p21WAF1/CIP1 mutants deficient in inhibiting cyclin-dependent kinases (CDKs) can promote assembly of active cyclin D/CDK4(6) complexes in human tumor cells

The cyclin-dependent kinase (CDK) inhibitor p21WAF1/CIP1 is a multidomain, multifunctional protein and a candidate tumor suppressor. Here, we show that, among rationally designed and tumor-associated mutants of human p21 ectopically expressed in U-2-OS cells, those that are selectively deficient in binding to either cyclin or CDK are partially impaired in inhibiting endogenous CDK activities but efficiently promote assembly of active cyclin D/CDK4(6) complexes. These results provide mechanistic insights into the p21-cyclin/CDK interplay in vivo and suggest a functional subclassification of tumor-specific aberrations of p21. Intriguingly, the subclass exemplified by the melanoma-derived N50S mutant may promote tumorigenesis, by both attenuating CDK-inhibitory function and concomitantly activating the proto-oncogenic cyclin D-dependent kinases.     

BCL-1/cyclin D1 oncoprotein oscillates and subverts the G1 phase control in B-cell neoplasms carrying the t(11;14) translocation

In an effort to elucidate the biological role played by cyclin D1, a candidate BCL-1 oncogene, in human B-cell tumours carrying the t(11;14) translocation, we have studied the properties of this cyclin protein in a series of human lymphoid lines with rearrangements in the BCL-1 locus. The BCL-1/cyclin D1 protein was easily detectable in both immunocytochemistry and immunoblotting, its abundance grossly correlating with the mRNA levels. The cyclin D1 protein was localised predominantly to nuclei and there was a striking variation of staining intensity among the exponentially growing cells, reflecting the maximum level reached in mid/late G1 and the lowest level in S-phase. This characteristic mode of cell cycle-dependent oscillation was confirmed by three independent approaches, demonstrating that even upon rearrangement, the expression of cyclin D1 is regulated in a cyclical manner. Antibody-mediated and anti-sense oligonucleotide 'knockout' experiments revealed that the aberrantly expressed BCL-1/cyclin D1 protein is required for G1 phase progression of all four B-cell tumours with the BCL-1 rearrangement. Consistent with the proposed oncogenic role of this cyclin, our data demonstrate that the BCL-1 deregulation caused by chromosomal rearrangement leads to expression of a functionally active cyclin D1 protein which subverts the G1 phase control in the human B-cell tumours carrying the t(11;14) translocation.     

Reversal of sleep disturbances in cocaine- and heroin-dependent men during chronic buprenorphine treatment.

Changes in sleep architecture and continuity are frequent side effects of drugs of abuse, and complaints of poor sleep are often reported by recovering drug abusers. As part of a Phase 1 assessment of the safety and efficacy of 4 and 8 mg/day of buprenorphine treatment. the sleep patterns of 20 male opiate- and cocaine-dependent patients were quantified by using standard polysomnographic recordings. During the drug-free prebuprenorphine period, all participants had disrupted sleep architecture and continuity patterns characterized by a significant delay in sleep latency, reduced rapid-eye movement latency, reduced total sleep time, increased wake time after sleep onset, a reduced sleep efficiency index, and had little or no Stage 3 or Stage 4 slow-wave sleep. All of these sleep variables improved during low-dose buprenorphine, whereas only sleep latency was improved during high-dose buprenorphine treatment. These data suggest that buprenorphine either reverses or allows many of the sleep disturbances during withdrawal from opiates and cocaine to return to more "normal" values. These data further suggest that low-dose buprenorphine is more effective than a higher dose in normalizing sleep patterns. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interfacial Self‐Assembly of Amphiphilic Dual Temperature Responsive Actuating Janus Particles

Amphiphilic Janus particles feature the combination of two different functional materials in one single colloid, as well as the possibility of self‐assembly at interfaces into complex superstructures. In this article, the self‐assembly of dual temperature responsive amphiphilic Janus particles at liquid–liquid interfaces and their subsequent conversion into an actuating layer‐shaped surface are presented. These microparticles are produced in a capillaries based continuous flow microfluidic device by photoinitiated radical polymerization. The hydrophobic part of the Janus particles contains a liquid crystalline elastomer (LCE), which performs a strong actuation up to 95% during the nematic–isotropic phase transition. The other side consists of a p(NIPAAm) hydrogel, which features volumetric expansions up to 280% below the lower critical solution temperature. A multistep molding process is developed to uniformly align the Janus particles at a toluene/water boundary surface and to embed the particles into a hydrogel matrix. A particle covered hydrogel layer is obtained, which features a collective actuation of the rod‐like LCE parts on the surface and a bundling of the resulting forces during the phase transition.     

