Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies

PRICING AND INVESTMENT STRATEGY FOR DIGITAL TECHNOLOGY IN A SUPPLY CHAIN

This study addresses the problem of the pricing and investment strategy for smart technology under a supply chain with one manufacturer and one retailer. The models are constructed to investigate the strategic choices of supply chain members for investing in digital/smart technology under three scenarios: the M–system, wherein only the manufacturer fully pays for the investment cost; the S–system, wherein the manufacturer and retailer share the investment cost; and the R–system, wherein the retailer fully pays for the investment cost. We formulate analytical models to determine the optimal wholesale price, retail price and investment strategy in a Stackelberg game setting. Our findings show that the S–system is the most appropriate choice for both the manufacturer and retailer. We also suggest the appropriate investment sharing ratio to achieve Pareto improvement under such an arrangement

Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia-negative myeloproliferative neoplasm

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Evolution of the second lowest extended state as a function of the effective magnetic field in the fractional quantum hall regime

It has been shown that, at a Landau level filling factor v=1/2, a two-dimensional electron system can be mathematically transformed into a composite fermion system interacting with a Chern-Simons gauge field. At v=1/2, the average of this Chern-Simons gauge field cancels the external magnetic field B-ext so that the effective magnetic field B-eff acting on the composite fermions is zero. Away from v=1/2, the composite fermions experience a net effective magnetic field B-eff. We present the first study of the evolution of the second lowest extended state in a vanishing effective magnetic field in the fractional quantum Hall regime. Our result shows that the evolution of the second lowest extended state has a good linear dependence on the effective magnetic field Beff within the composite fermion picture

Quantification of the effects of architectural traits on dry mass production and light interception of tomato canopy under different temperature regimes using a dynamic functional-structural plant model

There is increasing interest in evaluating the environmental effects on crop architectural traits and yield improvement. However, crop models describing the dynamic changes in canopy structure with environmental conditions and the complex interactions between canopy structure, light interception, and dry mass production are only gradually emerging. Using tomato (Solanum lycopersicum L.) as a model crop, a dynamic functional-structural plant model (FSPM) was constructed, parameterized, and evaluated to analyse the effects of temperature on architectural traits, which strongly influence canopy light interception and shoot dry mass. The FSPM predicted the organ growth, organ size, and shoot dry mass over time with high accuracy (>85%). Analyses of this FSPM showed that, in comparison with the reference canopy, shoot dry mass may be affected by leaf angle by as much as 20%, leaf curvature by up to 7%, the leaf length: width ratio by up to 5%, internode length by up to 9%, and curvature ratios and leaf arrangement by up to 6%. Tomato canopies at low temperature had higher canopy density and were more clumped due to higher leaf area and shorter internodes. Interestingly, dry mass production and light interception of the clumped canopy were more sensitive to changes in architectural traits. The complex interactions between architectural traits, canopy light interception, dry mass production, and environmental conditions can be studied by the dynamic FSPM, which may serve as a tool for designing a canopy structure which is 'ideal' in a given environment.DFGDF

Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins

SummaryAs the key effector in the Hippo pathway, YAP was identified as an oncoprotein whose expression is elevated in various human cancers. However, the development of potentially therapeutic compounds targeting YAP has been slow and limited. Here, we find that tankyrase inhibitors suppress YAP activity. This effect is mediated by anigomotin (AMOT) family proteins. Tankyrases associate with AMOT family proteins and promote their degradation through E3 ligase RNF146. By antagonizing tankyrase activity, tankyrase inhibitors stabilize AMOT family proteins, thereby suppressing YAP oncogenic functions. Together, our studies not only demonstrate the tankyrase-RNF146-AMOT axis as an upstream pathway regulating YAP but also reveal a therapeutic opportunity in targeting YAP for cancer treatment

Facile Synthesis of High Quality Graphene Nanoribbons

Graphene nanoribbons have attracted attention for their novel electronic and spin transport properties1-6, and because nanoribbons less than 10 nm wide have a band gap that can be used to make field effect transistors. However, producing nanoribbons of very high quality, or in high volumes, remains a challenge. Here, we show that pristine few-layer nanoribbons can be produced by unzipping mildly gas-phase oxidized multiwalled carbon nanotube using mechanical sonication in an organic solvent. The nanoribbons exhibit very high quality, with smooth edges (as seen by high-resolution transmission electron microscopy), low ratios of disorder to graphitic Raman bands, and the highest electrical conductance and mobility reported to date (up to 5e2/h and 1500 cm2/Vs for ribbons 10-20 nm in width). Further, at low temperature, the nanoribbons exhibit phase coherent transport and Fabry-Perot interference, suggesting minimal defects and edge roughness. The yield of nanoribbons was ~2% of the starting raw nanotube soot material, which was significantly higher than previous methods capable of producing high quality narrow nanoribbons1. The relatively high yield synthesis of pristine graphene nanoribbons will make these materials easily accessible for a wide range of fundamental and practical applications.Comment: Nature Nanotechnology in pres

