For the initiation of transcription, RNA polymerase II (Pol II) assembles with general transcription factors on promoter DNA to form the pre-initiation complex (PIC). Here we report cryo-electron ...microscopy structures of the Saccharomyces cerevisiae PIC and PIC-core Mediator complex at nominal resolutions of 4.7 Å and 5.8 Å, respectively. The structures reveal transcription factor IIH (TFIIH), and suggest how the core and kinase TFIIH modules function in the opening of promoter DNA and the phosphorylation of Pol II, respectively. The TFIIH core subunit Ssl2 (a homologue of human XPB) is positioned on downstream DNA by the 'E-bridge' helix in TFIIE, consistent with TFIIE-stimulated DNA opening. The TFIIH kinase module subunit Tfb3 (MAT1 in human) anchors the kinase Kin28 (CDK7), which is mobile in the PIC but preferentially located between the Mediator hook and shoulder in the PIC-core Mediator complex. Open spaces between the Mediator head and middle modules may allow access of the kinase to its substrate, the C-terminal domain of Pol II.
We study the cosmic MeV neutrino background from accretion disks formed during collapsars and the coalescence of compact-object mergers. We provide updated estimates, including detection rates, of ...relic neutrinos from collapsars, as well as estimates for neutrinos that are produced in mergers. Our results show that diffuse neutrinos detected at HyperK would likely include some that were emitted from binary neutron-star mergers. The collapsar rate is uncertain, but at its upper limit relic neutrinos from these sources would provide a significant contribution to the cosmic diffuse neutrino background.
Ectodysplasin, a member of the tumor necrosis factor family, is encoded by the anhidrotic ectodermal dysplasia (EDA) gene. Mutations in EDA give rise to a clinical syndrome characterized by loss of ...hair, sweat glands, and teeth. EDA-A1 and EDA-A2 are two isoforms of ectodysplasin that differ only by an insertion of two amino acids. This insertion functions to determine receptor binding specificity, such that EDA-A1 binds only the receptor EDAR, whereas EDA-A2 binds only the related, but distinct, X-linked ectodysplasin-A2 receptor (XEDAR). In situ binding and organ culture studies indicate that EDA-A1 and EDA-A2 are differentially expressed and play a role in epidermal morphogenesis.
The nuclear pore complex (NPC) controls the transport of macromolecules between the nucleus and cytoplasm, but its molecular architecture has thus far remained poorly defined. We biochemically ...reconstituted NPC core protomers and elucidated the underlying protein-protein interaction network. Flexible linker sequences, rather than interactions between the structured core scaffold nucleoporins, mediate the assembly of the inner ring complex and its attachment to the NPC coat. X-ray crystallographic analysis of these scaffold nucleoporins revealed the molecular details of their interactions with the flexible linker sequences and enabled construction of full-length atomic structures. By docking these structures into the cryoelectron tomographic reconstruction of the intact human NPC and validating their placement with our nucleoporin interactome, we built a composite structure of the NPC symmetric core that contains ~320,000 residues and accounts for ~56 megadaltons of the NPC's structured mass. Our approach provides a paradigm for the structure determination of similarly complex macromolecular assemblies.
We hypothesized that certain proteins encoded by temperature-responsive genes in brown adipose tissue (BAT) contribute to the remarkable metabolic shifts observed in this tissue, thus prompting a ...differential mRNA expression analysis to identify candidates involved in this process in mouse BAT. An mRNA species corresponding to a novel partial-length gene was found to be induced 2-3-fold above the control following cold exposure (4 degrees C), and repressed approximately 70% by warm acclimation (33 degrees C, 3 weeks) compared with controls (22 degrees C). The gene displayed robust BAT expression (i.e. approximately 7-100-fold higher than other tissues in controls). The full-length murine gene encodes a 594 amino acid ( approximately 67 kDa) open reading frame with significant homology to the human hypothetical acyl-CoA thioesterase KIAA0707. Based on cold-inducibility of the gene and the presence of two acyl-CoA thioesterase domains, we termed the protein brown-fat-inducible thioesterase (BFIT). Subsequent analyses and cloning efforts revealed the presence of a novel splice variant in humans (termed hBFIT2), encoding the orthologue to the murine BAT gene. BFIT was mapped to syntenic regions of chromosomes 1 (human) and 4 (mouse) associated with body fatness and diet-induced obesity, potentially linking a deficit of BFIT activity with exacerbation of these traits. Consistent with this notion, BFIT mRNA was significantly higher ( approximately 1.6-2-fold) in the BAT of obesity-resistant compared with obesity-prone mice fed a high-fat diet, and was 2.5-fold higher in controls compared with ob/ob mice. Its strong, cold-inducible BAT expression in mice suggests that BFIT supports the transition of this tissue towards increased metabolic activity, probably through alteration of intracellular fatty acyl-CoA concentration.
