Cytoplasmic PML function in TGF-beta signalling

Transforming growth factor beta (TGF-beta) is a pluripotent cytokine that controls key tumour suppressive functions, but cancer cells are often unresponsive to it. The promyelocytic leukaemia (PML) tumour suppressor of acute promyelocytic leukaemia (APL) accumulates in the PML nuclear body, but cytoplasmic PML isoforms of unknown function have also been described. Here we show that cytoplasmic Pml is an essential modulator of TGF-beta signalling. Pml-null primary cells are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signalling proteins Smad2 and Smad3, as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome. The PML-RARalpha oncoprotein of APL can antagonize cytoplasmic PML function and APL cells have defects in TGF-beta signalling similar to those observed in Pml-null cells. Our findings identify cytoplasmic PML as a critical TGF-beta regulator, and further implicate deregulated TGF-beta signalling in cancer pathogenesis.     

Extended surface chirality from supramolecular assemblies of adsorbed chiral molecules

The increasing demand of the chemical and pharmaceutical industries for enantiomerically pure compounds has spurred the development of a range of so-called 'chiral technologies' (ref. 1), which aim to exert the ultimate control over a chemical reaction by directing its enantioselectivity. Heterogeneous enantioselective catalysis is particularly attractive because it allows the production and ready separation of large quantities of chiral product while using only small quantities of catalyst. Heterogeneous enantioselectivity is usually induced by adsorbing chiral molecules onto catalytically active surfaces. A mimic of one such catalyst is formed by adsorbing (R,R)-tartaric acid molecules on Cu(110) surfaces: this generates a variety of surface phases, of which only one is potentially catalytically active, and leaves the question of how adsorbed chiral molecules give rise to enantioselectivity. Here we show that the active phase consists of extended supramolecular assemblies of adsorbed (R,R)-tartaric acid, which destroy existing symmetry elements of the underlying metal and directly bestow chirality to the modified surface. The adsorbed assemblies create chiral 'channels' exposing bare metal atoms, and it is these chiral spaces that we believe to be responsible for imparting enantioselectivity, by forcing the orientation of reactant molecules docking onto catalytically active metal sites. Our findings demonstrate that it is possible to sustain a single chiral domain across an extended surface--provided that reflection domains of opposite handedness are removed by a rigid and chiral local adsorption geometry, and that inequivalent rotation domains are removed by successful matching of the rotational symmetry of the adsorbed molecule with that of the underlying metal surface.     

Withdrawing Unfalsifiable Hypotheses

There has been little research into the weak kindsof negating hypotheses. Hypotheses may be unfalsifiable. In this case it is impossible tofind a contradiction in some area of the conceptualsystems in which they are incorporated.Notwithstanding this fact, it is sometimes necessaryto construct ways of rejecting the unfalsifiablehypothesis at hand by resorting to some external forms of negation, external because wewant to avoid any arbitrary and subjectiveelimination, which would be rationally orepistemologically unjustified. I will consider akind of ``weak' (unfalsifiable) hypotheses that arehard to negate and the ways for making it easy. Inthese cases the subject can ``rationally' decide towithdraw his hypotheses even in contexts where it is``impossible' to find ``explicit' contradictions: theuse of negation as failure (an interestingtechnique for negating hypotheses and accessing newones suggested by artificial intelligence) isilluminating. I plan to explore whether this kind ofnegation can be employed to model hypothesiswithdrawal in Poincaré's conventionalism of theprinciples of physics and in Freudian analyticreasoning.     

Chromosomal relationships among three species of jackrabbits ( Lepus : Leporidae) from Mexico

We studied differentially stained karyotypes of the leporids Lepus californicus, L. callotis, and L. flavigularis and described their banding patterns of euchromatin to decide whether results fit expectations of chromosomal rearrangements leading to the karyotypic evolution ancestral of the L. californicus--L. callotis--L. flavigularis lineage. Results confirmed previous findings on numbers of chromosomes (2 n 's) and fundamental numbers (FNs; except for L. californicus ). Homologous G-banding patterns allowed identification of chromosome rearrangements such as pericentric inversions and addition and deletion of euchromatin. Chromosomal rearrangements that we deduced mostly support hypotheses on karyotypic changes in the chromosomal evolution of the Lepus ancestral lineage that we examined. The karyotypic pattern coincides with patterns of geographic variation and distribution of the species examined.     

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.     

Isoform specific phosphorylation of p53 by protein kinase CK1

The ability of three isoforms of protein kinase CK1 (α, γ₁, and δ) to phosphorylate the N-terminal region of p53 has been assessed using either recombinant p53 or a synthetic peptide reproducing its 1–28 sequence. Both substrates are readily phosphoylated by CK1δ and CK1α, but not by the γ isoform. Affinity of full size p53 for CK1 is 3 orders of magnitude higher than that of its N-terminal peptide (K _m 0.82 μM vs 1.51 mM). The preferred target is S20, whose phosphorylation critically relies on E17, while S6 is unaffected despite displaying the same consensus (E-x-x-S). Our data support the concept that non-primed phosphorylation of p53 by CK1 is an isoform-specific reaction preferentially affecting S20 by a mechanism which is grounded both on a local consensus and on a remote docking site mapped to the K²²¹RQK²²⁴ loop according to modeling and mutational analysis.     

Structural features underlying the selectivity of the kinase inhibitors NBC and dNBC: role of a nitro group that discriminates between CK2 and DYRK1A

8-hydroxy-4-methyl-9-nitrobenzo(g)chromen-2-one (NBC) has been found to be a fairly potent ATP site-directed inhibitor of protein kinase CK2 (Ki = 0.22 μM). Here, we show that NBC also inhibits PIM kinases, especially PIM1 and PIM3, the latter as potently as CK2. Upon removal of the nitro group, to give 8-hydroxy-4-methyl-benzo(g)chromen-2-one (here referred to as “denitro NBC”, dNBC), the inhibitory power toward CK2 is almost entirely lost (IC₅₀ > 30 μM) whereas that toward PIM1 and PIM3 is maintained; in addition, dNBC is a potent inhibitor of a number of other kinases that are weakly inhibited or unaffected by NBC, with special reference to DYRK1A whose IC₅₀ values with NBC and dNBC are 15 and 0.60 μM, respectively. Therefore, the observation that NBC, unlike dNBC, is a potent inducer of apoptosis is consistent with the notion that this effect is mediated by inhibition of endogenous CK2. The structural features underlying NBC selectivity have been revealed by inspecting its 3D structure in complex with the catalytic subunit of Z. mays CK2. The crucial role of the nitro group is exerted both through a direct electrostatic interaction with the side chain of Lys68 and, indirectly, by enhancing the acidic dissociation constant of the adjacent hydroxyl group which interacts with a conserved water molecule in the deepest part of the cavity. By contrast, the very same nitro group is deleterious for the binding to the active site of DYRK1A, as disclosed by molecular docking. This provides the rationale for preferential inhibition of DYRK1A by dNBC.     

An extremely primitive star in the Galactic halo

The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z?相似文献