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1.
Pluripotent stem cells, including induced pluripotent and embryonic stem cells (ESCs), have less developed mitochondria than somatic cells and, therefore, rely more heavily on glycolysis for energy production.1-3 However, how mitochondrial homeostasis matches the demands of nuclear reprogramming and regulates pluripotency in ESCs is largely unknown. Here, we identified ATG3-dependent autophagy as an executor for both mitochondrial remodeling during somatic cell reprogramming and mitochondrial homeostasis regulation in ESCs. Dysfunctional autophagy by Atg3 deletion inhibited mitochondrial removal during pluripotency induction, resulting in decreased reprogramming efficiency and accumulation of abnormal mitochondria in established iPSCs. In Atg3 null mouse ESCs, accumulation of aberrant mitochondria was accompanied by enhanced ROS generation, defective ATP production and attenuated pluripotency gene expression, leading to abnormal self-renewal and differentiation. These defects were rescued by reacquisition of wild-type but not lipidation-deficient Atg3 expression. Taken together, our findings highlight a critical role of ATG3-dependent autophagy for mitochondrial homeostasis regulation in both pluripotency acquirement and maintenance. 相似文献
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Avinashnarayan Venkatanarayan Payal Raulji William Norton 《Cell cycle (Georgetown, Tex.)》2016,15(2):164-171
TP53 is highly mutated in human cancers, thus targeting this tumor suppressor pathway is highly desirable and will impact many cancer patients.1,2 Therapeutic strategies to reactivate the p53-pathway have been challenging,3,4 and no effective treatment exists.5 We utilized the p53-family members, p63 and p73, which are not frequently mutated in cancer, to treat p53-defective cancers. The N-terminal splice variants of p63 and p73 are denoted as the TA and ΔN isoforms. We recently demonstrated that deletion of either ΔNp63 or ΔNp73 in p53-deficient mouse tumors results in tumor regression mediated by metabolic programming. Using this strategy, we identified pramlintide, a synthetic analog of amylin, as an effective treatment for p53 deficient and mutant tumors. Here, we show the utility of using pramlintide, as a potential cancer preventive option for p53-deficient tumors in mouse models. Additionally, we found that in vivo inhibition of both ΔNp63 and ΔNp73 in combination accelerates tumor regression and increases survival of p53-deficient mice. We report that inhibition of both ΔNp63 and ΔNp73 in combination results in upregulation of 3 key metabolic regulators, IAPP, GLS2, and TIGAR resulting in an increase in apoptosis and tumor regression in ΔNp63/ΔNp73/p53 deficient thymic lymphomas. These data highlight the value of generating inhibitors that will simultaneously target ΔNp63 and ΔNp73 to treat cancer patients with alterations in p53. 相似文献
4.
Hana Popelka 《Autophagy》2017,13(3):449-451
Atg13 is an essential subunit of the Atg1 autophagy initiation complex in yeast and its mammalian counterpart, ATG13, is indispensable for autophagy induction by the ULK1 complex. The N terminus of the protein folds into a HORMA domain, an architecture that has been revealed by crystallography.1-4 In human cells, the ATG13 HORMA domain interacts directly with ATG14, a subunit of the class III phosphatidylinositol 3-kinase complex.5 In budding yeast, the HORMA domain of Atg13 recruits Atg14, but a direct interaction remains to be proven.1 The amino acid sequence that follows the HORMA domain does not adopt any 3-dimensional structure on its own; therefore, it is termed an intrinsically disordered region (IDR). Here we discuss the results of 2 recent studies in light of previous reports on Atg13 from yeast. Together, they yield an insight into the molecular mechanism for the function of this intriguing protein, and reveal why Atg13, as well as the mammalian homolog ATG13, cannot have a structurally rigid architecture. 相似文献
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Dennis J. Hazelett David V. Conti Ying Han Ali Amin Al Olama Doug Easton Rosalind A. Eeles 《Cell cycle (Georgetown, Tex.)》2016,15(1):22-24
Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality; we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 20151,2 from our groups. 相似文献
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《Cell Adhesion & Migration》2013,7(3):202-213
Neurons are highly polarized specialized cells. Neuronal integrity and functional roles are critically dependent on dendritic architecture and synaptic structure, function and plasticity. The cadherins are glycosylated transmembrane proteins that form cell adhesion complexes in various tissues. They are associated with a group of cytosolic proteins, the catenins. While the functional roles of the complex have been extensively investigates in non-neuronal cells, it is becoming increasingly clear that components of the complex have critical roles in regulating dendritic and synaptic architecture, function and plasticity in neurons. Consistent with these functional roles, aberrations in components of the complex have been implicated in a variety of neurodevelopmental disorders. In this review, we discuss the roles of the classical cadherins and catenins in various aspects of dendrite and synapse architecture and function and their relevance to human neurological disorders. Cadherins are glycosylated transmembrane proteins that were initially identified as Ca2+-dependent cell adhesion molecules. They are present on plasma membrane of a variety of cell types from primitive metazoans to humans. In the past several years, it has become clear that in addition to providing mechanical adhesion between cells, cadherins play integral roles in tissue morphogenesis and homeostasis. The cadherin family is composed of more than 100 members and classified into several subfamilies, including