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The mammalian circadian clock uses interlocked negative feedback loops in which the heterodimeric basic helix-loop-helix transcription factor BMAL1/CLOCK is a master regulator. While there is prominent control of liver functions by the circadian clock, the detailed links between circadian regulators and downstream targets are poorly known. Using chromatin(More)
Tim23, an essential component of the protein import machinery of the inner membrane of mitochondria (TIM complex), forms dimers that display a dynamic behavior. Dimer formation is promoted by the membrane potential delta psi. Binding of a matrix targeting sequence to Tim23 triggers dimer dissociation. Monomeric Tim23 is present when a preprotein chain is in(More)
FREQUENCY (FRQ) is a crucial element of the circadian clock in Neurospora crassa. In the course of a circadian day FRQ is successively phosphorylated and degraded. Here we report that two PEST-like elements in FRQ, PEST-1 and PEST-2, are phosphorylated in vitro by recombinant CK-1a and CK-1b, two newly identified Neurospora homologs of casein kinase 1(More)
Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized(More)
Proteins that are destined for the matrix of mitochondria are transported into this organelle by two translocases: the TOM complex, which transports proteins across the outer mitochondrial membrane; and the TIM23 complex, which gets them through the inner mitochondrial membrane. Two models have been proposed to explain how this protein-import machinery(More)
Circadian clocks consist of three elements: entrainment pathways (inputs), the mechanism generating the rhythmicity (oscillator), and the output pathways that control the circadian rhythms. It is difficult to assign molecular clock components to any one of these elements. Experiments show that inputs can be circadianly regulated and outputs can feed back on(More)
The circadian clock protein Frequency (FRQ) feedback-regulates its own expression by inhibiting its transcriptional activator, White Collar Complex (WCC). We present evidence that FRQ regulates the bulk of WCC through modulation of its phosphorylation status rather than via direct complex formation. In the absence of FRQ, WCC is hypophosphorylated and(More)
We have identified a complex in mitochondria that functions as a part of the preprotein import machinery of the inner membrane (MIM complex). Two known components, MIM23 and MIM17, and two novel components, MIM33 and MIM14, were found as constituents of this complex. In the presence of a translocating chain, the outer membrane import machinery (MOM complex)(More)
Tim23, a key component of the mitochondrial preprotein translocase, is anchored in the inner membrane by its C-terminal domain and exposes an intermediate domain in the intermembrane space that functions as a presequence receptor. We show that the N-terminal domain of Tim23 is exposed on the surface of the outer membrane. The two-membrane-spanning topology(More)
Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of(More)