We study the cosmic MeV neutrino background from accretion disks formed during collapsars and the coalescence of compact-object mergers. We provide updated estimates, including detection rates, of ...relic neutrinos from collapsars, as well as estimates for neutrinos that are produced in mergers. Furthermore, our results show that diffuse neutrinos detected at HyperK would likely include some that were emitted from binary neutron-star mergers. The collapsar rate is uncertain, but at its upper limit relic neutrinos from these sources would provide a significant contribution to the cosmic diffuse neutrino background.
The nuclear pore complex (NPC) is the primary gateway for transport of macromolecules between the nucleus and cytoplasm, serving as both a critical mediator and regulator of gene expression. NPCs are ...enormous ~120 MDa macromolecular machines embedded in the nuclear envelope, each containing ~1000 protein subunits, termed nucleoporins. Despite substantial progress in visualizing the overall shape of the NPC by cryoelectron tomography and in determining atomic resolution crystal structures of nucleoporins, the molecular architecture of the assembled NPC remains poorly understood, hindering the design of mechanistic studies that could investigate its many roles in cell biology.
The mechanism controlling the development of dopaminergic (DA) and serotonergic (5HT) neurons in vertebrates is not well understood. Here we characterized a zebrafish mutant--too few (tof)--that ...develops hindbrain 5HT and noradrenergic neurons, but does not develop hypothalamic DA and 5HT neurons. tof encodes a forebrain-specific zinc finger transcription repressor that is homologous to the mammalian Fezl (forebrain embryonic zinc finger-like protein). Mosaic and co-staining analyses showed that fezl was not expressed in DA or 5HT neurons and instead controlled development of these neurons non-cell-autonomously. Both the eh1-related repressor motif and the second zinc finger domain were necessary for tof function. Our results indicate that tof/fezl is a key component in regulating the development of monoaminergic neurons in the vertebrate brain.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The prevalence of outpatient treatment with various drug groups is significantly higher in diabetics than in non-diabetic control patients. In addition to the specific diabetes-related prescriptions, ...diabetics were more frequently treated with drugs acting on the alimentary tract or used in metabolic disorders (ATC code A), drugs used in disorders of the blood and blood-forming organs (ATC B), cardiovascular system (ATC C), musculo-skeletal system (ATC M) and nervous system (ATC N)-- resulting in markedly higher outpatient costs in this patient group. Objective of this investigation was to analyze the pre-hospital prescription pattern of diabetics and non-diabetic controls at the time of admission to hospital.
A sample survey of a total of 189 general medical and 68 surgical admissions involving diabetics and 676 and 143 non-diabetic control patients corresponding in age, sex and main diagnosis--were analyzed with regard to selected medical and demographic characteristics and pharmacotherapy.
The prevalence of non-diabetic drug treatment in diabetics was highest for ATC C (87.8% and 69.1%), ATC A (40.7% and 27.9%; without A10) and ATC B (39.2% and 29.4%) in internal and surgical admissions, respectively. A substantially higher prevalence was found for ATC groups B and C in diabetics and controls admitted to medical wards than in epidemiological prescription analyses.
Data indicate that the need for treatment with cardiovascular drugs and drugs used to treat disorders of the blood and blood-forming organs may be associated with a higher risk of hospitalization in general medical wards.
The development of distinct vertebrate neurons is defined by the unique
profiles of genes that neurons express. It is accepted that neural genes are
regulated at the point of transcription ...initiation, but the role of messenger
RNA elongation in neural gene regulation has not been examined.
Here we describe the mutant foggy, identified in a genetic screen for
mutations that affect neuronal development in zebrafish, that
displayed a reduction of dopamine-containing neurons and a corresponding surplus
of serotonin-containing neurons in the hypothalamus. Positional cloning disclosed
that Foggy is a brain-enriched nuclear protein that is structurally related
to the transcription elongation factor Spt5 (refs 5,6,7,8,9,10,11
,12). Foggy is not part of the basic
transcription apparatus but a phosphorylation-dependent, dual regulator of
transcription elongation. The mutation disrupts its repressive but not its
stimulatory activity. Our results provide molecular, genetic and biochemical
evidence that negative regulators of transcription elongation control key
aspects of neuronal development.
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