classical cadherins and protocadherins. Several of these cadherin family members have been implicated in various aspects of neuronal development and function.1-3 The classical cadherins are associated with a group of cytosolic proteins, collectively called the catenins. While the functional roles of the cadherin-catenin cell adhesion complex have been extensively investigated in epithelial cells, it is now clear that components of the complex are well expressed in central neurons at different stages during development.4,5 Recent exciting studies have shed some light on the functional roles of cadherins and catenins in central neurons. In this review, we will provide a brief overview of the cadherin superfamily, describe cadherin family members expressed in central neurons, cadherin-catenin complexes in central neurons and then focus on role of the cadherin-catenin complex in dendrite morphogenesis and synapse morphogenesis, function and plasticity. The final section is dedicated to discussion of the emerging list of neural disorders linked to cadherins and catenins. While the roles of cadherins and catenins have been examined in several different types of neurons, the focus of this review is their role in mammalian central neurons, particularly those of the cortex and hippocampus. Accompanying this review is a series of excellent reviews targeting the roles of cadherins and protocadherins in other aspects of neural development. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(3):229-241
The Divakar-Reese procedure has been successfully applied for transforming 7-oxo-isothiazolo[4,5-d]pyrimidine C-nucleosides (4a,b, 5a,b, 6a) via 1,2,4-triazol-1-yl intermediates (7a,b, 8a,b) into various 7-substituted C-nucle- osides 15a,b, 16a,b, 17a, 18a, 19a,b, 20a,b; their subsequent deprotection provides novel types of unusual C-glycosides 22b, 23a, 24a,b, 25b, 26b. C-Nucleosides, possessing on its heterocyclic base other than naturally occuring oxo- or amino substituents, are important model compounds for biological or medicinal studies [2a], [2b], [2c], [2d], [2e], [2f], [2g], [2h], [2i] [3a], [3b], [3c], [3d], [3e], [3f], [3g], [3h]. We want to report on the synthesis of novel 7-substituted isothiazolo = [4,5-d]pyrimidine C-nucleosides. As we could show in previous papers [1], [4], there exists a simple approach to the protected C-glycosides 4–6. 相似文献
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Beate Hintersteiner Nico Lingg Peiqing Zhang Susanto Woen Kong Meng Hoi Stefan Stranner 《MABS-AUSTIN》2016,8(8):1548-1560
We identified active isoforms of the chimeric anti-GD2 antibody, ch14.18, a recombinant antibody produced in Chinese hamster ovary cells, which is already used in clinical trials.1,2,3 We separated the antibody by high resolution ion-exchange chromatography with linear pH gradient elution into acidic, main and basic charge variants on a preparative scale yielding enough material for an in-depth study of the sources and the effects of microheterogeneity. The binding affinity of the charge variants toward the antigen and various cell surface receptors was studied by Biacore. Effector functions were evaluated using cellular assays for antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Basic charge variants showed increased binding to cell surface receptor FcγRIIIa, which plays a major role in regulating effector functions. Furthermore, increased binding of the basic fractions to the neonatal receptor was observed. As this receptor mediates the prolonged half-life of IgG in human serum, this data may well hint at an increased serum half-life of these basic variants compared to their more acidic counterparts. Different glycoform patterns, C-terminal lysine clipping and N-terminal pyroglutamate formation were identified as the main structural sources for the observed isoform pattern. Potential differences in structural stability between individual charge variant fractions by nano differential scanning calorimetry could not been detected. Our in-vitro data suggests that the connection between microheterogeneity and the biological activity of recombinant antibody therapeutics deserves more attention than commonly accepted. 相似文献
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We investigated the morphology, morphogenesis and small subunit rRNA gene-based phylogeny of three marine urostylids, Uncinata gigantea Bullington, 1940, Holosticha heterofoissneri Hu & Song, 2001, and Holosticha cf. heterofoissneri. The dorsal morphogenesis of Uncinata gigantea shows de novo formation of two groups of anlagen near the marginal rows. Holosticha cf. heterofoissneri demonstrates fragmentation of the first dorsal kinety anlage as in Holosticha heterofoissneri. Our population of H. heterofoissneri corresponds well with previously described populations in terms of its general morphology and ciliary pattern. Uncinata gigantea can be recognized by its large and highly contractile body, yellowish to brownish cell colour, two types of cortical granules, and 20–30 transversely oriented and densely arranged cirri in the left marginal row, which often overlie the buccal vertex. Based on the new data, especially infraciliature, the genus Uncinata is here redefined. Both the morphology and phylogenetic analyses suggest that the genus Uncinata should be classified within the family Urostylidae. In addition, both morphological and morphogenetic data suggest that Holosticha bradburyae Gong et al., 2001 should be transferred to Uncinata as U. bradburyae (Gong et al., 2001) comb. nov., due to its possession of a characteristically prominent beak-like, leftwards curved projection and the developmental mode of the dorsal kineties. This assignment is supported by the phylogenetic analyses, which placed Uncinata gigantea in a clade with U. bradburyae (Gong et al., 2001) comb. nov., and revealed only 1.13% (19 bp) difference in their SSU-rDNA gene sequence. 相似文献
10.
