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Cell Biology
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017   Developmental Biology
Yang Z, Sun J, Hu Y, Wang F, Wang X,   . . . . . .   , Li H, Chang Z, Liu LP, Liu Q, Ni JQ
Histone H1 defect in escort cells triggers germline tumor in Drosophila ovary
Feb 24, 2017
Developmental Biology
Drosophila ovary is recognized as one of the best model systems to study stem cell biology in vivo. We had previously identified an autonomous role of the histone H1 in germline stem cell (GSC) maintenance. Here, we found that histone H1 depletion in escort cells (ECs) resulted in an increase of spectrosome-containing cells (SCCs), an ovary tumor-like phenotype. Further analysis showed that the Dpp pathway is excessively activated in these SCC cells, while the expression of bam is attenuated. In the H1-depleted ECs, both transposon activity and DNA damage had increased dramatically, followed by EC apoptosis, which is consistent with the role of H1 in other somatic cells. Surprisingly, H1-depleted ECs acquired cap cell characteristics including dpp expression, and the resulting abnormal Dpp level inhibits SCC further differentiation. Most interestingly, double knockdown of H1 and dpp in ECs can reduce the number of SCCs to the normal level, indicating that the additional Dpp secreted by ECs contributes to the germline tumor. Taken together, our findings indicate that histone H1 is an important epigenetic factor in controlling EC characteristics and a key suppressor of germline tumor.Copyright © 2017. Published by Elsevier Inc.
Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease
Feb 24, 2017   Current Hypertension Reports
Reyes S, Varagic J, Ahmad S, VonCannon J, Kon ND, Wang H, Groban L, Cheng CP, Dell'Italia LJ, Ferrario CM
Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease
Feb 24, 2017
Current Hypertension Reports
PURPOSE OF THE REVIEW: Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF). RECENT FINDINGS: Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF. Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.
Moving and positioning the endolysosomal system
Feb 23, 2017   Current Opinion In Cell Biology
Bonifacino JS, Neefjes J
Moving and positioning the endolysosomal system
Feb 23, 2017
Current Opinion In Cell Biology
The endolysosomal system is extremely dynamic, yet highly organized. The spatio-temporal distribution of endolysosomal organelles depends on transport driven by microtubule motors such as kinesins and dynein, and by actin-based myosin motors. It has recently become appreciated that interactions with motors are controlled by contacts with other organelles, particularly the endoplasmic reticulum (ER). The ER also controls the concentration of endolysosomal organelles in the perinuclear area, as well as their fission and fusion, through a complex system of tethering proteins. Dynamic interactions go both ways, as contacts with endosomes can influence the movement of the ER and peroxisomes. The dynamics of endolysosomal organelles should thus no longer be studied in isolation, but in the context of the whole endomembrane system.Published by Elsevier Ltd.
Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons
Feb 23, 2017   Neuron
Cao M, Wu Y, Ashrafi G, McCartney AJ, Wheeler H, Bushong EA, Boassa D, Ellisman MH, Ryan TA, De Camilli P
Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons
Feb 23, 2017
Neuron
Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)PCopyright © 2017 Elsevier Inc. All rights reserved.
Rapid evolution of distinct Helicobacter pylori subpopulations in the Americas
Feb 23, 2017   PLoS Genetics
Thorell K, Yahara K, Berthenet E, Lawson DJ, Mikhail J, Kato I, Mendez A, Rizzato C, Bravo MM, Suzuki R, Yamaoka Y, Torres J, Sheppard SK, Falush D
Rapid evolution of distinct Helicobacter pylori subpopulations in the Americas
Feb 23, 2017
PLoS Genetics
For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind) bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.
Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper
Feb 24, 2017   Clinical Neurophysiology : Official Journal Of The International Federation Of Clinical Neurophysiology
Thut G, Bergmann TO, Fröhlich F, Soekadar SR, Brittain JS, Valero-Cabré A, Sack A, Miniussi C, Antal A, Siebner HR, Ziemann U, Herrmann CS
Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: A position paper
Feb 24, 2017
Clinical Neurophysiology : Official Journal Of The International Federation Of Clinical Neurophysiology
Non-invasive transcranial brain stimulation (NTBS) techniques have a wide range of applications but also suffer from a number of limitations mainly related to poor specificity of intervention and variable effect size. These limitations motivated recent efforts to focus on the temporal dimension of NTBS with respect to the ongoing brain activity. Temporal patterns of ongoing neuronal activity, in particular brain oscillations and their fluctuations, can be traced with electro- or magnetoencephalography (EEG/MEG), to guide the timing as well as the stimulation settings of NTBS. These novel, online and offline EEG/MEG-guided NTBS-approaches are tailored to specifically interact with the underlying brain activity. Online EEG/MEG has been used to guide the timing of NTBS (i.e., when to stimulate): by taking into account instantaneous phase or power of oscillatory brain activity, NTBS can be aligned to fluctuations in excitability states. Moreover, offline EEG/MEG recordings prior to interventions can inform researchers and clinicians how to stimulate: by frequency-tuning NTBS to the oscillation of interest, intrinsic brain oscillations can be up- or down-regulated. In this paper, we provide an overview of existing approaches and ideas of EEG/MEG-guided interventions, and their promises and caveats. We point out potential future lines of research to address challenges.Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.
Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis
Feb 24, 2017   Bioorganic & Medicinal Chemistry
Mook RA, Ren XR, Wang J, Piao H, Barak LS, Kim Lyerly H, Chen W
Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis
Feb 24, 2017
Bioorganic & Medicinal Chemistry
The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.Copyright © 2017 Elsevier Ltd. All rights reserved.
Interplay between Penicillin-binding proteins and SEDS proteins promotes bacterial cell wall synthesis
Feb 24, 2017   Scientific Reports
Leclercq S, Derouaux A, Olatunji S, Fraipont C, Egan AJ, Vollmer W, Breukink E, Terrak M
Interplay between Penicillin-binding proteins and SEDS proteins promotes bacterial cell wall synthesis
Feb 24, 2017
Scientific Reports
Bacteria utilize specialized multi-protein machineries to synthesize the essential peptidoglycan (PG) cell wall during growth and division. The divisome controls septal PG synthesis and separation of daughter cells. In E. coli, the lipid II transporter candidate FtsW is thought to work in concert with the PG synthases penicillin-binding proteins PBP3 and PBP1b. Yet, the exact molecular mechanisms of their function in complexes are largely unknown. We show that FtsW interacts with PBP1b and lipid II and that PBP1b, FtsW and PBP3 co-purify suggesting that they form a trimeric complex. We also show that the large loop between transmembrane helices 7 and 8 of FtsW is important for the interaction with PBP3. Moreover, we found that FtsW, but not the other flippase candidate MurJ, impairs lipid II polymerization and peptide cross-linking activities of PBP1b, and that PBP3 relieves these inhibitory effects. All together the results suggest that FtsW interacts with lipid II preventing its polymerization by PBP1b unless PBP3 is also present, indicating that PBP3 facilitates lipid II release and/or its transfer to PBP1b after transport across the cytoplasmic membrane. This tight regulatory mechanism is consistent with the cell's need to ensure appropriate use of the limited pool of lipid II.
Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing
Feb 24, 2017   Scientific Reports
Ch'ng JH, Sirel M, Zandian A, Del Pilar Quintana M, Chun Leung Chan S, Moll K, Tellgren-Roth A, Nilsson I, Nilsson P, Qundos U, Wahlgren M
Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing
Feb 24, 2017
Scientific Reports
Variable surface antigens of Plasmodium falciparum have been a major research focus since they facilitate parasite sequestration and give rise to deadly malaria complications. Coupled with its potential use as a vaccine candidate, the recent suggestion that the repetitive interspersed families of polypeptides (RIFINs) mediate blood group A rosetting and influence blood group distribution has raised the research profile of these adhesins. Nevertheless, detailed investigations into the functions of this highly diverse multigene family remain hampered by the limited number of validated reagents. In this study, we assess the specificities of three promising polyclonal anti-RIFIN antibodies that were IgG-purified from sera of immunized animals. Their epitope regions were mapped using a 175,000-peptide microarray holding overlapping peptides of the P. falciparum variable surface antigens. Through immunoblotting and immunofluorescence imaging, we show that different antibodies give varying results in different applications/assays. Finally, we authenticate the antibody-based detection of RIFINs in two previously uncharacterized non-rosetting parasite lines by identifying the dominant rif transcripts using RNA sequencing.
IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting
Feb 24, 2017   Nature Communications
Takeda K, Nakayama M, Hayakawa Y, Kojima Y, Ikeda H, Imai N, Ogasawara K, Okumura K, Thomas DM, Smyth MJ
IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting
Feb 24, 2017
Nature Communications
Genetic evolution that occurs during cancer progression enables tumour heterogeneity, thereby fostering tumour adaptation, therapeutic resistance and metastatic potential. Immune responses are known to select (immunoedit) tumour cells displaying immunoevasive properties. Here we address the role of IFN-γ in mediating the immunoediting process. We observe that, in several mouse tumour models such as HA-expressing 4T1 mammary carcinoma cells, OVA-expressing EG7 lymphoma cells and CMS5 MCA-induced fibrosarcoma cells naturally expressing mutated extracellular signal-regulated kinase (ERK) antigen, the action of antigen-specific cytotoxic T cell (CTL) in vivo results in the emergence of resistant cancer cell clones only in the presence of IFN-γ within the tumour microenvironment. Moreover, we show that exposure of tumours to IFN-γ-producing antigen-specific CTLs in vivo results in copy-number alterations (CNAs) associated with DNA damage response and modulation of DNA editing/repair gene expression. These results suggest that enhanced genetic instability might be one of the mechanisms by which CTLs and IFN-γ immunoedits tumours, altering their immune resistance as a result of genetic evolution.
RD26 mediates crosstalk between drought and brassinosteroid signalling pathways
Feb 24, 2017   Nature Communications
Ye H, Liu S, Tang B, Chen J, Xie Z,   . . . . . .   , Li Z, Aluru M, Aluru S, Schnable PS, Yin Y
RD26 mediates crosstalk between drought and brassinosteroid signalling pathways
Feb 24, 2017
Nature Communications
Brassinosteroids (BRs) regulate plant growth and stress responses via the BES1/BZR1 family of transcription factors, which regulate the expression of thousands of downstream genes. BRs are involved in the response to drought, however the mechanistic understanding of interactions between BR signalling and drought response remains to be established. Here we show that transcription factor RD26 mediates crosstalk between drought and BR signalling. When overexpressed, BES1 target gene RD26 can inhibit BR-regulated growth. Global gene expression studies suggest that RD26 can act antagonistically to BR to regulate the expression of a subset of BES1-regulated genes, thereby inhibiting BR function. We show that RD26 can interact with BES1 protein and antagonize BES1 transcriptional activity on BR-regulated genes and that BR signalling can also repress expression of RD26 and its homologues and inhibit drought responses. Our results thus reveal a mechanism coordinating plant growth and drought tolerance.
Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons
Feb 23, 2017   ELife
Ripamonti S, Ambrozkiewicz MC, Guzzi F, Gravati M, Biella G,   . . . . . .   , Nishimori K, Toselli M, Brose N, Parenti M, Rhee J
Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons
Feb 23, 2017
ELife
Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure
Common Chemical Inductors of Replication Stress:  Focus on Cell-Based Studies
Feb 23, 2017   Biomolecules
Vesela E, Chroma K, Turi Z, Mistrik M
Common Chemical Inductors of Replication Stress:  Focus on Cell-Based Studies
Feb 23, 2017
Biomolecules
DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin), chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea), direct inhibition of the activity of replicative DNA polymerases (aphidicolin) and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide). As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses.
Evaluation of trained immunity by β-1, 3 (D)-glucan on murine monocytes in vitro and duration of response in vivo
Feb 23, 2017   Immunology And Cell Biology
Garcia-Valtanen P, Guzman-Genuino RM, Williams DL, Hayball JD, Diener KR
Evaluation of trained immunity by β-1, 3 (D)-glucan on murine monocytes in vitro and duration of response in vivo
Feb 23, 2017
Immunology And Cell Biology
The β-1, 3 (D)-glucan (β-glucan) present in the cell wall of Candida albicans induces epigenetic changes in human monocytes resulting in primed macrophages exhibiting increased cytokine responsiveness to reinfection. This phenomenon is referred to as trained immunity or innate immune memory. However, whether β-glucan can reprogram murine monocytes in vitro or induce lasting effects in vivo has yet to be elucidated. Thus purified murine spleen-derived monocytes were primed with β-glucan in vitro and assessed for markers of differentiation and survival. Important macrophage cell markers during monocyte-to-macrophage differentiation were downregulated and survival enhanced due to partial inhibition of apoptosis. Increased survival and not the β-glucan training effect explained the elevated production of TNFα and IL6 induced by subsequent LPS challenge. In vivo, four days after systemic administration of β-glucan, mice were more responsive to LPS challenge as shown by the increased serum levels of TNFα, IL6 and IL10, an effect shown to be short lived as enhanced cytokine production was lost by day 20. Here, we have characterised murine macrophages derived from β-glucan-primed monocytes based on their surface marker expression and for the first time provide evidence that the training effect of β-glucan in vivo declines within a three week period.Immunology and Cell Biology accepted article preview online, 23 February 2017. doi:10.1038/icb.2017.13.
