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Intracellular accumulation of misfolded proteins causes serious human proteinopathies. The transmembrane emp24 domain 9 (TMED9) cargo receptor promotes a general mechanism of cytotoxicity by entrapping misfolded protein cargos in the early secretory pathway. However, the molecular basis for this TMED9-mediated cargo retention remains elusive. Here, we report cryo-electron microscopy structures of TMED9, which reveal its unexpected self-oligomerization into octamers, dodecamers, and, by extension, even higher-order oligomers. The TMED9 oligomerization is driven by an intrinsic symmetry mismatch between the trimeric coiled coil domain and the tetrameric transmembrane domain. Using frameshifted Mucin 1 as an example of aggregated disease-related protein cargo, we implicate a mode of direct interaction with the TMED9 luminal Golgi-dynamics domain. The structures suggest and we confirm that TMED9 oligomerization favors the recruitment of coat protein I (COPI), but not COPII coatomers, facilitating retrograde transport and explaining the observed cargo entrapment. Our work thus reveals a molecular basis for TMED9-mediated misfolded protein retention in the early secretory pathway. [ABSTRACT FROM AUTHOR]

Objective: To compare the incidence and risk factors of superior facet joint violation (FJV) during cortical bone trajectory screw placement in robot‐assisted approach versus conventional technique. Methods: A retrospective study, including 69 patients having cortical bone trajectory (CBT) screw instrumentation for symptomatic degenerated diseases or trauma, was conducted between June 2015 to January 2019. All patients underwent CBT surgery performed by the same team of experienced surgeons. Patients were randomly divided into two groups: a conventional group (CG, 46 cases) and a robot group (RG, 23 cases). The surgical robotic system was used for screw instrumentation in the robot group and the traditional screw instrumentation with fluoroscopic guidance was used in the conventional group. Cortical screws followed a medio‐to‐lateral path in the transverse plane and a caudal‐to‐cephalad path in the sagittal plane. Preoperative and postoperative computed tomography (CT) scans were obtained to determine the degree and incidence of FJV. The violation status of facet joint was evaluated according to the modified classification: grade 0, no violation; grade 1, screw shaft, screw head or rod within 1 mm of or abutting the facet joint, but did not enter the articular facet joint; grade 2, screw shaft, screw head or rod clearly in the facet joint. The following factors that may contribute to the occurrence of FJV were analyzed: age, sex, body mass index (BMI), proximal fusion level, fusion length, the side of screw, preoperative vertebral slip, superior facet angle, and degenerative scoliosis. The chi‐squared test and Student's t‐test were used for analysis of the variables for significance (P < 0.05). Results: FJV occurred in 41.3% of patients in CG and 17.3% of patients in RG. A chi‐squared analysis revealed a significantly lower rate of FJV for RG compared with CG (P = 0.04). In the CG, 17 of the 109 cephalad screws were grade 1 (15.6%), and five were grade 2 (4.6%). In the RG, three of the 46 cephalad screws were grade 1 (6.5%), and three were grade 2 (6.5%). There was a statistically significant difference in the incidence of FJV between the left and right screw with fluoroscopy‐assisted CBT screw instrumentation (P < 0.05). A significant correlation between scoliosis with the FJV was found in CG (P < 0.05) and in RG (P < 0.05). With regard to superior facet angle, a measurement ≥45° was a significant risk factor of FJV in CG (P < 0.05) and in RG (P < 0.05). Conclusions: A robot‐assisted approach could reduce the incidence of FJV compared with the conventional approach in CBT technique. [ABSTRACT FROM AUTHOR]

Abstract: An “off‐the‐shelf” hydrogel with high‐efficiency shape memory property is designed on the basis of the dynamic borax‐diol chemistry. The system is facilely prepared from only several unmodified commercially available components: acrylamide (AAm), bis‐acrylamide (Bis), poly(vinyl alcohol) (PVA), and borax. The chemically crosslinked poly(acrylamide) network works to fix the permanent shapes of the hydrogel, while the dynamic PVA–borax boronate ester bonds serve as the reversible crosslinks to memorize the deformed temporary shapes. Retreatment of the hydrogel in acid/glucose solutions dissipates the PVA–borax ester bonds to recover its permanent shape. Because of the highly invertible nature of borax‐diol chemistry, the developed hydrogel system is characterized by high shape memory/recovery ratios, continuously adjusted shape memory/recovery rates, thus having a wealth of potential applications. [ABSTRACT FROM AUTHOR]

Abstract: Realization of shape memory process in polymeric hydrogels at ambient condition is a significant development to shape memory materials. The sound understanding of the dynamic shape memory process is fundamentally important but limited. Here, a novel shape memory hydrogel with simultaneously switchable fluorescence behavior is developed. The hydrogel is prepared by incorporating a pH‐responsive fluorescent molecule, perylene tetracarboxylic acid, into chitosan‐based hydrogel, and the assembly and disassembly of chitosan chains into microcrystals upon the trigger of pH are applied as reversible crosslinks to achieve shape memory effect. Therefore, the formation and disassociation of microcrystalline chitosan, and the switchable fluorescence performance happen concurrently, which bring convenience to monitoring the shape memory process by fluorescent imaging. Moreover, the erasable fluorescence behavior also gives the hydrogel potential applications in information storage. [ABSTRACT FROM AUTHOR]