Design and Qualification of Pr–Fe–Cu–B Alloys for the Additive Manufacturing of Permanent Magnets

The direct use of an advanced binder-free additive manufacturing technique, namely laser powder bed fusion (L-PBF), does not easily allow obtaining variously shaped, fully dense Nd–Fe–B magnets with high coercivity. The process inherently leads to the re-melting of the powder and appearance/disappearance of undesired/desired microstructural features responsible for low and large coercivity. In this work, the development of a useful microstructure responsible for high coercivity in Pr₂₁Fe_73.5Cu₂B_3.5 and Nd₂₁Fe_73.5Cu₂B_3.5 alloys and a possible way to produce fully dense permanent magnets via additive manufacturing processes is demonstrated using: (i) suction casting technique, which provides a high cooling rate and thus similar microstructures as in L-PBF but requires only very small amounts of powder; (ii) conventional L-PBF processing using kg of powder, and (iii) a subsequent annealing treatment that is similar to a conventional sintering treatment. The subsequent heat treatment is necessary to develop high coercivity by forming a novel microstructure: hard magnetic (Nd,Pr)₂Fe₁₄B grains embedded in a matrix of intermetallic (Nd,Pr)₆Fe₁₃Cu phase. Furthermore, it is demonstrated that Pr₂₁Fe_73.5Cu₂B_3.5 exhibits a higher coercivity than Nd₂₁Fe_73.5Cu₂B_3.5 because of a finer and more homogeneous grain size distribution of the Pr₂Fe₁₄B phase. The final L-PBF printed Pr₂₁Fe_73.5Cu₂B_3.5 samples provide a coercivity of 0.75 T.     

Directed Emission from Self‐Assembled Microhelices

Bottom‐up assembly can organize simple building blocks into complex architectures for light manipulation. The optical properties of self‐assembled polycrystalline barium carbonate/silica double helices are studied using fluorescent Fourier and Mueller matrix microscopy. Helices doped with fluorescein direct light emission along the long axis of the structure. Furthermore, light transmission measured normal and parallel to the long axis exhibits twist sense‐specific circular retardance and waveguiding, respectively, although the measurements suffer from depolarization. The helices thus integrate highly directional emission with enantiomorph‐specific polarization. This optical response emerges from the arrangement of nanoscopic mineral crystallites in the microscopic helix, and demonstrates how bottom‐up assembly can achieve ordering across multiple length scales to form complex functional materials.     

Direct Patterning of Metal Chalcogenide Semiconductor Materials

Lithography is one of the most widely used methods for cutting‐edge research and industrial applications, mainly owing to its ability to draw patterns in the micro and even nanoscale. However, the fabrication of semiconductor micro/nanostructures via conventional electron or optical lithography technologies often requires a time‐consuming multistep process and the use of expensive facilities. Herein, a low‐cost, high‐resolution, facile, and versatile direct patterning method based on metal–organic molecular precursors is reported. The ink‐based metal–organic precursors are found to operate as negative resists, with the material exposed by different methods (electron‐beam/laser/heat/ultraviolet (UV)) to render them insoluble in the development process. This technical process can deliver metal chalcogenide semiconductors with arbitrary 2D/3D patterns with sub‐50 nm resolution. Electron beam lithography, two‐photon absorption lithography, thermal scanning probe lithography, and UV photolithography are demonstrated for the direct patterning process. Different metal chalcogenide semiconductor nanodevices, such as photoconductive selenium‐doped Sb₂S₃ nanoribbons, p‐type PbS single‐nanowire field‐effect transistors, and p‐n junction CdS/Cu₂S nanowire solar cells, are fabricated by this method. This direct patterning technique is a versatile and simple micro/nanolithography technology with considerable potential for “lab‐on‐a‐chip” preparation of semiconductor devices.     

Session-based item recommendation in e-commerce: on short-term intents,reminders, trends and discounts

Many e-commerce sites present additional item recommendations to their visitors while they navigate the site, and ample evidence exists that such recommendations are valuable for both customers and providers. Academic research often focuses on the capability of recommender systems to help users discover items they presumably do not know yet and which match their long-term preference profiles. In reality, however, recommendations can be helpful for customers also for other reasons, for example, when they remind them of items they were recently interested in or when they point site visitors to items that are currently discounted. In this work, we first adopt a systematic statistical approach to analyze what makes recommendations effective in practice and then propose ways of operationalizing these insights into novel recommendation algorithms. Our data analysis is based on log data of a large e-commerce site. It shows that various factors should be considered in parallel when selecting items for recommendation, including their match with the customer’s shopping interests in the previous sessions, the general popularity of the items in the last few days, as well as information about discounts. Based on these analyses we propose a novel algorithm that combines a neighborhood-based scheme with a deep neural network to predict the relevance of items for a given shopping session.