A variant in a Cis-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones
Feb 23, 2017   Human Mutation
Ure ME, Heydari E, Pan W, Ramesh A, Rehman S, Morgan C, Pinsk M, Erickson R, Herrmann JM, Dimke H, Cordat E, Lemaire M, Walter M, Alexander RT
A variant in a Cis-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones
Feb 23, 2017
Human Mutation
The greatest risk factor for kidney stones is hypercalciuria, the etiology of which is largely unknown. A recent genome-wide association study (GWAS) linked hypercalciuria and kidney stones to a claudin-14 (CLDN14) risk haplotype. However, the underlying molecular mechanism was not delineated. Recently, renal CLDN14 expression was found to increase in response to increased plasma calcium, thereby inducing calciuria. We hypothesized therefore that some children with hypercalciuria and kidney stones harbor a CLDN14 variant that inappropriately increases gene expression. To test this hypothesis, we sequenced the CLDN14 risk haplotype in a cohort of children with idiopathic hypercalciuria and kidney stones. An intronic single nucleotide polymorphism (SNP) was more frequent in affected children. Dual luciferase and cell based assays demonstrated increased reporter or CLDN14 expression when this polymorphism was introduced. In silico studies predicted the SNP introduced a novel insulinoma-associated 1 (INSM1) transcription factor binding site. Consistent with this, repeating the dual luciferase assay in the presence of INSM1, further increased reporter expression. Our data suggest that children with the INSM1 binding site within the CLDN14 risk haplotype have a higher likelihood of hypercalciruia and kidney stones. Enhanced CLDN14 expression may play a role in the pathophysiology of their hypercalciuria. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Feb 23, 2017   Science Translational Medicine
Ler LD, Ghosh S, Chai X, Thike AA, Heng HL,   . . . . . .   , Creasy CL, Pang ST, McCabe MT, Poon SL, Teh BT
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2
Feb 23, 2017
Science Translational Medicine
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, Copyright © 2017, American Association for the Advancement of Science.
ER protein SCAP inhibits Dengue virus NS2B3 protease by suppressing its K27-linked polyubiquitylation
Feb 23, 2017   Journal Of Virology
Liu H, Zhang L, Sun J, Chen W, Li S, Wang Q, Yu H, Xia Z, Jin X, Wang C
ER protein SCAP inhibits Dengue virus NS2B3 protease by suppressing its K27-linked polyubiquitylation
Feb 23, 2017
Journal Of Virology
Dengue viruses (DENVs) are an emerging threat to global public health. The NS2B3 protease complex of DENV has recently been shown to cleave antiviral protein STING and thereby subverting the innate immune signaling to facilitate virus replication. Whether host cells have mechanism to counteract this virus-mediated immunosuppression is unclear. We discovered that the K27-linked poly-ubiquitination of NS3 protein facilitates its recruitment of NS2B and the formation of NS2B3, and consequently the enhanced cleavage of STING. However, an ER protein SCAP, through binding to NS2B protein, inhibits the ubiquitination of NS3, rendering NS2B3 protease incapable of binding and cleavage of STING. Importantly, ectopic-expression of SCAP impaired DENV infection, whereas silencing of SCAP potentiated DENV infection. Collectively, this study uncovered a novel function of SCAP to counteract the inhibitory action of DENV NS2B3 protease on the STING signaling, suggesting that modulation of SCAP levels may have therapeutic implications.Copyright © 2017 American Society for Microbiology.
Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements
Feb 23, 2017   Molecular Biology Of The Cell
Suzuki Y, Schwartz SL, Mueller NC, Schmitt MJ
Cysteine residues in a yeast viral A/B toxin crucially control host cell killing via pH-triggered disulfide rearrangements
Feb 23, 2017
Molecular Biology Of The Cell
K28 is a viral A/B protein toxin that intoxicates yeast and fungal cells by endocytosis and retrograde transport to the endoplasmic reticulum (ER). While toxin translocation into the cytosol occurs on the oxidized α/β heterodimer, the precise mechanism of how the toxin crosses the ER membrane is unknown. Here we identified pH-triggered toxin-intrinsic thiol rearrangements that crucially control toxin conformation and host cell killing. In the natural habitat and low pH environment of toxin-secreting killer yeasts, K28 is structurally stable and biologically active as disulfide-bonded heterodimer while it forms inactive disulfide-bonded oligomers at neutral pH that are caused by activation and thiol deprotonation of β-subunit cysteines. Since such pH increase reflects the pH gradient during compartmental transport within target cells, potential K28 oligomerization in the ER lumen is prevented by protein disulfide isomerase, PDI. In addition we show that pH-triggered thiol rearrangements in K28 can cause the release of cytotoxic α monomers, suggesting a toxin-intrinsic mechanism of disulfide bond reduction and α/β heterodimer dissociation in the cytosol.© 2017 by The American Society for Cell Biology.
Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency
Feb 23, 2017   EBioMedicine
Bénit P, Pelhaître A, Saunier E, Bortoli S, Coulibaly A, Rak M, Schiff M, Kroemer G, Zeviani M, Rustin P
Paradoxical Inhibition of Glycolysis by Pioglitazone Opposes the Mitochondriopathy Caused by AIF Deficiency
Feb 23, 2017
EBioMedicine
Mice with the hypomorphic AIF-Harlequin mutation exhibit a highly heterogeneous mitochondriopathy that mostly affects respiratory chain complex I, causing a cerebral pathology that resembles that found in patients with AIF loss-of-function mutations. Here we describe that the antidiabetic drug pioglitazone (PIO) can improve the phenotype of a mouse Harlequin (Hq) subgroup, presumably due to an inhibition of glycolysis that causes an increase in blood glucose levels. This glycolysis-inhibitory PIO effect was observed in cultured astrocytes from Hq mice, as well as in human skin fibroblasts from patients with AIF mutation. Glycolysis inhibition by PIO resulted from direct competitive inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, GAPDH protein levels were reduced in the cerebellum and in the muscle from Hq mice that exhibited an improved phenotype upon PIO treatment. Altogether, our results suggest that excessive glycolysis participates to the pathogenesis of mitochondriopathies and that pharmacological inhibition of glycolysis may have beneficial effects in this condition.Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.
A novel physiological role for cardiac myoglobin in lipid metabolism
Feb 23, 2017   Scientific Reports
Hendgen-Cotta UB, Esfeld S, Coman C, Ahrends R, Klein-Hitpass L, Flögel U, Rassaf T, Totzeck M
A novel physiological role for cardiac myoglobin in lipid metabolism
Feb 23, 2017
Scientific Reports
Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivo
Undergraduate medical academic performance is improved by scientific training
Feb 23, 2017   Biochemistry And Molecular Biology Education : A Bimonthly Publication Of The International Union Of Biochemistry And Molecular Biology
Zhang L, Zhang W, Wu C, Liu Z, Cai Y, Cao X, He Y, Liu G, Miao H
Undergraduate medical academic performance is improved by scientific training
Feb 23, 2017
Biochemistry And Molecular Biology Education : A Bimonthly Publication Of The International Union Of Biochemistry And Molecular Biology
The effect of scientific training on course learning in undergraduates is still controversial. In this study, we investigated the academic performance of undergraduate students with and without scientific training. The results show that scientific training improves students' test scores in general medical courses, such as biochemistry and molecular biology, cell biology, physiology, and even English. We classified scientific training into four levels. We found that literature reading could significantly improve students' test scores in general courses. Students who received scientific training carried out experiments more effectively and published articles performed better than their untrained counterparts in biochemistry and molecular biology examinations. The questionnaire survey demonstrated that the trained students were more confident of their course learning, and displayed more interest, motivation and capability in course learning. In summary, undergraduate academic performance is improved by scientific training. Our findings shed light on the novel strategies in the management of undergraduate education in the medical school. © 2017 by The International Union of Biochemistry and Molecular Biology, 2017.© 2017 The International Union of Biochemistry and Molecular Biology.