Abstract: Although shape memory polymers have been highlighted widely and developed rapidly, it is still a challenging task to realize complex temporary shapes automatically in practical applications. Herein, a novel shape memory hydrogel with the ability of self‐deformation is presented. Through constructing an anisotropic poly(acrylic acid)–polyacrylamide (PAAc–PAAm) structure, the obtained hydrogel exhibits stable self‐deformation behavior in response to pH stimulus, and the shapes that formed automatically can be fixed by the coordination between carboxylic groups and Fe3+; therefore, self‐deformation and shape memory behaviors are integrated in one system. Moreover, the magnitude of auto‐deformation and shape memory could be adjusted with the concentration of corresponding ions, leading to programmable shape memory and shape recovery processes. [ABSTRACT FROM AUTHOR]

This paper considers the detection of a distributed target in a partial observation scenario. A distributed targetmodel is usually adopted when the target size is larger than the range bin, for example, in some high-resolution radars. Based on the distributed target model, joint processing of several consecutive range bins can be adopted to achieve performance improvement with respect to processing just one range bin. In applications in complex electromagnetic environments, the radars may miss some of their observations, a phenomenon that usually caused by interference, spectrum sharing, and so on. This partial observation problem leads to degradation of the estimation accuracy for the disturbance (clutter plus noise) covariance matrix and target amplitude vector, which results in decline of the target detection performance. In this paper, a scheme is proposed by using the low-rank priori knowledge of clutter covariance matrix to estimate the detector's unknown parameters. Specifically, the target amplitude vector is obtained by maximizing the likelihood function, and the disturbance covariance matrix is reconstructed by solving an optimization that considers both the likelihood maximization and low-rank property of the clutter covariance matrix. The simulation results indicate that this algorithm improves the estimation accuracy, and achieves a better detection performance in the partial observation scenarios. [ABSTRACT FROM AUTHOR]

Identifying conservation units is crucial for the effective conservation of threatened species. Previous cases are almost exclusively based on large‐scale but coarse sampling for genetic structure analyses. Significant genetic structure can occur within a small range, and thus multiple conservation units may exist in narrowly distributed plants. However, small‐scale genetic structure is often overlooked in conservation planning especially for wind‐pollinated and wind‐dispersed trees, largely due to the absence of dense and elaborate sampling. In this study, we focused on a representative endangered relict plant, Metasequoia glyptostroboides. Using both nuclear microsatellites (nSSRs) and chloroplast DNA (cpDNA) fragments, we sampled across the narrow distribution range of this species and determined its conservation units by exploring its genetic structure and historical demography. cpDNA haplotypes were classified into two groups, but mixed in space, suggesting that the existent wild trees of M. glyptostroboides cannot be divided into different evolutionarily significant units. However, using nSSRs, we detected strong spatial genetic structure, with significant genetic differentiation and weak gene flow between the samples in the east of the species' distribution range and other samples. The divergence between the two nSSR groups was dated to the Last Glacial Maximum (c. 19.6 kya), suggesting that such spatial genetic structure has been maintained for a long term. Therefore, these two nSSR groups should be considered as different conservation units, that is, management units, to protect intergroup genetic variations, which is likely to be the outputs of local adaptation. Our findings highlight the necessity to reveal small‐scale genetic structure and population demography to improve the conservation strategies of evolutionary potential of endangered plants. [ABSTRACT FROM AUTHOR]

MoS2 nanomaterial has unique properties, including innate affinity with ss-DNA and quenching ability for fluorescence dyes. Here, we present the development of a simple fluorescence biosensor based on water-soluble MoS2 nanosheets and restriction endonuclease BstUI for methylation analysis of p16 promoter. The biosensing platform exhibited excellent sensitivity in detecting DNA with a linear range of 100 pM~20 nM and a detection limit of 140 pM. More importantly, our method could distinguish as low as 1% difference in methylation level. Compared with previous methylation analysis, our design is both time saving and simple to operate, avoiding the limitations of PCR-based assays without compromising performance. [ABSTRACT FROM AUTHOR]

This study investigated the impact of different drying methods on Eucommia ulmoides Oliver male flowers (EUOMF), which were separately dried by hot air drying (HAD), microwave drying (MWD), and vacuum freeze drying (VFD) methods under different conditions. The results of HPLC showed that the geniposide (GP), and VB2 in the stamens were higher than those in the whole flowers. The contents of CGA, GPA, and GP in the stamens treated by MWD were 1.68, 1.52, and 5.88 times of those treated by HAD. However, compared with HAD, the destroy degree of free amino acid in MWD is up to 80%. VB2 and VE are the most damaged by VFD. The contents of VB2 and VE in the stamens treated by HAD were 11.5 and 1.85 times of those treated by VFD. Emphatically, principal component analysis indicated that the optimal drying conditions was MWD. Based on the economic efficiency, MWD is more suitable to produce the EUOMF tea than other methods for industrialization process. [Display omitted] • The EUOMF were subjected to hot air, microwave, and vacuum freeze drying methods. • The quality of EUOMF tea derived from different parts were systematically analyzed. • The maximum content of geniposidic acid in EUOMF reached 27.22 mg/g. • PCA and economic assessment indicated that the optimal drying method was MWD. [ABSTRACT FROM AUTHOR]

Background Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. Methods A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27Kip1, Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Results Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft–bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs dasatinib: 0.28 vs 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27Kip1 decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs p27Kip1 siRNA: 42.5% vs 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27Kip1 enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Conclusion Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27Kip1-mediated suppression of Bcl-2 and Cdk1 expression. [ABSTRACT FROM PUBLISHER]