Christopher J. Derrick 《Cell cycle (Georgetown, Tex.)》2017,16(1):23-32
Localized mRNA translation is a widespread mechanism for targeting protein synthesis, important for cell fate, motility and pathogenesis. In Drosophila, the spatiotemporal control of gurken/TGF-α mRNA translation is required for establishing the embryonic body axes. A number of recent studies have highlighted key aspects of the mechanism of gurken mRNA translational control at the dorsoanterior corner of the mid-stage oocyte. Orb/CPEB and Wispy/GLD-2 are required for polyadenylation of gurken mRNA, but unlocalized gurken mRNA in the oocyte is not fully polyadenylated.1 At the dorsoanterior corner, Orb and gurken mRNA have been shown to be enriched at the edge of Processing bodies, where translation occurs.2 Over-expression of Orb in the adjacent nurse cells, where gurken mRNA is transcribed, is sufficient to cause mis-expression of Gurken protein.3 In orb mutant egg chambers, reducing the activity of CK2, a Serine/Threonine protein kinase, enhances the ventralized phenotype, consistent with perturbation of gurken translation.4 Here we show that sites phosphorylated by CK2 overlap with active Orb and with Gurken protein expression. Together with our new findings we consolidate the literature into a working model for gurken mRNA translational control and review the role of kinases, cell cycle factors and polyadenylation machinery highlighting a multitude of conserved factors and mechanisms in the Drosophila egg chamber. 相似文献
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ABSTRACTDiscovered in 1954 by Ambroggi and Lapparent, the Tagragra tracksite (Maastrichtian, Agadir, Morocco) yielded tracks of theropod dinosaurs, birds and enigmatic forms tentatively attributed to Lacertilia under the name Agadirichnus elegans. The original specimens are today considered to be lost, and the status of A. elegans has been questioned, even though these footprints can retrospectively be referred to pterodactyloid pterosaur tracks. In order to discuss the status of these foot prints, the historical site has been actively sought and recently rediscovered by one of us (MdD). New material confirms the presence of pterodactyloid footprints, with two morphotypes, in two different facies, respectively associated with bird and theropod tracks. Morphotype I is tentatively conferred to Pteraichnus Stokes 1957, which extends the stratigraphical distribution of this ichnotaxon to the Maastrichtian. Morphotype II corresponds to the original ichnospecies A. elegans Ambroggi and Lapparent 1954, which is here reassessed as a valid ichnotaxon, with the designation of a neotype. Thus, A. elegans Ambroggi and Lapparent 1954 is historically the first pterosaurian ichnotaxon ever described. 相似文献
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Background: Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death.1 The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet. Methods: We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety". Conclusion: As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening. 相似文献
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The existence of extrema, maximum and/or minimum and negative gradients of melting curves observed for several elements at high pressure is investigated by molecular dynamics simulation using the two-species model (TSM) proposed by Ogura et al. [1]. TSM is a model which imitates the change in the electronic structure of an atom in terms of a species change in particles. The TSM phase diagram has two solid phases and one liquid phase with a solid–solid–liquid triple point which corresponds to the melting curve minimum. The melting curve has both a maximum and a minimum, and the gradient of the melting curve is negative between these extrema. These peculiar melting curve properties and phase diagram are common to alkali metals and some other elements. 相似文献
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Benjamin Boëns Tan-Sothea Ouk Yves Champavier Rachida Zerrouki 《Nucleosides, nucleotides & nucleic acids》2015,34(7):500-514
This paper describes the synthesis of new click-generated nitrogen mustards and their biological evaluation. By using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, we managed to synthesize eight new nitrogen mustards. This strategy paves the way for the synthesis of a new family of nitrogen mustard, with an important structural variability. Furthermore, we studied the biological activity of synthesized compounds by testing their cytotoxicity on four representative cancer cell lines A431, JURKAT, K562, and U266. One structure, 1-benzyl-4-(N,N-di-2-chloroethylaminomethyl)-1H-[1,2,3]triazole, showed an interesting cytotoxic effect. 相似文献
