated a complex, high-quality dataset uncovering a broad spectrum of insightful biology from early development to "adult" epithelial morphogenesis. Our functional dataset allows improving mesoderm induction by ROCK inhibition, contains monogenetic and complex trait kidney disease genes, confirms two additional congenital anomalies of the kidney and urinary tract (CAKUT) genes (CCDC170 and MYH7B), and provides a large candidate list of ciliopathy-related genes. Finally, identification of a cis-inhibitory effect of Jagged1 controlling epithelial proliferation shows how mosaic knockouts in pooled CRISPR screening can reveal ways of communication between heterogeneous cell populations in complex tissues. These data serve as a rich resource for the kidney research community and as a benchmark for future iPSC-derived organoid CRISPR screens., Competing Interests: Declaration of interests All authors are or were employees of Novartis Pharma AG and may own stock in the company., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
26. Immune cell landscaping reveals a protective role for regulatory T cells during kidney injury and fibrosis.
- Author
-
do Valle Duraes F, Lafont A, Beibel M, Martin K, Darribat K, Cuttat R, Waldt A, Naumann U, Wieczorek G, Gaulis S, Pfister S, Mertz KD, Li J, Roma G, and Warncke M
- Subjects
- Acute Kidney Injury etiology, Acute Kidney Injury genetics, Acute Kidney Injury prevention & control, Animals, Biopsy, Disease Models, Animal, Fibrosis genetics, Fibrosis immunology, Fibrosis prevention & control, Gene Expression Profiling, Interleukin-2 immunology, Interleukin-33 immunology, Kidney pathology, Kidney physiopathology, Mice, Regeneration, Reperfusion Injury complications, Acute Kidney Injury immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Acute kidney injury (AKI) and chronic kidney diseases are associated with high mortality and morbidity. Although the underlying mechanisms determining the transition from acute to chronic injury are not completely understood, immune-mediated processes are critical in renal injury. We have performed a comparison of 2 mouse models leading to either kidney regeneration or fibrosis. Using global gene expression profiling we could identify immune-related pathways accounting for the majority of the observed transcriptional changes during fibrosis. Unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed major changes in tissue-resident macrophages and T cells. Following injury, there was a marked increase in tissue-resident IL-33R+ and IL-2Ra+ regulatory T cells (Tregs). Expansion of this population before injury protected the kidney from injury and fibrosis. Transcriptional profiling of Tregs showed a differential upregulation of regenerative and proangiogenic pathways during regeneration, whereas in the fibrotic environment they expressed markers of hyperactivation and fibrosis. Our data point to a hitherto underappreciated plasticity in Treg function within the same tissue, dictated by environmental cues. Overall, we provide a detailed cellular and molecular characterization of the immunological changes during kidney injury, regeneration, and fibrosis.
- Published
- 2020
- Full Text
- View/download PDF
27. Discovery of a ZIP7 inhibitor from a Notch pathway screen.
- Author
-
Nolin E, Gans S, Llamas L, Bandyopadhyay S, Brittain SM, Bernasconi-Elias P, Carter KP, Loureiro JJ, Thomas JR, Schirle M, Yang Y, Guo N, Roma G, Schuierer S, Beibel M, Lindeman A, Sigoillot F, Chen A, Xie KX, Ho S, Reece-Hoyes J, Weihofen WA, Tyskiewicz K, Hoepfner D, McDonald RI, Guthrie N, Dogra A, Guo H, Shao J, Ding J, Canham SM, Boynton G, George EL, Kang ZB, Antczak C, Porter JA, Wallace O, Tallarico JA, Palmer AE, Jenkins JL, Jain RK, Bushell SM, and Fryer CJ
- Subjects
- Animals, Apoptosis, Carrier Proteins metabolism, Cation Transport Proteins metabolism, Cation Transport Proteins physiology, Cell Line, Cell Transformation, Neoplastic, Endoplasmic Reticulum physiology, Humans, Mutation, Protein Transport, Receptor, Notch1 physiology, Signal Transduction, Zinc metabolism, Cation Transport Proteins genetics, Endoplasmic Reticulum Stress physiology, Receptor, Notch1 genetics
- Abstract
The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.