Background: The proteasome inhibitor bortezomib represents an important advance in the treatment of multiple myeloma (MM). Bortezomib inhibits the activity of the 26S proteasome and induces cell death in a variety of tumor cells; however, the mechanism of cytotoxicity is not well understood. Methodology/Principal Findings: We investigated the differential phosphoproteome upon proteasome inhibition by using stable isotope labeling by amino acids in cell culture (SILAC) in combination with phosphoprotein enrichment and LC-MS/ MS analysis. In total 233 phosphoproteins were identified and 72 phosphoproteins showed a 1.5-fold or greater change upon bortezomib treatment. The phosphoproteins with expression alterations encompass all major protein classes, including a large number of nucleic acid binding proteins. Site-specific phosphopeptide quantitation revealed that Ser38 phosphorylation on stathmin increased upon bortezomib treatment, suggesting new mechanisms associated to bortezomib-induced apoptosis in MM cells. Further studies demonstrated that stathmin phosphorylation profile was modified in response to bortezomib treatment and the regulation of stathmin by phosphorylation at specific Ser/Thr residues participated in the cellular response induced by bortezomib. Conclusions/Significance: Our systematic profiling of phosphorylation changes in response to bortezomib treatment not only advanced the global mechanistic understanding of the action of bortezomib on myeloma cells but also identified previously uncharacterized signaling proteins in myeloma cells. [ABSTRACT FROM AUTHOR]

The α preformation factor and penetration probability have been analyzed for even-even nuclei of Po, Rn, Ra using experimental released energies and α decay half-lives in the frame of the double folding model. It is shown that N = 126 is a neutron magic number from α preformation and shell effects play an important role in α preformation. The closer the nucleon number is to the magic number, the more difficult α formation in the parent nucleus is. The preformation factor can supply information on the nuclear structure and the penetration probability mainly determines α decay half-life. [ABSTRACT FROM AUTHOR]

Coulomb potentials for spherical-deformed reaction partners are calculated in terms of the double folding model as well as the conventional formulas. Our results show that the Coulomb potentials calculated with different approaches have quite different behaviours in the internal region of the potential. Because fusion process is sensitive to the barrier height and the internal part of the potential, the fusion excitation function, especially the fusion barrier distribution, should provide a strict test of the interaction potentials. Therefore, we calculate the fusion excitation function and barrier distribution for the 16O+154 Sm system with different versions of the Coulomb potentials, in comparison with the experimental results. It is found that the fusion excitation function and barrier distribution of 16O+154 Sm are obviously different for the different versions of the Coulomb potentials. By means of this comparison, we may conclude that the double folding model with the accurate approximate form can provide rather reasonable Coulomb potentials. [ABSTRACT FROM AUTHOR]

Abstract: Ni3Al base alloy was irradiated by intense pulsed ion beam (IPIB) with 250kV acceleration voltage, 100–200A/cm2 current density and 60ns pulse duration. The surface morphology and the cross-section microstructures were observed with SEM, and the compositions were characterized by XEDS. The results showed that the appearance of craters induced by irradiation is one of the major factors affecting the irradiated surface roughness; irradiation leads to composition changes on the surface of IC6 alloy and may improve mechanical properties of IC6 alloy. [Copyright &y& Elsevier]

The 70 kDa ribosomal S6 kinase (p70S6K) is important for cell growth and survival. Activation of p70S6K requires sequential phosphorylation of multiple serine and threonine sites often triggered by growth factors and hormones. Here, we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis and Western blot analysis by serine-/threonine-specific antibodies further confirms that both serine and threonine residues are phosphorylated in p70S6K following treatment with paclitaxel. Paclitaxel-induced p70S6KT421/S424 phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca++, PI3K, and mammalian target of rapamycin (mTOR). Despite phosphorylation of p70S6KT421/S424, paclitaxel inactivates this kinase in a concentration- and time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of mTOR, PI3K, and Ca++ impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxel-induced p70S6K inactivation. Moreover, the paclitaxel-induced phosphorylation and low activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able to induce p70S6KT421/S424 phosphorylation and decrease its activity in mitotic cells via multiple signaling pathways. Our data suggest that paclitaxel-induced p70S6KT421/S424 phosphorylation and kinase inactivation are differentially regulated. Our data also indicate that paclitaxel may exert its antitumor effect, at least in part, via inhibition of p70S6K.Oncogene (2003) 22, 484–497. doi:10.1038/sj.onc.1206175 [ABSTRACT FROM AUTHOR]

Heregulins are a group of growth factors that play diverse and critical roles in the signaling network of the human epidermal growth factor receptor (HER or EGFR) superfamily. Our earlier studies have shown that recombinant heregulinβ1 (HRG) induces apoptosis in SKBr3 breast cancer cells that overexpress HER2. Here we report molecular mechanisms of HRG-induced apoptosis. HRG treatment of SKBr3 cells for 72 h decreased the level of Bcl-2 protein. HRG treatment led to degradation of poly (ADP-ribose) polymerase (PARP) and activated both caspase-9 and caspase-7. No significant activation of caspase-3, -6, or -8 was detected. Expression of exogenous caspase-7 by adenovirus-caspase-7 (Ad-casp-7) in SKBr3 cells resulted in apoptosis, which mimicked the effect of HRG treatment. Expression of exogenous caspase-7 had no impact on Bcl-2 expression, but promoted PARP degradation. Two highly selective inhibitors of protein kinase C (PKC), GF109203X (GF) and Ro318425 (Ro), significantly enhanced HRG-induced apoptosis as determined by flow cytometric analysis and DNA fragmentation assay. Accordingly, the PKC inhibitor GF further decreased the level of Bcl-2 protein and further degraded PARP in HRG-treated cells. Assay of PKC activity indicated that HRG activated PKC in SKBr3 cells, predominantly affecting the PKCα isoform. To confirm which PKC isoform(s) mediated potentiation of HRG-induced apoptosis, the profile of PKC isoforms was measured in SKBr3 cells. Five PKC isoforms, PKCα, PKCι, PKCζ, PKCλ, and PKCδ as well as their receptors (RACK1) were expressed in this cell line. Treatment with PKC inhibitors GF and Ro decreased protein levels of both PKCα and PKCδ at 24 h. PKCα levels were still depressed at 72 h. GF and Ro had little effect on the expression of other PKC isoforms. An inhibitor of classical PKC isoforms (Go6976) enhanced HRG-induced apoptosis, whereas the PKCδ selective inhibitor rottlerin did not. As... [ABSTRACT FROM AUTHOR]

