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Deregulation of cell proliferation is a hallmark of cancer. In many transformed cells, the cyclin A/CDK2 complex that contains S-phase kinase associated proteins 1 and 2 (SKP1 and SKP2) is highly induced. To determine the roles of this complex in the cell cycle regulation and transformation, we have examined the composition of this complex. We report here that this complex contained an additional protein, human CUL-1, a member of the cullin/CDC53 family. The identification of CUL-1 as a member of the complex raises the possibility that the p19(SKP1)/p45(SKP2)/CUL-1 complex may function as the yeast SKP1-CDC53-F-box (SCF) protein complex that acts as a ubiquitin E3 ligase to regulate the G1/S transition. In mammalian cells, cyclin D, p21(CIP1/WAF1), and p27(KIP1) are short-lived proteins that are controlled by ubiquitin-dependent proteolysis. To determine the potential in vivo targets of the p19(SKP1)/p45(SKP2)/CUL-1 complex, we have used the specific antisense oligodeoxynucleotides against either SKP1, SKP2, or CUL-1 RNA to inhibit their expression. Treatment of cells with these oligonucleotides caused the selective accumulation of p21 and cyclin D proteins. The protein level of p27 was not affected. These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. Aberrant expression of human p19(SKP1)/p45(SKP2)/CUL-1 complex thus may contribute to tumorigenesis by regulating the protein levels of G1 cell cycle regulators.

As the average age of our citizens rises, this book argues that success at ameliorating the effects of disability and age-related bias, prejudice, and discrimination requires a psycholegal approach that reconciles legal theory with psychological reality.

In a previous paper, we proposed a construction of \\(U_q(sl(2))\\) quantum group symmetry generators for 2d gravity, where we took the chiral vertex operators of the theory to be the quantum group covariant ones established in earlier works. The basic idea was that the covariant fields in the spin \\(1/2\\) representation themselves can be viewed as generators, as they act, by braiding, on the other fields exactly in the required way. Here we transform this construction to the more conventional description of 2d gravity in terms of Bloch wave/Coulomb gas vertex operators, thereby establishing for the first time its quantum group symmetry properties. A \\(U_q(sl(2))\\otimes U_q(sl(2))\\) symmetry of a novel type emerges: The two Cartan-generator eigenvalues are specified by the choice of matrix element (bra/ket Verma-modules); the two Casimir eigenvalues are equal and specified by the Virasoro weight of the vertex operator considered; the co-product is defined with a matching condition dictated by the Hilbert space structure of the operator product. This hidden symmetry possesses a novel Hopf like structure compatible with these conditions. At roots of unity it gives the right truncation. Its (non linear) connection with the \\(U_q(sl(2))\\) previously discussed is disentangled.

A simple connection between the universal \\(R\\) matrix of \\(U_q(sl(2))\\) (for spins \\(\\demi\\) and \\(J\\)) and the required form of the co-product action of the Hilbert space generators of the quantum group symmetry is put forward. This gives an explicit operator realization of the co-product action on the covariant operators. It allows us to derive the quantum group covariance of the fusion and braiding matrices, although it is of a new type: the generators depend upon worldsheet variables, and obey a new central extension of \\(U_q(sl(2))\\) realized by (what we call) fixed point commutation relations. This is explained by showing that the link between the algebra of field transformations and that of the co-product generators is much weaker than previously thought. The central charges of our extended \\(U_q(sl(2))\\) algebra, which includes the Liouville zero-mode momentum in a nontrivial way are related to Virasoro-descendants of unity. We also show how our approach can be used to derive the Hopf algebra structure of the extended quantum-group symmetry \\(U_q(sl(2))\\odot U_{\\qhat}(sl(2))\\) related to the presence of both of the screening charges of 2D gravity.

We investigate higher grading integrable generalizations of the affine Toda systems. The extra fields, associated to non zero grade generators, obey field equations of the Dirac type and are regarded as matter fields. The models possess soliton configurations, which can be interpreted as particles of the theory, on the same footing as those associated to fundamental fields. A special subclass of these models is remarkable. They possess a \\(U(1)\\) Noether current which, after a special gauge fixing of the conformal symmetry, is proportional to a topological current. This leads to the confinement of the matter field inside the solitons, which can be regarded as a one dimensional bag model for QCD. These models are also relevent to the study of electron self--localization in (quasi)-one-dimensional electron--phonon systems.