Mice lacking BCAS1, a novel myelin-associated protein, display hypomyelination, schizophrenia-like abnormal behaviors, and upregulation of inflammatory genes in the brain
Feb 23, 2017   Glia
Ishimoto T, Ninomiya K, Inoue R, Koike M, Uchiyama Y, Mori H
Mice lacking BCAS1, a novel myelin-associated protein, display hypomyelination, schizophrenia-like abnormal behaviors, and upregulation of inflammatory genes in the brain
Feb 23, 2017
Glia
The abnormal expression and function of myelin-related proteins contribute to nervous system dysfunction associated with neuropsychiatric disorders; however, the underlying mechanism of this remains unclear. We found here that breast carcinoma amplified sequence 1 (BCAS1), a basic protein abundant in the brain, was expressed specifically in oligodendrocytes and Schwann cells, and that its expression level was decreased by demyelination. This suggests that BCAS1 is a novel myelin-associated protein. BCAS1 knockout mice displayed schizophrenia-like behavioral abnormalities and a tendency toward reduced anxiety-like behaviors. Moreover, we found that the loss of BCAS1 specifically induced hypomyelination and the expression of inflammation-related genes in the brain. These observations provide a novel insight into the functional link between oligodendrocytes and inflammation and/or abnormal behaviors.© 2017 Wiley Periodicals, Inc.
Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals
Feb 23, 2017   The Prostate
Huang H, Du T, Zhang Y, Lai Y, Li K, Fan X, Zhu D, Lin T, Xu K, Huang J, Liu L, Guo Z
Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals
Feb 23, 2017
The Prostate
BACKGROUND: SHARPIN, SHANK-associated RH domain interacting protein, associates with a linear ubiquitin chain assembly complex (LUBAC) to regulate inflammation and immunity. It has been reported that SHARPIN is highly expressed in several human tumors including ovarian cancer and liver cancer. We found that SHARPIN is also highly expressed in prostate cancer cell lines of DU145, LNCAP, and PC-3. Suppression of SHARPIN caused an inhibition of NF-κB signal and decreases in tumorigenesis of cultured cells in NOD/SCID mouse model. Overexpression of SHARPIN in prostate cancer cells promoted cell growth and reduced apoptosis through NF-kB/ERK/Akt pathway and apoptosis-associated proteins. METHODS: We analyzed the expression of SHARPIN in prostate cancer tissues from 95 patients and its relationship with other clinical characteristics associated with PCA malignancies and patient survivals, and examined the impacts of SHARPIN suppression with siRNA on proliferation, angiogenesis, invasion, and expression levels of MMP-9 of prostate cancer cells and metastasis to lung by these cells in nude mice. RESULTS: High levels of SHARPIN were associated with high malignancies of PCA and predicted shorter survivals of PCA patients. Suppression of SHARPIN impaired cell proliferation, angiogenesis, and invasion and reduced levels of MMP-9 in prostate cancer cells and reduced the size of metastatic lung tumors induced by these cells in mice. CONCLUSIONS: SHARPIN enhances the metastasis of prostate cancer and impair patient survivals. Prostate. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
Establishment of planar cell polarity is coupled to regional cell cycle exit and cell differentiation in the mouse utricle
Feb 23, 2017   Scientific Reports
Yang X, Qian X, Ma R, Wang X, Yang J, Luo W, Chen P, Chi F, Ren D
Establishment of planar cell polarity is coupled to regional cell cycle exit and cell differentiation in the mouse utricle
Feb 23, 2017
Scientific Reports
Sensory hair cells are coordinately oriented within each inner ear sensory organ to exhibit a particular form of planar cell polarity (PCP) necessary for mechanotransduction. However, the developmental events associated with establishing PCP in the vestibule are unclear, hindering data interpretation and employment of the vestibule for PCP studies. Herein, we investigated PCP of the mouse vestibular organs. We further characterised cell cycle exit, cell differentiation, and PCP establishment in the utricle. We found that hair cells formed first in the striolar and medial extrastriolar (MES) regions of the utricle at embryonic day 11.5 (E11.5), while cells in the lateral extrastriolar region (LES) mostly formed at E13.5. Cell differentiation was initiated in the striolar region, which expanded first toward the MES, then to the LES by E15.5. The polarity of hair cells was established at birth along a putative line of polarity reversal (LPR), lateral to the striolar region. Core PCP protein Vangl2 emerged in the cell boundaries since E11.5, while cell intrinsic polarity protein Gαi3 appeared at E12.5, then polarized to the bare zone of individual hair cell at E13.5. These findings provide a blueprint of the developmental events associated with establishing PCP in the utricle.
Feb 22, 2017   ELife
Sisquella X, Nebl T, Thompson JK, Whitehead L, Malpede BM, Salinas ND, Rogers K, Tolia NH, Fleig A, O'Neill J, Tham WH, Horgen FD, Cowman AF
Feb 22, 2017
ELife
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