PH and Thermo Dual-Responsive Fluorescent Hydrogel Actuator GLO:OLR/01oct21:marc202100527-fig-0001.jpg PHOTO (COLOR): 5 a) Illustration showing the thermo-induced actuating process. b-c) Shape deformation behavior: by changing the UV-irradiated domains of straight hydrogels, and putting the hydrogels into warm water, different numbers "1" "2" "3" "4" "5" "6" "7" "8" "9" can be achieved. B 2019 b , 40, 1800648 https://doi.org/10.1002/marc.201800648 In the original version of this article, the images in Figure 5c were incorrection for "2", "5", "6" and "9". [Extracted from the article]

Our previous studies demonstrated that the promyelocytic leukemia gene, PML which involved in the 15;17 translocation in acute promyelocytic leukemia (APL) is a growth and transformation suppressor. In this study, recombinant PML adenovirus, Ad-PML was constructed and used to infect human breast cancer cells in vitro and in vivo, the anti-oncogenic function of PML and its mechanism of growth suppressing effect in breast cancer cells were examined. We showed that Ad-PML effectively infected the MCF-7 and SK-BR-3 cells. A high level of PML protein was expressed within 24 h post-infection and a detectable level remained at day 16. Ad-PML significantly suppressed the growth rate, clonogenicity, and tumorigenicity of breast cancer cells. Intratumoral injections of MCF-7-induced tumors by high titer Ad-PML suppressed tumor growth in nude mice by about 80%. The injection sites expressed high level of PML and associated with a massive apoptotic cell death. To elucidate the molecular mechanism of PML's growth suppressing function, we examined the effect of Ad-PML on cell cycle distribution in MCF-7 and SK-BR-3 cells. We found that Ad-PML infection caused a cell cycle arrest at the G1 phase. We further showed that G1 arrest of MCF-7 cells is associated with a significant decrease in cyclin D1 and CDK2. An increased expression of p53, p21 and cyclin E was found. The Rb protein became predominantly hypophosphorylated 48 h post-infection. These findings indicate that PML exerts its growth suppressing effects by modulating several key G1 regulatory proteins. Our study provides important insight into the mechanism of tumor suppressing function of PML and suggests a potential application of Ad-PML in human cancer gene therapy. [ABSTRACT FROM AUTHOR]

Focuses on the bacterial transformation of pyrene in marine environments. Separation of metabolite from marine sediment; How was concentration of pyrene in sediment samples obtained; Effect of hydrocarbon-degrading microorganisms in ecosystems; Results and discussion.

The concept of self-healing that involves a built-in ability to heal in response to damage wherever and whenever it occurs in a material, analogous to the healing process in living organisms, has emerged a couple of decades ago. Driven primarily by the demands for life-like materials and soft smart materials, therefore, the development of self-healing polymeric hydrogels has continually attracted the attention of the scientific community. Here, this review is intended to give an in-depth overview of the state-of-the-art advances in the field of self-healing polymeric hydrogels. Specifically, recently emerging trends in self-healing polymeric hydrogels are summarized, and notably, recommendations to endow these hydrogels with fascinating multi-functionalities including luminescence, conductivity/magnetism and shape memory etc. are presented. To close, the current challenges and future opportunities in this field are also discussed. [ABSTRACT FROM AUTHOR]

An introduction to the journal is presented in which the author discusses lateral habenula and its notification of behaviors through cues for reward signals.

As one of the most important smart materials, fluorescent hydrogel actuators can produce both color and shape changes under external stimuli. In the present work, an effective approach to develop a novel fluorescent hydrogel actuator with pH and thermo dual responsiveness is proposed. Through incorporating pH‐responsive perylene tetracarboxylic acid (PTCA), which is a typical fluorescent moiety with aggregation‐caused quenching (ACQ) effect, into an anisotropic poly(N‐isopropylacrylamide)–polyacrylamide (PNIPAm‐PAAm) structure, the obtained hydrogel exhibits stable thermoresponsive shape deformation and switchable fluorescence performance upon a pH trigger. Therefore, fluorescence‐quenching‐based and actuation‐based information can be revealed when exposed to UV light and immersed into warm water, respectively. Moreover, the thermoresponsive actuating behavior can be applied to further hide the fluorescence‐quenching‐based images. The present work may provide new insights into the design and preparation of novel stimuli‐responsive hydrogel actuators. A novel fluorescent hydrogel with Janus structure is fabricated. The hydrogel exhibits pH‐responsive fluorescence and thermally induced actuating behaviors, which may provide new insights into the design and fabrication of novel intelligent materials. [ABSTRACT FROM AUTHOR]

