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Nobiletin Affects Circadian Rhythms and Oncogenic Characteristics in a Cell-Dependent Manner
No full textThe natural product nobiletin is a small molecule, widely studied with regard to its therapeutic effects, including in cancer cell lines and tumors. Recently, nobiletin has also been shown to affect circadian rhythms via their enhancement, resulting in protection against metabolic syndrome. We hypothesized that nobiletin’s anti-oncogenic effects, such as prevention of cell migration and formation of anchorage independent colonies, are correspondingly accompanied by modulation of circadian rhythms. Concurrently, we wished to determine whether the circadian and anti-oncogenic effects of nobiletin differed across cancer cell lines. In this study, we assessed nobiletin’s circadian and therapeutic characteristics to ascertain whether these effects depend on cell line, which here also varied in terms of baseline circadian rhythmicity. Three cell culture models where nobiletin’s effects on cell proliferation and migration have been studied previously were evaluated: U2OS (bone osteosarcoma), which possesses robust circadian rhythms; MCF7 (breast adenocarcinoma), which has weak circadian rhythms; and MDA-MB-231 (breast adenocarcinoma), which is arrhythmic. We found that circadian, migration, and proliferative effects following nobiletin treatment were subtle in the U2OS and MCF7 cells. On the other hand, changes were clear in MDA-MB-231s, where nobiletin rescued rhythmicity and substantially reduced oncogenic features, specifically two-dimensional cell motility and anchorage-independent growth. Based on these results and those previously described, we posit that the effects of nobiletin are indeed cell-type dependent, and that a positive correlation may exist between nobiletin’s circadian and therapeutic effects
Draft Genome of the Filarial Nematode Parasite \u3ci\u3eBrugia malayi\u3c/i\u3e
No full textParasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during ∼350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design
Differential AIP activation for precision and whole-hand visually-guided grasping
No full textBackground
Recent neuroimaging evidence suggests that, in humans, special mechanisms are engaged in the planning and execution of grasping movements.
Grasping requires a visuomotor transformation of object properties into a specific motor program, giving the hand a shape suitable to grasp the object: a fundamental role in this process is played by the anterior intraparietal area (AIP), whose selective involvement in grasping but not reaching actions has been demonstrated by several studies (Binkofski, 1998; Culham, 2004).
Thus, experimental evidence seems to converge on the hypothesis of a key role of AIP in the "hand-shaping" process. However, the extent to which different types of grasp are represented in the same or different cortical loci remains matter of debate. To date, no studies have considered the influence of object dimensions - and thus, the type of prehension required- on AIP involvement.
Methods
A functional magnetic resonance imaging study has been conducted. Spherical 3D plastic objects (3 and 6 cm) were presented, requiring either precision grip -thumb-index finger opposition- or whole-hand prehension: participants had to reach or grasp them.
Hypotheses
We hypothesize that the subtraction of the BOLD signal (Blood Oxygenation Level Dependent) detected for reaching trials from that detected for grasping trials should isolate brain areas responsible for the "hand-shaping" process.Vice versa, the subtraction of grasping-related activation from that detected for reaching trials should highlight areas engaged in inhibition of the act of prehension, presumably elicited by the vision of graspable objects (Handy, 2003).
Results
Results indicate that the two kinds of grasping actions are supported by different patterns of brain activations. AIP contribution seems to be significant only for actions requiring high level of precision: while for whole-hand prehension significant BOLD increase is restricted to primary motor cortex (BA 6) and cerebellum, precision grip involves also parietal areas, as the inferior parietal lobule (BA 40) and the post-central gyrus (BA 3).
The opposite contrast (reaching - grasping) underlines contribution of the right inferior frontal gyrus (BA 44, 45) and of the left superior frontal gyrus (BA 6). Increase of activity in these brain regions was detected only for actions performed toward the small object.