In a basket trial that included patients with a variety of cancers, all of which contained a BRAF V600 mutation, the rate of response to vemurafenib was highly variable. The histologic context influences the response to BRAF inhibition. BRAF V600 mutations occur in approximately 50% of cutaneous melanomas and result in constitutive activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway. 1 , 2 Vemurafenib (Zelboraf, F. Hoffmann–La Roche/Genentech) is a selective oral inhibitor of the BRAF V600 kinase and is associated with a response rate of approximately 50% and improved survival among patients with BRAF V600E mutation–positive metastatic melanoma. 3 Efforts by the Cancer Genome Atlas 4 and other initiatives to characterize the genetic landscape of most tumor types have identified BRAF V600 mutations in nonmelanoma cancers, including colorectal cancer, 5 , 6 non–small-cell lung cancer, 7 papillary thyroid cancer, 8 diffuse gliomas, . . .

Many placebo-controlled trials have demonstrated the efficacy of individual pharmacotherapies approved for smoking cessation. However, few direct or indirect comparisons of such interventions have been conducted. We performed a meta-analysis to compare the treatment effects of 7 approved pharmacologic interventions for smoking cessation. We searched the US Centers for Disease Control and Prevention's Tobacco Information and Prevention database as well as MEDLINE, EMBASE and the Cochrane Library for published reports of placebo-controlled, double-blind randomized controlled trials of pharmacotherapies for smoking cessation. We included studies that reported biochemically validated measures of abstinence at 6 and 12 months. We used a hierarchical Bayesian random-effects model to summarize the results for each intervention. We identified 70 published reports of 69 trials involving a total of 32 908 patients. Six of the 7 pharmacotherapies studied were found to be more efficacious than placebo: varenicline (odds ratio [OR] 2.41, 95% credible interval [CrI] 1.91-3.12), nicotine nasal spray (OR 2.37, 95% CrI 1.12-5.13), bupropion (OR 2.07, 95% CrI 1.73-2.55), transdermal nicotine (OR 2.07, 95% CrI 1.69-2.62), nicotine tablet (OR 2.06, 95% CrI 1.12-5.13) and nicotine gum (OR 1.71, 95% CrI 1.35-2.21). Similar results were obtained regardless of which measure of abstinence was used. Although the point estimate favoured nicotine inhaler over placebo (OR 2.17), these results were not conclusive because the credible interval included unity (95% CrI 0.95-5.43). When all 7 interventions were included in the same model, all were more efficacious than placebo. In our analysis of data from the varenicline trials that included bupropion control arms, we found that varenicline was superior to bupropion (OR 2.18, 95% CrI 1.09-4.08). Varenicline, bupropion and the 5 nicotine replacement therapies were all more efficacious than placebo at promoting smoking abstinence at 6 and 12 months.

One-dimensional (1D) interacting electronic systems exhibit distinct properties when compared to their counterparts in higher dimensions. We report Coulomb drag measurements between vertically integrated quantum wires separated by a barrier only 15 nanometers wide. The temperature dependence of the drag resistance is measured in the true 1D regime where both wires have less than one 1D subband occupied. As a function of temperature, an upturn in the drag resistance is observed below a temperature T* ∼ 1.6 kelvin. This crossover in Coulomb drag behavior is consistent with Tomonaga-Luttinger liquid models for the 1D-1D drag between quantum wires.

Background Salmonid species have followed markedly divergent evolutionary trajectories in their interactions with sea lice. While sea lice parasitism poses significant economic, environmental, and animal welfare challenges for Atlantic salmon ( Salmo salar ) aquaculture, coho salmon ( Oncorhynchus kisutch ) exhibit near-complete resistance to sea lice, achieved through a potent epithelial hyperplasia response leading to rapid louse detachment. The molecular mechanisms underlying these divergent responses to sea lice are unknown. Results We characterized the cellular and molecular responses of Atlantic salmon and coho salmon to sea lice using single-nuclei RNA sequencing. Juvenile fish were exposed to copepodid sea lice ( Lepeophtheirus salmonis ), and lice-attached pelvic fin and skin samples were collected 12 h, 24 h, 36 h, 48 h, and 60 h after exposure, along with control samples. Comparative analysis of control and treatment samples revealed an immune and wound-healing response that was common to both species, but attenuated in Atlantic salmon, potentially reflecting greater sea louse immunomodulation. Our results revealed unique but complementary roles of three layers of keratinocytes in the epithelial hyperplasia response leading to rapid sea lice rejection in coho salmon. Our results suggest that basal keratinocytes direct the expansion and mobility of intermediate and, especially, superficial keratinocytes, which eventually encapsulate the parasite. Conclusions Our results highlight the key role of keratinocytes in coho salmon’s sea lice resistance and the diverged biological response of the two salmonid host species when interacting with this parasite. This study has identified key pathways and candidate genes that could be manipulated using various biotechnological solutions to improve Atlantic salmon sea lice resistance.