The evolution of microstructure and formation mechanism of incipient melting microstructure of DD5 single crystal superalloy during solution heat treatment were studied by scanning electron microscopy (SEM), electron probe microanalysis (EPMA), and energy dispersive spectroscopy (EDS). The solidus and liquidus of single crystal alloy were obtained by differential scanning calorimetry (DSC). Results show that the mosaic-like eutectic and fan-like eutectic are dissolved at first, and the coarse γ' phase is dissolved later during the solution heat treatment of 1,390 °C/2 h+1,310 °C/4 h+1,320 °C/10 h + air cooling (AC). The composition segregations of Al, Ta, W and Re are 0.99, 0.96, 1.04 and 1.16, respectively, which close to 1. The incipient melting is caused by the low local temperature of the alloy, and the micropore region with a lower melting point is the preferred position for incipient melting. [ABSTRACT FROM AUTHOR]

To compare one-time accuracy rate between simulated freehand (SFH) and navigation simulated (NS) pedicle screw insertion, assuming no second chance to correct screws. A simulated, comparative, cross-sectional study was conducted on 69 patients undergoing lumbar spine surgery. An intraoperative registration system captured the planned point of entry and trajectory of pedicle screws for both SFH under direct visualization and NS under navigation-aided visualization. Pedicle screw insertion was simulated for each captured image (370 screws) using Surgimap. Rajasekaran's method helped evaluate the point of entry accuracy and trajectory. Accuracy rate was better for the NS method (97.8%) than for the SFH method (63.8%). Of 370 screws in the SFH group, 134 penetrated the cortex, with 31 resulting in >4 mm penetration. Of 370 screws in the NS group, 8 penetrated the cortex, <4 mm penetration. Of 134 misplaced screws in the SFH group, 64 were due to error in the point of entry, 63 were due to error in the trajectory angle, and 7 were due to both errors. Of 8 errors in the NS group, 7 were due to the point of entry. Intraoperative navigation had significantly better one-time accuracy of pedicle screw insertion than freehand insertion and should be used to avoid injury to the pedicle and surrounding tissue from screw reinsertion. [ABSTRACT FROM AUTHOR]

The unique anatomical and functional features of principal and interneuron populations are critical for the appropriate function of neuronal circuits. Cell type-specific properties are encoded by selective gene expression programs that shape molecular repertoires and synaptic protein complexes. However, the nature of such programs, particularly for post-transcriptional regulation at the level of alternative splicing is only beginning to emerge. We here demonstrate that transcripts encoding the synaptic adhesion molecules neurexin-1,2,3 are commonly expressed in principal cells and interneurons of the mouse hippocampus but undergo highly differential, cell type-specific alternative splicing. Principal cell-specific neurexin splice isoforms depend on the RNA-binding protein Slm2. By contrast, most parvalbumin-positive (PV+) interneurons lack Slm2, express a different neurexin splice isoform and co-express the corresponding splice isoform-specific neurexin ligand Cbln4. Conditional ablation of Nrxn alternative splice insertions selectively in PV+ cells results in elevated hippocampal network activity and impairment in a learning task. Thus, PV-cell-specific alternative splicing of neurexins is critical for neuronal circuit function. [ABSTRACT FROM AUTHOR]

Objective: The authors compared measurement-based care with standard treatment in major depression. Methods: Outpatients with moderate to severe major depression were consecutively randomized to 24 weeks of either measurement-based care (guideline- and rating scale-based decisions; N=61), or standard treatment (clinicians' choice decisions; N=59). Pharmacotherapy was restricted to paroxetine (20-60 mg/day) or mirtazapine (15-45 mg/day) in both groups. Depressive symptoms were measured with the Hamilton Depression Rating Scale (HAM-D) and the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR). Time to response (a decrease of at least 50% in HAM-D score) and remission (a HAM-D score of 7 or less) were the primary endpoints. Outcomes were evaluated by raters blind to study protocol and treatment. Results: Significantly more patients in the measurement-based care group than in the standard treatment group achieved response (86.9% compared with 62.7%) and remission (73.8% compared with 28.8%). Similarly, time to response and remission were significantly shorter with measurement-based care (for response, 5.6 weeks compared with 11.6 weeks, and for remission, 10.2 weeks compared with 19.2 weeks). HAM-D scores decreased significantly in both groups, but the reduction was significantly larger for the measurement-based care group (-17.8 compared with -13.6). The measurement-based care group had significantly more treatment adjustments (44 compared with 23) and higher antidepressant dosages from week 2 to week 24. Rates of study discontinuation, adverse effects, and concomitant medications did not differ between groups. Conclusions: The results demonstrate the feasibility and effectiveness of measurement-based care for outpatients with moderate to severe major depression, suggesting that this approach can be incorporated in the clinical care of patients with major depression. [ABSTRACT FROM AUTHOR]

The article presents a study on the MEKK3 expression with nuclear factor κ B activity and the role of antiapoptic genes in ovarian cancer. A background on ovarian cancer and the effect of nuclear factor κ B in the development of cancer is given. The study uses Western blotting and real-time polymerase chain reaction. Results show that ovarian cancer with high MEKK3 also showed high nuclear factor κ B activity. It concludes that MEKK3 plays an important role in tumors.