An Assessment Of Traditional Uighur Medicine In Current Xinjiang Region (China)

Background: The main objectives of this study were to assess the current research and development of traditional Uighur medicine in Xinjiang (China), and to evaluate the promising pharmacological products of traditional Uighur medicine for further studies.Materials and Methods: Traditional Uighur medicine data of medicine registry, patent, and academic publications was collected and analyzed.Results: Data showed that, among the registered and studied traditional Uighur medicine, the main therapeutic areas of traditional Uighur medicine focused on skin disease, urogenital disease, rheumatism and digestive system disease. The representative traditional Uighur patent medicine included the following: BaixuanXiatare Tablets, Kaliziran Tincture and Vernoniaanthelmintica Injection (Psoriasis and vitiligo); Xi-payimazibiziLiquid (prostatitis); KursiKaknaq (urinary tract infection); Tongzhisurunjiang Capsules (anti-rheumatism medicine); HuganBuzure Granules (digestive system disease). Moreover, ten Uighur herbs were widely used, including: ResinaScammoniae, Folium FumicisDentati, HerbaDracocephali, Semen AmygdaliDulcis, HerbaChamomillae, FructusPimpinellaeanisi, Cortex Foeniculi, FructusVernoniae, FructusApii, and Radix AnacycliPyrethri.Conclusion: This study concluded by indicating that traditional Uighur medicine with excellent curative effect should be screened in details for their phytochemical properties and pharmacological activity to discover new bioactive constituents.Key words: Traditional Uighur medicine, Traditional Uighur patent medicine, Uighur her

The two PPX-GppA homologues from Mycobacterium tuberculosis have distinct biochemical activities

Inorganic polyphosphate (poly-P), guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) are ubiquitous in bacteria. These molecules play a variety of important physiological roles associated with stress resistance, persistence, and virulence. In the bacterial pathogen Mycobacterium tuberculosis, the identities of the proteins responsible for the metabolism of polyphosphate and (p)ppGpp remain to be fully established. M. tuberculosis encodes two PPX-GppA homologues, Rv0496 (MTB-PPX1) and Rv1026, which share significant sequence similarity with bacterial exopolyphosphatase (PPX) and guanosine pentaphosphate 5′-phosphohydrolase (GPP) proteins. Here we delineate the respective biochemical activities of the Rv0496 and Rv1026 proteins and benchmark these against the activities of the PPX and GPP proteins from Escherichia coli. We demonstrate that Rv0496 functions as an exopolyphosphatase, showing a distinct preference for relatively short-chain poly-P substrates. In contrast, Rv1026 has no detectable exopolyphosphatase activities. Analogous to the E. coli PPX and GPP enzymes, the exopolyphosphatase activities of Rv0496 are inhibited by pppGpp and, to a lesser extent, by ppGpp alarmones, which are produced during the bacterial stringent response. However, neither Rv0496 nor Rv1026 have the ability to hydrolyze pppGpp to ppGpp; a reaction catalyzed by E. coli PPX and GPP. Both the Rv0496 and Rv1026 proteins have modest ATPase and to a lesser extent ADPase activities. pppGpp alarmones inhibit the ATPase activities of Rv1026 and, to a lesser extent, the ATPase activities of Rv0496. We conclude that PPX-GppA family proteins may not possess all the catalytic activities implied by their name and may play distinct biochemical roles involved in polyphosphate and (p)ppGpp metabolic pathways. © 2012 2012 Choi et al.published_or_final_versio

A cohort study of Chlamydia trachomatis treatment failure in women: A study protocol

Background: Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection in the developed world and diagnosis rates have increased dramatically over the last decade. Repeat infections of chlamydia are very common and may represent re-infection from an untreated partner or treatment failure. The aim of this cohort study is to estimate the proportion of women infected with chlamydia who experience treatment failure after treatment with 1 gram azithromycin.Methods/design: This cohort study will follow women diagnosed with chlamydia for up to 56 days post treatment. Women will provide weekly genital specimens for further assay. The primary outcome is the proportion of women who are classified as having treatment failure 28, 42 or 56 days after recruitment. Comprehensive sexual behavior data collection and the detection of Y chromosome DNA and high discriminatory chlamydial genotyping will be used to differentiate between chlamydia re-infection and treatment failure. Azithromycin levels in high-vaginal specimens will be measured using a validated liquid chromatography - tandem mass spectrometry method to assess whether poor azithromycin absorption could be a cause of treatment failure. Chlamydia culture and minimal inhibitory concentrations will be performed to further characterize the chlamydia infections. Discussion: Distinguishing between treatment failure and re-infection is important in order to refine treatment recommendations and focus infection control mechanisms. If a large proportion of repeat chlamydia infections are due to antibiotic treatment failure, then international recommendations on chlamydia treatment may need to be re-evaluated. If most are re-infections, then strategies to expedite partner treatment are necessary. © 2013 Hocking et al.; licensee BioMed Central Ltd