LNK (SH2B3): paradoxical effects in ovarian cancer.

LNK (SH2B3) is an adaptor protein studied extensively in normal and malignant hematopoietic cells. In these cells, it downregulates activated tyrosine kinases at the cell surface resulting in an antiproliferative effect. To date, no studies have examined activities of LNK in solid tumors. In this study, we found by in silico analysis and staining tissue arrays that the levels of LNK expression were elevated in high-grade ovarian cancer. To test the functional importance of this observation, LNK was either overexpressed or silenced in several ovarian cancer cell lines. Remarkably, overexpression of LNK rendered the cells resistant to death induced by either serum starvation or nutrient deprivation, and generated larger tumors using a murine xenograft model. In contrast, silencing of LNK decreased ovarian cancer cell growth in vitro and in vivo. Western blot studies indicated that overexpression of LNK upregulated and extended the transduction of the mitogenic signal, whereas silencing of LNK produced the opposite effects. Furthermore, forced expression of LNK reduced cell size, inhibited cell migration and markedly enhanced cell adhesion. Liquid chromatography-mass spectroscopy identified 14-3-3 as one of the LNK-binding partners. Our results suggest that in contrast to the findings in hematologic malignancies, the adaptor protein LNK acts as a positive signal transduction modulator in ovarian cancers

Heat dissipation in atomic-scale junctions

Atomic and single-molecule junctions represent the ultimate limit to the miniaturization of electrical circuits. They are also ideal platforms to test quantum transport theories that are required to describe charge and energy transfer in novel functional nanodevices. Recent work has successfully probed electric and thermoelectric phenomena in atomic-scale junctions. However, heat dissipation and transport in atomic-scale devices remain poorly characterized due to experimental challenges. Here, using custom-fabricated scanning probes with integrated nanoscale thermocouples, we show that heat dissipation in the electrodes of molecular junctions, whose transmission characteristics are strongly dependent on energy, is asymmetric, i.e. unequal and dependent on both the bias polarity and the identity of majority charge carriers (electrons vs. holes). In contrast, atomic junctions whose transmission characteristics show weak energy dependence do not exhibit appreciable asymmetry. Our results unambiguously relate the electronic transmission characteristics of atomic-scale junctions to their heat dissipation properties establishing a framework for understanding heat dissipation in a range of mesoscopic systems where transport is elastic. We anticipate that the techniques established here will enable the study of Peltier effects at the atomic scale, a field that has been barely explored experimentally despite interesting theoretical predictions. Furthermore, the experimental advances described here are also expected to enable the study of heat transport in atomic and molecular junctions, which is an important and challenging scientific and technological goal that has remained elusive.Comment: supporting information available in the journal web site or upon reques

Evaluation of subsidence, chondrocyte survival and graft incorporation following autologous osteochondral transplantation

Contains fulltext : 95878.pdf (publisher's version ) (Open Access)PURPOSE: The aim of this study was to evaluate subsidence tendency, surface congruency, chondrocyte survival and plug incorporation after osteochondral transplantation in an animal model. The potential benefit of precise seating of the transplanted osteochondral plug on the recipient subchondral host bone ('bottoming') on these parameters was assessed in particular. METHODS: In 18 goats, two osteochondral autografts were harvested from the trochlea of the ipsilateral knee joint and inserted press-fit in a standardized articular cartilage defect in the medial femoral condyle. In half of the goats, the transplanted plugs were matched exactly to the depth of the recipient hole (bottomed plugs; n = 9), whereas in the other half of the goats, a gap of 2 mm was left between the plugs and the recipient bottom (unbottomed plugs; n = 9). After 6 weeks, all transplants were evaluated on gross morphology, subsidence, histology, and chondrocyte vitality. RESULTS: The macroscopic morphology scored significantly higher for surface congruency in bottomed plugs as compared to unbottomed reconstructions (P = 0.04). However, no differences in histological subsidence scoring between bottomed and unbottomed plugs were found. The transplanted articular cartilage of both bottomed and unbottomed plugs was vital. Only at the edges some matrix destaining, chondrocyte death and cluster formation was observed. At the subchondral bone level, active remodeling occurred, whereas integration at the cartilaginous surface of the osteochondral plugs failed to occur. Subchondral cysts were found in both groups. CONCLUSIONS: In this animal model, subsidence tendency was significantly lower after 'bottomed' versus 'unbottomed' osteochondral transplants on gross appearance, whereas for histological scoring no significant differences were encountered. Since the clinical outcome may be negatively influenced by subsidence, the use of 'bottomed' grafts is recommended for osteochondral transplantation in patients