Nucleus-nucleus potentials are determined in the framework of double folding model for M3Y-Reid and M3Y-Paris effective nucleon-nucleon (NN) interactions. Both zero-range and finite-range exchange parts of NN interactions are considered in the folding procedure. In this paper the spherical projectile-spherical target system 16O+208Pb is selected for calculating the barrier energies, fusion cross sections and barrier distributions with the density-independent and density-dependent NN interactions on the basis of M3Y-Reid and M3Y-Paris NN interactions. The barrier energies become lower for Paris NN interactions in comparison with Reid NN interactions, and also for finite-range exchange part in comparison with zero-range exchange part. The density-dependent NN interactions give similar fusion cross sections and barrier distributions, and the density-independent NN interaction causes the barrier distribution moving to a higher position. However, the density-independent Reid NN interaction with zero-range exchange part gives the lowest fusion cross sections. We find that the calculated fusion cross sections and the barrier distributions are in agreement with the experimental data after renormalization of the nuclear potential due to coupled-channel effect. [ABSTRACT FROM AUTHOR]

Background: Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. Results: Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. Conclusion: We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system. [ABSTRACT FROM AUTHOR]

Objective: To compare the superior‐level facet joint violations (FJV) between robot‐assisted (RA) percutaneous pedicle screw placement and conventional open fluoroscopic‐guided (FG) pedicle screw placement in a prospective cohort study. Methods: This was a prospective cohort study without randomization. One‐hundred patients scheduled to undergo RA (n = 50) or FG (n = 50) transforaminal lumbar interbody fusion were included from February 2016 to May 2018. The grade of FJV, the distance between pedicle screws and the corresponding proximal facet joint, and intra‐pedicle accuracy of the top screw were evaluated based on postoperative CT scan. Patient demographics, perioperative outcomes, and radiation exposure were recorded and compared. Perioperative outcomes include surgical time, intraoperative blood loss, postoperative length of stay, conversion, and revision surgeries. Results: Of the 100 screws in the RA group, 4 violated the proximal facet joint, while 26 of 100 in the FG group had FJV (P = 0.000). In the RA group, 3 and 1 screws were classified as grade 1 and 2, respectively. Of the 26 FJV screws in the FG group, 17 screws were scored as grade 1, 6 screws were grade 2, and 3 screws were grade 3. Significantly more severe FJV were noted in the FG group than in the RA group (P = 0.000). There was a statistically significant difference between RA and FG for overall violation grade (0.05 vs 0.38, P = 0.000). The average distance of pedicle screws from facet joints in the RA group (4.16 ± 2.60 mm) was larger than that in the FG group (1.92 ± 1.55 mm; P = 0.000). For intra‐pedicle accuracy, the rate of perfect screw position was greater in the RA group than in the FG group (85% vs 71%; P = 0.017). No statistically significant difference was found between the clinically acceptable screws between groups (P = 0.279). The radiation dose was higher in the FG group (30.3 ± 11.3 vs 65.3 ± 28.3 μSv; P = 0.000). The operative time in the RA group was significantly longer (184.7 ± 54.3 vs 117.8 ± 36.9 min; P = 0.000). Conclusions: Compared to the open FG technique, minimally invasive RA spine surgery was associated with fewer proximal facet joint violations, larger facet to screw distance, and higher intra‐pedicle accuracy. [ABSTRACT FROM AUTHOR]

The one-variable-at-a-time method for sensor R&D has received extensive research effort, yet it has reached the local maxima for specific sensing characteristics. To achieve the quasi-global maxima for suitable sensors, we developed the Design–Build–Test–Machine learning (DBTM) method for efficiently developing sensors on demand. In addition, the automation of the preparation and characterization processes frees researchers from labor-intensive work, generates adequate high-quality data, and enables researchers to discover valuable information in high-dimensional space. As a proof-of-concept, we built a high-throughput algorithm-driven autonomous system (HAAS) that supports the DBTM approach for developing a CO 2 sensor. With the DBTM approach, we can simultaneously optimize multiple sensor units, each for a specific concentration interval. Therefore, such an array can achieve an extensive range and sound sensitivity. Our work demonstrates the superiority of the DBTM method for multi-target and multi-variable sensor development. In contrast to single target optimization in other research areas, multiple characteristics should be improved for sensors. Our multi-target optimization algorithm optimizes four sensor characteristics. Our sensor array could rapidly detect CO 2 concentrations from 400 ppm to 30 % with a root mean square error (RMSE) of 0.27 %. The DBTM method is anticipated to be a new paradigm and accelerator of practical application for sensors after the initial proof of the sensing mechanism. [Display omitted] • A colorimetric CO 2 sensor array was constructed by the DBTM approach in four iterations and 864 experimental data points. • The sensor array could reversibly detect CO 2 from 400 ppm to 30 % with an RMSE of 0.27 % and a few seconds of response time. • A multi-target algorithm was designed to optimize multiple characteristics of the sensor simultaneously. • A high throughput strategy and Bayesian algorithm were used to explore multi-variation space efficiently. • Robots prepared and characterized sensor units with high reproducibility and low human labor within 5 days. [ABSTRACT FROM AUTHOR]

The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly396→Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly390→Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination. [ABSTRACT FROM AUTHOR]