- Published
- 2019
- Full Text
- View/download PDF
28. Transcriptomic analysis reveals reduced transcriptional activity in the malaria parasite Plasmodium cynomolgi during progression into dormancy.
- Author
-
Bertschi NL, Voorberg-van der Wel A, Zeeman AM, Schuierer S, Nigsch F, Carbone W, Knehr J, Gupta DK, Hofman SO, van der Werff N, Nieuwenhuis I, Klooster E, Faber BW, Flannery EL, Mikolajczak SA, Chuenchob V, Shrestha B, Beibel M, Bouwmeester T, Kangwanrangsan N, Sattabongkot J, Diagana TT, Kocken CH, and Roma G
- Subjects
- Animals, Primates, Time Factors, Gene Expression Profiling, Liver parasitology, Plasmodium cynomolgi genetics, Plasmodium cynomolgi growth & development
- Abstract
Relapses of Plasmodium dormant liver hypnozoites compromise malaria eradication efforts. New radical cure drugs are urgently needed, yet the vast gap in knowledge of hypnozoite biology impedes drug discovery. We previously unraveled the transcriptome of 6 to 7 day-old P. cynomolgi liver stages, highlighting pathways associated with hypnozoite dormancy (Voorberg-van der Wel et al., 2017). We now extend these findings by transcriptome profiling of 9 to 10 day-old liver stage parasites, thus revealing for the first time the maturation of the dormant stage over time. Although progression of dormancy leads to a 10-fold decrease in transcription and expression of only 840 genes, including genes associated with housekeeping functions, we show that pathways involved in quiescence, energy metabolism and maintenance of genome integrity remain the prevalent pathways active in mature hypnozoites., Competing Interests: NB, SS, FN, WC, JK, DG, EF, SM, VC, BS, MB, TB, TD, GR Employed by and/or shareholder of Novartis Pharma AG. AV, AZ, SH, Nv, IN, EK, BF, NK, JS, CK No competing interests declared, (© 2018, Bertschi et al.)
- Published
- 2018
- Full Text
- View/download PDF
29. HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis.
- Author
-
Lang M, Berry D, Passecker K, Mesteri I, Bhuju S, Ebner F, Sedlyarov V, Evstatiev R, Dammann K, Loy A, Kuzyk O, Kovarik P, Khare V, Beibel M, Roma G, Meisner-Kober N, and Gasche C
- Subjects
- Adenomatous Polyposis Coli microbiology, Adenomatous Polyposis Coli pathology, Animals, Apoptosis drug effects, Carcinogenesis genetics, Cell Proliferation drug effects, Chemokine CCL11 genetics, Colorectal Neoplasms microbiology, Colorectal Neoplasms pathology, ELAV-Like Protein 1 antagonists & inhibitors, Feces microbiology, Furans administration & dosage, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome genetics, HCT116 Cells, Humans, Inflammatory Bowel Diseases microbiology, Inflammatory Bowel Diseases pathology, Interleukin-18 genetics, Mice, Naphthols administration & dosage, RAW 264.7 Cells, Adenomatous Polyposis Coli genetics, Colorectal Neoplasms genetics, ELAV-Like Protein 1 genetics, Inflammatory Bowel Diseases genetics
- Abstract
HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3' untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APC
Min mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of Prevotella, Akkermansia , and Lachnospiraceae Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. Cancer Res; 77(9); 2424-38. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
- Full Text
- View/download PDF
30. CGG Repeat-Induced FMR1 Silencing Depends on the Expansion Size in Human iPSCs and Neurons Carrying Unmethylated Full Mutations.