Attenuation Imaging with Pulse-Echo Ultrasound based on an Acoustic Reflector

Ultrasound attenuation is caused by absorption and scattering in tissue and is thus a function of tissue composition, hence its imaging offers great potential for screening and differential diagnosis. In this paper we propose a novel method that allows to reconstruct spatial attenuation distribution in tissue based on computed tomography, using reflections from a passive acoustic reflector. This requires a standard ultrasound transducer operating in pulse-echo mode, thus it can be implemented on conventional ultrasound systems with minor modifications. We use calibration with water measurements in order to normalize measurements for quantitative imaging of attenuation. In contrast to earlier techniques, we herein show that attenuation reconstructions are possible without any geometric prior on the inclusion location or shape. We present a quantitative evaluation of reconstructions based on simulations, gelatin phantoms, and ex-vivo bovine skeletal muscle tissue, achieving contrast-to-noise ratio of up to 2.3 for an inclusion in ex-vivo tissue.Comment: Accepted at MICCAI 2019 (International Conference on Medical Image Computing and Computer Assisted Intervention

Research on an online self-organizing radial basis function neural network

A new growing and pruning algorithm is proposed for radial basis function (RBF) neural network structure design in this paper, which is named as self-organizing RBF (SORBF). The structure of the RBF neural network is introduced in this paper first, and then the growing and pruning algorithm is used to design the structure of the RBF neural network automatically. The growing and pruning approach is based on the radius of the receptive field of the RBF nodes. Meanwhile, the parameters adjusting algorithms are proposed for the whole RBF neural network. The performance of the proposed method is evaluated through functions approximation and dynamic system identification. Then, the method is used to capture the biochemical oxygen demand (BOD) concentration in a wastewater treatment system. Experimental results show that the proposed method is efficient for network structure optimization, and it achieves better performance than some of the existing algorithms

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression

The OMERACT Core Domain Set for Clinical Trials of Shoulder Disorders.

OBJECTIVE:To reach consensus on the core domains to be included in a core domain set for clinical trials of shoulder disorders using the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Core Domain Set process. METHODS:At OMERACT 2018, the OMERACT Shoulder Working Group conducted a workshop that presented the OMERACT 2016 preliminary core domain set and its rationale based upon a systematic review of domains measured in shoulder trials and international Delphi sessions involving patients, clinicians, and researchers, as well as a new systematic review of qualitative studies on the experiences of people with shoulder disorders. After discussions in breakout groups, the OMERACT core domain set for clinical trials of shoulder disorders was presented for endorsement by OMERACT 2018 participants. RESULTS:The qualitative review (n = 8) identified all domains included in the preliminary core set. An additional domain, cognitive dysfunction, was also identified, but confidence that this represents a core domain was very low. The core domain set that was endorsed by the OMERACT participants, with 71% agreement, includes 4 "mandatory" trial domains: pain, function, patient global - shoulder, and adverse events including death; and 4 "important but optional" domains: participation (recreation/work), sleep, emotional well-being, and condition-specific pathophysiological manifestations. Cognitive dysfunction was voted out of the core domain set. CONCLUSION:OMERACT 2018 delegates endorsed a core domain set for clinical trials of shoulder disorders. The next step includes identification of a core outcome measurement set that passes the OMERACT 2.1 Filter for measuring each domain

Nanoscale Dynamics of Phase Flipping in Water near its Hypothesized Liquid-Liquid Critical Point

Achieving a coherent understanding of the many thermodynamic and dynamic anomalies of water is among the most important unsolved puzzles in physics, chemistry, and biology. One hypothesized explanation imagines the existence of a line of first order phase transitions separating two liquid phases and terminating at a novel "liquid-liquid" critical point in a region of low temperature ($T \approx 250 \rm{K}$) and high pressure ($P \approx 200 \rm{MPa}$). Here we analyze a common model of water, the ST2 model, and find that the entire system flips between liquid states of high and low density. Further, we find that in the critical region crystallites melt on a time scale of nanoseconds. We perform a finite-size scaling analysis that accurately locates both the liquid-liquid coexistence line and its associated liquid-liquid critical point.Comment: 22 pages, 5 figure