Aim: Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance. Experimental Design: Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance. Results: High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P = 0.035), shorter overall (P = 0.019) and disease-free (P = 0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C. Conclusion: Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Trastuzumab is part of the standard treatment for patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer, but not all patients respond to trastuzumab. Altered microRNA (miR) expression levels in cancer cells have been correlated with prognosis and response to chemotherapy. The authors of this report hypothesized that altered miR expression levels in plasma are associated with sensitivity to trastuzumab in patients with HER-2 positive breast cancer. METHODS: Quantitative reverse transcriptase-polymerase chain reaction was used to analyze plasma samples, including samples from patients with breast cancer who were enrolled in a clinical trial of neoadjuvant trastuzumab-based chemotherapy. Expression levels of miR-210, miR-21, miR-29a, and miR-126 were analyzed according to the type of response (pathologic complete response [n = 18] vs residual disease [n = 11]). MicroRNA expression levels also were compared in trastuzumab-sensitive and trastuzumab-resistant breast cancer cells derived from BT474 cells and in an independent set of preoperative plasma samples (n = 39) and postoperative plasma samples (n = 30) from 43 breast cancer patients who did not receive any treatment. RESULTS: At baseline before patients received neoadjuvant chemotherapy combined with trastuzumab, circulating miR-210 levels were significantly higher in those who had residual disease than in those who achieved a pathologic complete response ( P = .0359). The mean expression ratio for miR-210 was significantly higher in trastuzumab-resistant BT474 cells, and miR-210 expression was significantly higher before surgery than after surgery ( P = .0297) and in patients whose cancer metastasized to the lymph nodes ( P = .0030). CONCLUSIONS: Circulating miR-210 levels were associated with trastuzumab sensitivity, tumor presence, and lymph node metastases. These results suggest that plasma miR-210 may be used to predict and perhaps monitor response to therapies that contain trastuzumab. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Zhao F, Siu M K Y, Jiang L L, Tam K F, Ngan H Y S, Le X-F, Wong O G W, Wong E S Y, Chan H Y & Cheung A N Y (2011) Histopathology 59, 1163-1172 Overexpression of dedicator of cytokinesis I (Dock180) in ovarian cancer correlated with aggressive phenotype and poor patient survival Aims: Dedicator of cytokinesis I (Dock180) is a novel guanine nucleotide exchange factor for Rho guanosine triphosphates (GTPases) important for cell migration. The aim of this study was to evaluate the role of Dock180 in ovarian carcinogenesis. Methods and results: Using immunohistochemistry, real-time polymerase chain reaction and Western blotting, overexpression of Dock180 RNA and protein was demonstrated in the nucleus and cytoplasm of ovarian cancer cell lines ( n = 5) and clinical samples of ovarian borderline tumours ( n = 21) and invasive cancers ( n = 108) when compared with ovarian epithelial cell lines ( n = 3) and benign cystadenomas ( n = 10) ( P < 0.05). High Dock180 cytoplasmic expression in ovarian cancer ( n = 108) was associated significantly with serous histological type, high-grade cancer and advanced stage ( P < 0.05), as well as poor overall and disease-free survival ( P = 0.004). Using multivariate progression analysis, high Dock180 cytoplasmic expression and advanced cancer stage were found to be independent prognostic factors for short overall survival and disease-free survival ( P < 0.05). Exogenous expression of Dock180 by transient transfection enhanced cancer cell migration and invasion, whereas knockdown of Dock180 by an siRNA approach retarded cancer cell migration and invasion in association with down-regulation of matrix metalloproteinase 2. Conclusions: Our findings suggest that Dock180 contributes to ovarian carcinogenesis and dissemination and is a potential prognostic marker and therapeutic target. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the mechanistic basis of the anti-tumor effect of the compound ITB-301. Methods: Chemical modifications of genistein have been introduced to improve its solubility and efficacy. The anti-tumor effects were tested in ovarian cancer cells using proliferation assays, cell cycle analysis, immunofluorescence, and microscopy. Results: In this work, we show that a unique glycoside of genistein, ITB-301, inhibits the proliferation of SKOv3 ovarian cancer cells. We found that the 50% growth inhibitory concentration of ITB-301 in SKOv3 cells was 0.5 μM. Similar results were obtained in breast cancer, ovarian cancer, and acute myelogenous leukemia cell lines. ITB-301 induced significant time- and dose-dependent microtubule depolymerization. This depolymerization resulted in mitotic arrest and inhibited proliferation in all ovarian cancer cell lines examined including SKOv3, ES2, HeyA8, and HeyA8-MDR cells. The cytotoxic effect of ITB-301 was dependent on its induction of mitotic arrest as siRNA-mediated depletion of BUBR1 significantly reduced the cytotoxic effects of ITB-301, even at a concentration of 10 μM. Importantly, efflux-mediated drug resistance did not alter the cytotoxic effect of ITB-301 in two independent cancer cell models of drug resistance. Conclusion: These results identify ITB-301 as a novel anti-tubulin agent that could be used in cancers that are multidrug resistant. We propose a structural model for the binding of ITB-301 to α- and β-tubulin dimers on the basis of molecular docking simulations. This model provides a rationale for future work aimed at designing of more potent analogs. [ABSTRACT FROM AUTHOR]

Background: Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity.Methods: A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided.Results: Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression.Conclusion: Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. [ABSTRACT FROM AUTHOR]

AbstractPhosphorylation dysregulation has been implicated in various diseases including cancer. The phosphorylation change of proteins in secretome may be a novel source for the discovery of biomarkers and drug targets. In this study, the phosphoproteins in cancer secretome (phosphosecretome) were globally analyzed for the first time by phosphoproteomics. One hundred forty-two phosphorylation sites on 62 unique phosphopeptides representing 49 nonredundant proteins were identified, several of which are known as secreted proteins involved in carcinogenesis, invasion, and metastasis. Most of them were first found as secreted proteins with no previously known function. Protein sublocation analysis showed that 33 proteins were found to be sectreted as phosphoproteins, in which 27 (81.81%) were secreted by a nonclassic, ER/Golgi-independent pathway, suggestting that the phosphorylation modification of these proteins might play an important role in their nonconventional secretion processes. Their protein kinases and regulatory phosphosites involved in the secretion regulation of these phosphoproteins, such as stanniocalcin 2, annexin A2, and HSP90 alphạ, were first identified. The phosphosecretome data enriched the secretome database and phosphoproteome database, and will help us to discover cancer biomarkers and drug targets, illustrating the mystery of the nonclassic protein secretion pathway. [ABSTRACT FROM AUTHOR]