- Author
-
Brykczynska U, Pecho-Vrieseling E, Thiemeyer A, Klein J, Fruh I, Doll T, Manneville C, Fuchs S, Iazeolla M, Beibel M, Roma G, Naumann U, Kelley N, Oakeley EJ, Mueller M, Gomez-Mancilla B, Bühler M, Tabolacci E, Chiurazzi P, Neri G, Bouwmeester T, Di Giorgio FP, and Fodor BD
- Subjects
- Cell Differentiation genetics, Clone Cells, Epigenesis, Genetic, Female, Fragile X Syndrome genetics, Genetic Loci, Humans, Induced Pluripotent Stem Cells cytology, Male, Pedigree, DNA Methylation genetics, Fragile X Mental Retardation Protein genetics, Gene Silencing, Induced Pluripotent Stem Cells metabolism, Mutation genetics, Neurons metabolism, Trinucleotide Repeat Expansion genetics
- Abstract
In fragile X syndrome (FXS), CGG repeat expansion greater than 200 triplets is believed to trigger FMR1 gene silencing and disease etiology. However, FXS siblings have been identified with more than 200 CGGs, termed unmethylated full mutation (UFM) carriers, without gene silencing and disease symptoms. Here, we show that hypomethylation of the FMR1 promoter is maintained in induced pluripotent stem cells (iPSCs) derived from two UFM individuals. However, a subset of iPSC clones with large CGG expansions carries silenced FMR1. Furthermore, we demonstrate de novo silencing upon expansion of the CGG repeat size. FMR1 does not undergo silencing during neuronal differentiation of UFM iPSCs, and expression of large unmethylated CGG repeats has phenotypic consequences resulting in neurodegenerative features. Our data suggest that UFM individuals do not lack the cell-intrinsic ability to silence FMR1 and that inter-individual variability in the CGG repeat size required for silencing exists in the FXS population., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
31. Corrigendum: SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
- Author
-
Palacino J, Swalley SE, Song C, Cheung AK, Shu L, Zhang X, Van Hoosear M, Shin Y, Chin DN, Keller CG, Beibel M, Renaud NA, Smith TM, Salcius M, Shi X, Hild M, Servais R, Jain M, Deng L, Bullock C, McLellan M, Schuierer S, Murphy L, Blommers MJ, Blaustein C, Berenshteyn F, Lacoste A, Thomas JR, Roma G, Michaud GA, Tseng BS, Porter JA, Myer VE, Tallarico JA, Hamann LG, Curtis D, Fishman MC, Dietrich WF, Dales NA, and Sivasankaran R
- Published
- 2016
- Full Text
- View/download PDF
32. Validation of volume-pressure recording tail-cuff blood pressure measurements.
- Author
-
Feng M, Whitesall S, Zhang Y, Beibel M, D'Alecy L, and DiPetrillo K
- Subjects
- Animals, Blood Pressure Monitors, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Telemetry instrumentation, Telemetry methods, Blood Pressure, Blood Pressure Determination instrumentation, Blood Pressure Determination methods, Tail blood supply
- Abstract
Background: The American Heart Association has recommended tail-cuff blood pressure measurement for high-throughput experimental designs, including mutagenesis screens and genetic crosses. However, some tail-cuff methods show good agreement with radiotelemetry and others do not, indicating that each tail-cuff method requires independent validation., Methods: We validated the volume-pressure recording (VPR) tail-cuff method by comparison to simultaneous radiotelemetry measurements., Results: Bland-Altman analysis of 560 cycles from 26 independent measurement sessions showed good agreement between VPR and radiotelemetry measurements, with tail-cuff measurements being 0.25 mm Hg lower than telemetry measurements on average. However, the VPR method was less accurate, compared to radiotelemetry, at extreme high and low (i.e., <110 or >180 mm Hg) systolic blood pressures (SBPs)., Conclusions: We conclude that the VPR tail-cuff method provides accurate blood pressure measurements over the physiological range of blood pressure in mice.
- Published
- 2008
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.