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ABSTRACTThe larval stages of the genus Kempynus Navás, 1912 (probably K. falcatus Navás, 1912 based on the presence of synchronic and sympatric adults) are described for the Neotropical Region for the first time, and the larval stages of Isostenosmylus pulverulentus (Gerstaecker, 1893) are redescribed. The external morphology of third-instar larvae of both species and their habitats are described and compared. Kempynus sp. is a water-dependent species and can be considered semi-aquatic, whereas I. pulverulentus larvae are terrestrial and live in undergrowth vegetation. The first key to identification of Neotropical Osmylidae larvae is provided, based on third-instar larvae of both species. 相似文献
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《Fly》2013,7(4):155-159
ABSTRACTAnimals have modular cis-regulatory regions in their genomes, and expression of a single gene is often regulated by multiple enhancers residing in such a region. In the laboratory, and also in natural populations, loss of an enhancer can result in a loss of gene expression. Although only a few examples have been well characterized to date, some studies have suggested that an evolutionary gain of a new enhancer function can establish a new gene expression domain. Our recent study showed that Drosophila guttifera has more enhancers and additional expression domains of the wingless gene during the pupal stage, compared to D. melanogaster, and that these new features appear to have evolved in the ancestral lineage leading to D. guttifera.1 Gain of a new expression domain of a developmental regulatory gene (toolkit gene), such as wingless, can cause co-option of the expression of its downstream genes to the new domain, resulting in duplication of a preexisting structure at this new body position. Recently, with the advancement of evo-devo studies, we have learned that the developmental regulatory systems are strikingly similar across various animal taxa, in spite of the great diversity of the animals' morphology. Even behind “new” traits, co-options of essential developmental genes from known systems are very common. We previously provided concrete evidence of gains of enhancer activities of a developmental regulatory gene underlying gains of new traits.1 Broad occurrence of this scenario is testable and should be validated in the future. 相似文献
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The enzymatic oxidization of dissolved Fe(II) to Fe(III) by neutrophilic Fe-oxidizing bacteria plays a significant role in biological cycling of iron by inducing the precipitation of Fe(III) oxyhydroxide in aqueous environments. Among the diverse neutrophilic Fe-oxidizing bacteria, the genus Gallionella has received wide attention for its production of unique twisted extracellular stalks. Hallberg and Tai (2014) recently reported the detection of multi-wall carbon nanotubes on the twisted-stalks, and they viewed those carbon nanotubes as being biologically produced by Gallionella. We scrutinized Gallionella-produced biofilms collected from natural environments by scanning electron microscopy and high-resolution transmission electron microscopy. Ferrihydrite and lepidocrocite were the only nano-scaled minerals observed on the stalk, while there were nanometer-sized sheet-like graphitic contaminants on the grid in the vicinity of the sample which showed the same morphology as Hallberg and Tai (2014) observed. Moreover, similar materials on an empty grid and a grid loaded with randomly selected synthesized materials were also observed. Based on the current knowledge of carbon nanotube syntheses, none of the three known synthesizing methods including root-growth, rolling-up and bottom-up could be biochemically produced by any life because of the significant kinetic and energy obstacles. The carbon nanomaterials reported by Hallberg and Tai (2014) were clearly contaminations from amorphous carbon film on the grids for holding samples for transmission electron microscopic observations. 相似文献
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The Inter-Tribal Fisheries and Assessment Program (ITFAP) of the Chippewa Ottawa Resource Authority (CORA) in Sault Ste. Marie, Michigan, has been monitoring contaminant concentrations in the fillet portions of lake trout (Salvelinus namaycush) and lake whitefish (Coregonus clupeaformis) from the waters of lakes Superior, Huron, and Michigan since 1991. The primary purpose of this article is to present a risk quantification of methylmercury (MeHg) that is adjusted for nutritional benefit, originally presented by Ginsberg and Toal (2009, 2015) on trends in contaminant concentrations in fillet portions of these commercial fish that we recently reported in Dellinger et al. (2014). Both species of fish caught by tribal fishermen showed clear benefits to cardiovascular health and infant neurodevelopment if consumed at a rate of six ounces per week. However, other popularly consumed fish such as cod, tuna, and tilapia are estimated to have only marginal benefit or net negative effects on cardiovascular health and infant neurodevelopment. This dynamic assessment of benefits and risks further demonstrates the importance of traditionally caught fish in tribal health. 相似文献