This report establishes an in vitro model on glass surfaces for patterning multiple types of cells to simulate cell−cell interactions in vivo. The model employs a microfluidic system and poly(ethylene glycol)-terminated oxysilane (PEG-oxysilane) to modify glass surfaces in order to resist cell adhesion. The system allows the selective confinement of different types of cells to realize complete confinement, partial confinement, and no confinement of three types of cells on glass surfaces. The model was applied to study intercellular interactions among human umbilical vein endothelial cells (HUVEC), PLA 801 C and PLA801 D cells. [ABSTRACT FROM AUTHOR]

Abstract: A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth. [ABSTRACT FROM AUTHOR]

Summary: Regulators of mitosis have been successfully targeted to enhance response to taxane chemotherapy. Here, we show that the salt inducible kinase 2 (SIK2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, C-Nap1, through S2392 phosphorylation. Interference with the known SIK2 inhibitor PKA induced SIK2-dependent centrosome splitting in interphase while SIK2 depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers. We believe these data identify SIK2 as a plausible target for therapy in ovarian cancers. [ABSTRACT FROM AUTHOR]

The silent information regulator (Sir2) family proteins are NAD+-dependent deacetylases. Although a few substrates have been identified, functions of the bacteria Sir2-like protein (CobB) still remain unclear. Here the role of CobB on Escherichia coli chemotaxis was investigated. We used Western blotting and mass spectrometry to show that the response regulator CheY is a substrate of CobB. Surface plasmon resonance (SPR) indicated that acetylation affects the interaction between CheY and the flagellar switch protein FliM. The presence of intact flagella in knockout strains Δ cobB, Δ acs, Δ( cobB) Δ( acs), Δ( cheA) Δ( cheZ), Δ( cheA) Δ( cheZ) Δ( cobB) and Δ( cheA) Δ( cheZ) Δ( acs) was confirmed by electron microscopy. Genetic analysis of these knockout strains showed that: (i) the Δ cobB mutant exhibited reduced responses to chemotactic stimuli in chemotactic assays, whereas the Δ acs mutant was indistinguishable from the parental strain, (ii) CheY from the Δ cobB mutant showed a higher level of acetylation, indicating that CobB can mediate the deacetylation of CheY in vivo, and (iii) deletion of cobB reversed the phenotype of Δ( cheA) Δ( cheZ). Our findings suggest that CobB regulates E. coli chemotaxis by deacetylating CheY. Thus a new function of bacterial cobB was identified and also new insights of regulation of bacterial chemotaxis were provided. [ABSTRACT FROM AUTHOR]

Background: Constitutively activated nuclear factor kappa B (NFkappaB) contributes to the development of cancer by regulating the expression of genes involved in cell survival, metastasis, and angiogenesis. The authors have demonstrated that MEKK3 plays a critical role in cytokine-mediated NFkappaB activation, and that stable expression of MEKK3 in cultured cells leads to increased NFkappaB activity.Methods: MEKK3 expression in ovarian cancer cells or tumors was assessed by Western blotting and real-time polymerase chain reaction. NFkappaB activities were analyzed by electrophoretic mobility shift assay and luciferase reporter assays. Western blot analysis for the survival factors were also performed and correlated with MEKK3 and NFkappaB activities. Cell survival assays were used to determine the sensitivity of ovarian cancer cells to various chemotherapeutic agents.Results: The authors found that 63% of the ovarian cancers had higher MEKK3 expression than the normal ovarian epithelial cells. Ovarian cancers with high MEKK3 showed correspondingly high IkappaB kinase and NFkappaB activity. Moreover, MEKK3 coimmunoprecipitated with Akt and cooperated with Akt to synergistically activate NFkappaB. Consistent with increased MEKK3 and NFkappaB activity in ovarian cancers, Bcl-2, Bcl-xL, survivin, and X-linked inhibitor of apoptosis levels were increased, which correlated with increased resistance to chemotherapeutic agents. Knockdown of MEKK3 with small interfering RNA significantly increased cancer cell sensitivity to paclitaxel.Conclusions: MEKK3 may be aberrantly expressed in ovarian cancers and plays an important role in tumors with constitutively activated NFkappaB. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the changes in the pituitary-thyroid axis (PTA) and the time course of the hormonal alterations in subjects with opioid dependence after abstinence. Blood samples from in-patients with opioid dependence and age- and sex-matched healthy controls were collected. The severity of opioid abuse and of withdrawal symptoms was assessed. Results were compared between patients with opioid dependence ( n = 30) and healthy controls ( n = 30). We found that free triiodothyronine and free thyroxine levels were comparable with healthy controls while thyroid-stimulating hormone (TSH) was lower in patients in acute opioid abstinence period. Also, TSH levels in patients remained lower than controls after 30 days of abstinence. These results indicate that PTA function is altered in opioid-dependent subjects. These data highlight the importance of screening the thyroid function for individuals with chronic opioid dependence. [ABSTRACT FROM AUTHOR]

This paper derives the expressions for the ordering degree and the modulation factor of A and B atoms in AxB1 - xC epilayers of ternary III-V semiconductor alloys. Using these expressions, it identifies quantitatively the alternating atom-enhanced planes, compositional modulations, atomic ordering degree on the group-III sublattices and the fine structure of NMR spectra. [ABSTRACT FROM AUTHOR]