Conclusions
Our results are not in a complete agreement with the hypothesis emerging from the literature suggesting AIP as the "grasping area" in humans: its involvement seems to be necessary only when action goal requires high level of precision. Also prehension inhibition seems to be more demanding when occurring toward a small object than toward a bigger object
Taken together, our results suggest the hypothesis of a modulatory role of target dimension on brain activity supporting hand-object interactions
Reactions of Diazo Carbonyls with [PtX(CH3) (chiral diphosphine)] (X = Cl, Br, I): Chemoselectivity and Diastereoselectivity of Pt-C and Pt-X Carbene Insertion
No full textIn polar solvents (e.g. MeCN), ethyl diazoacetate reacts with [PtXMe(S,S-diop)], where X = Cl, Br, I, to give the corresponding [PtX(CHMeCO2Et)(S,S-diop)] as a 2:1 mixture of diastereoisomers in high yields. The major diastereoisomer of [PtCl(CHMeCO2Et)(S,S-diop)] is readily separated in crystalline form, and its crystal structure reveals that the configuration at the α-carbon is R; it is configurationally stable in CDCl3 for at least 14 days. The factors that influence the diastereoselectivity have been examined by comparing (by 31P NMR spectroscopy) the ratio of diastereoisomers formed in the reactions between [PtXMe(diphos*)] and N2CHCOR: X = Cl, Br, I; diphos* = S,S-diop, R,R-diop, S,S-skewphos, S,S-chiraphos; R = OEt, O(l-menthyl), Ph. In MeCN, the diastereoselectivity is independent of halogen but is a sensitive function of the chiral diphosphine and diazo carbonyl, though no systematic correlations have been divined. In solvents of lower polarity (e.g. CH2Cl2), diazo carbonyls react with [PtXMe(diphos*)] to give the products derived from Pt-X insertion as well as Pt-C insertion. When C6H6 is used as the solvent, the compounds [PtMe(CHICOR)(S,S-diop)], where R = OEt, O(l-menthyl), Ph, are formed in high yields and have been isolated. Redissolving these compounds in MeCN did not lead to isomerization to the Pt-C insertion species [PtI(CHMeCOR)(S,S-diop)]. Several trends have been found relating the extent of Pt-C insertion to the nature of the solvent and the structure of the reagents: the proportion of Pt-C insertion increases with (i) increasing polarity of the solvent (C6H6< CHCl3< CH2-Cl2< (CH3)2SO), (ii) increasing nucleofugacity of the halogen (I < Br < Cl), (iii) decreasing bite angle of the diphosphine (diop < chiraphos, skewphos), and (iv) diazo ketone < diazo ester. A mechanism which is consistent with these observations is discussed. Many of the compounds discussed here have been observed in solution only by 31P NMR, but representative species have been isolated and fully characterized by a combination of elemental analysis, IR spectroscopy, and 1H, 13C, 31P, and 195Pt NMR spectroscopy. © 1995, American Chemical Society. All rights reserved
Heat map for genes induced upon inhibition of Ssn3<sup>AS</sup> by 3-MB-PP1.
No full textTranscripts for seventy-three genes were 2-fold higher (pAS with 3-MB-PP1 compared to WT with 3-MB-PP1 and of Ssn3AS with 3-MB-PP1 compared to with the DMSO control. Genes are listed in order with the greatest magnitude difference between Ssn3AS with and without 3-MB-PP1 at the top. The heat map shows three replicates per sample of Log2-transformed counts per million for expressed transcripts.</p
Microscopic images of MNP aggregates orientation in MDA-MB-231 cells.
No full textOptical microscopy and TEM micrographs of the orientation of MDA-MB-231 cells incubated (A) at B0 = 4.7T magnetic field (i) optical image at 40x, (ii) TEM at 17,500x (scale bar, 500 nm), and (iii) TEM at 65,000x (scale bar, 100 nm), or (B) at a non-magnetic condition (i) optical image at 40x, (ii) TEM at 17,500x (scale bar, 500 nm), and (iii) TEM at 65,000x (scale bar, 100 nm).</p
Surface plasmon resonance (SPR) sensorgrams of S-MB or MB binding to immobilized Cys-S-MB or Cys-MB.
No full text<p>S-MB and MB, each with a cysteine added to its N-terminus, were attached to the thiol Biacore chip as described in the text. Solutions of S-MB or MB in HBS-EP buffer (i.e., 10 mM Hepes, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% surfactant P20) were then flowed over the respective chip-linked peptides. Typical SPR responses [Y-axis indicates the relative amount of binding in arbitrary response units (RU)] are shown for either 1 µg S-MB/ml buffer to chipped Cys-S-MB (black line) or chipped Cys-MB (green line), or with 1 µg MB/ml buffer to chipped Cys-S-MB (red line) or Cys-MB (blue line). Relative peptide affinities are: S-MB to S-MB ≫ S-MB to MB∼ MB to S-MB ∼ MB to MB.</p
Dehydration-driven solvent exposure of hydrophobic surfaces as a driving force in peptide folding
No full textRecent work has shown that the nature of hydration of pure hydrophobic surfaces changes with the length scale considered: water hydrogen-bonding networks adapt to small exposed hydrophobic species, hydrating or ‘‘wetting’’ them at relatively high
densities, whereas larger hydrophobic areas are ‘‘dewetted’’
[Chandler D (2005), Nature 29:640 – 647]. Here we determine whether this effect is also present in peptides by examining the
folding of a beta-hairpin (the 14-residue amyloidogenic prion protein
H1 peptide), using microsecond time-scale molecular dynamics
simulations. Two simulation models are compared, one explicitly
including the water molecules, which may thus adapt locally to
peptide configurations, and the other using a popular continuum
approximation, the generalized Born/surface area implicit solvent
model. The results obtained show that, in explicit solvent, peptide
conformers with high solvent-accessible hydrophobic surface area
indeed also have low hydration density around hydrophobic residues, whereas a concomitant higher hydration density around
hydrophilic residues is observed. This dewetting effect stabilizes
the fully folded beta-hairpin state found experimentally. In contrast,
the implicit solvent model destabilizes the fully folded hairpin, tending to cluster hydrophobic residues regardless of the size of
the exposed hydrophobic surface. Furthermore, the rate of the
conformational transitions in the implicit solvent simulation is
almost doubled with respect to that of the explicit solvent. The
results suggest that dehydration-driven solvent exposure of hydrophobic surfaces may be a significant factor determining peptide
conformational equilibria
The INFIR Cohort Study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in North India
No full textThe aim of this study was to find predictors of neuropathy and reactions, determine the most sensitive methods for detecting peripheral neuropathy, study the pathogenesis of neuropathy and reactions and create a bank of specimen, backed up by detailed clinical documentation. A multi-centre cohort study of 303 multibacillary leprosy patients in Northern India was followed for 2 years. All newly registered MB patients requiring a full course of MDT, who were smear positive and/or had six or more skin lesions and/or had two or more nerve trunks involved, were eligible. A detailed history was taken and physical and neurological examinations were performed. Nerve function was assessed at each visit with nerve conduction testing, warm and cold detection thresholds, vibrometry, dynamometry, monofilaments and voluntary muscle testing. Because the latter two are widely used in leprosy clinics, they were used as ‘gold standard’ for sensory and motor impairment. Other outcome events were type 1 and 2 reactions and neuritis. All subjects had a skin biopsy at registration, repeated at the time of an outcome event, along with a skin biopsy at registration, repeated at the time of an outcome event, along with a nerve biopsy. These were examined using a variety immunohistological techniques. Blood sampling for serological testing was done at every 4-weekly clinic visit. At diagnosis, 115 patients had an outcome event of recent onset. Many people had skin lesions overlying a major nerve trunk, which were shown to be significantly associated with an increased of sensory or motor impairment. The most important adjusted odds ratios for motor impairment were, facial 4.5 (1.3-16) and ulnar 3.5 (1.0-8.5); for sensory impairment they were, ulnar 2.9 (1.3-6.5), median 3.6 (1.1-12) and posterior tibial 4.0 (1.8-8.7). Nerve enlargement was found in 94% of patients, while only 24% and 3% had paraesthesia and nerve tenderness on palpation, respectively. These increased the risk of reactions only marginally. Seven subjects had abnormal tendon reflexes and seven abnormal joint position sense. In all but one case, there impairments were accompanied by abnormalities in two or more other nerve function tests and thus seemed in indicate more serve neuropathy. At diagnosis, 38% of a cohort of newly diagnosed MB leprosy patients had recent or new reactions or nerve damage at the time of intake into the study. The main risk factor for neuropathy found in this baseline analysis was the presence of skin lesions overlying nerve trunks. They increased the risk of sensory or motor impairment in the concerned nerve by 3-4 times. For some nerves, reactional signs in the lesions further increased this risk to 6-8 times the risk for those without such lesions. Patients with skin lesions overlying peripheral nerve trunks should be carefully monitored for development of sensory or motor impairment
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