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In this paper we mainly discuss the determinant factors on urban cluster evolutionary, we find that: when considering the labor mobility, the increase of urban cluster degree accelerates the high skilled labor force to agglomerate in the core area, and then intensifies the urban spatial concentration. We get the same result for capital flow.

Introduction: RAS oncogenes are the most frequently mutated gene family in human cancers. 50% of newly diagnosed multiple myeloma patients carry a RAS/MAPK pathway mutation, with a rising percentage in the relapsed situation1. Thus, targeting RAS mutations in multiple myeloma will increase therapeutic efficiency and potentially overcome drug-resistance. Unfortunately, RAS mutations have been considered "undruggable" due to a lack of traditional small molecule binding pockets on the proteins. Therefore, key component in the RAS/MAPK pathway may represent an alternative therapeutic target for MM. Germinal center kinase (GCK), also named mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), is an upstream activator in the MAPK pathway. Indeed, we recently discovered the critical role of GCK in RAS mutated (RASmut) MM cell survival and growth. GCK knockdown in RASmut MM cells induced MM cell growth inhibition both in vitro and in vivo. However, the detailed mechanism is yet to be defined. Methods and Results: Our previous data showed that GCK knockdown induces MM cell growth inhibition, associated with the blockage of MKK4/7-JNK phosphorylation and the downregulation of critical transcriptional factors (TFs) including IKZF1/3, BCL-6, and c-MYC proteins. To confirm that GCK knockdown downregulates IKZF1/3 etc at protein level but not mRNA level, we conducted real-time PCR on GCK knockdown MM cells and compared the expression of GCK and TFs to the empty vector (EV) infected MM cells. Results showed that shRNA induced GCK silencing only led to the significantly decreased GCK mRNA, however, did not affect IKZF1 and c-MYC expressions at mRNA level. Consistent with the effects of GCK knockdown, the GCK inhibitor TL4-12 dose-dependently downregulated IKZF1 and BCL-6 proteins, inhibited MM cell proliferation and induced cell apoptosis. IKZF1/3 are the key targets of the immunomodulatory drugs (IMiDs), which are the backbone of MM therapy. IMiDs bind to cereblon (CRBN) and induce IKZF1/3 protein degradation, which subsequently lead to MM cell growth inhibition. Importantly, our data showed that IMiDs-resistant RPMI-8226 MM cells have high expression of GCK. GCK knockdown and inhibition induced IKZF1 downregulation, triggered growth inhibition and cell apoptosis in RPMI-8226 cells, suggesting that GCK regulates IKZF1 degradation via a CRBN-independent mechanism. To confirm this hypothesis, we silenced CRBN in N-Rasmut H929 MM cells by shRNA lentiviral infection and examined the response to IMiDs and GCK inhibitor. CRBN knockdown was confirmed by western blotting. CRBN silencing in H929 cells resulted in lenalidomide (LEN) resistance, evidenced by the WTS proliferation assay. In contrast, CRBN silencing failed to rescue N-Rasmut H929 MM cells from TL4-12 induced proliferation inhibition and IKZF1 downregulation, confirming that GCK regulated IKZF1 and cell growth is independent of CRBN. Conclusion: Taken together, our data demonstrated that GCK inhibition induces cell growth inhibition and triggers apoptosis especially in RASmut MM cells. Importantly, GCK inhibitor downregulates IKZF1 via a CRBN-independent mechanism. Our findings thus provide a rationale for the clinical evaluation of targeting GCK in RASmut MM patients and further mechanistic insight into the role of GCK in MM tumorigenesis as well as drug resistance. GCK inhibitors may represent a novel therapy for the treatment of RASmut MM patients, especially those who are resistant to IMiDs as well as with refractory or relapsed MM. References Walker, B.A., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol33, 3911-3920 (2015). Disclosures Marcireau: Sanofi: Current Employment. Lentzsch:Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Sorrento: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celularity: Consultancy; Magenta: Current equity holder in private company; Sanofi: Research Funding.

Keloids are fibroproliferative disorders characterized by the overabundant deposition of extracellular matrix (ECM), especially collagen and overgrowth of scar tissue in response to cutaneous injury. In this study, we isolated a selenium (Se)-containing polysaccharide (Se-ZGTP-I) from Ziyang green tea and explored its potential therapeutic effects on keloid fibroblasts formation. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and annexin V/propidium iodide (PI) staining assays demonstrated that Se-ZGTP-I or neuron-glia 2 (NG2) short hairpin RNA (shRNA) significantly inhibited proliferation of human keloid fibroblasts via induction of apoptosis. Besides, the activation of caspase-3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP) were observed in keloid fibroblasts following Se-ZGTP-I (200 and 400 μg/ml) or NG2 shRNA treatment. Moreover, Western blotting analysis showed that treatment of keloid fibroblasts with Se-ZGTP-I (200 and 400 μg/ml) or NG2 shRNA resulted in an increase of pro-apoptotic protein Bax expression and a decrease in expression levels of anti-apoptotic protein Bcl-2 and NG2. In addition, type I collagen biosynthesis and protein expression in keloid fibroblasts following TGF-β1 stimulation were decreased by Se-ZGTP-I (200 and 400 μg/ml) or NG2 shRNA management. Current findings imply that Se-ZGTP-I has a therapeutic potential to intervene and prevent keloid formation and other fibrotic diseases.

ClC-3, a member of the ClC chloride (Cl(-)) channel family, has recently been proposed as the primary Cl(-) channel involved in cell volume regulation. Changes in cell volume influence excitability, contraction, migration, pathogen-host interactions, cell proliferation, and cell death processes. In this study, expression and function of ClC-3 channels were investigated during epidermal stem cell (ESC) migration. We observed differential expression of CLC-3 regulates migration of ESCs. Further, whole-cell patch-clamp recordings and image analysis demonstrated ClC-3 expression affected volume-activated Cl(-) current (I Cl,Vol) within ESCs. Live cell imaging systems, designed to observe cellular responses to overexpression and suppression of ClC-3 in real time, indicated ClC-3 may regulate ESC migratory dynamics. We employed IMARIS software to analyze the velocity and distance of ESC migration in vitro to demonstrate the function of ClC-3 channel in ESCs. As our data suggest volume-activated Cl(-) channels play a vital role in migration of ESCs, which contribute to skin repair by migrating from neighboring unwounded epidermis infundibulum, hair follicle or sebaceous glands, ClC-3 may represent a new and valuable target for stem cell therapies.

Let G be a finite group. A subgroup H of G is called a BNA-subgroup if eitherH = H or x ∈ ⟨H,H⟩ for all x ∈ G. In this paper, some interesting properties of BNA-subgroups are given and, as applications, the structure of the finite groups in which all minimal subgroups are BNA-subgroups have been characterized. Mathematics Subject Classification (2010). 20D10, 20D20, 20D25.

The relationship between the critical buckling loads of functionally graded material (FGM) Levinson beams (LBs) and those of the corresponding homogeneous Euler-Bernoulli beams (HEBBs) is investigated. Properties of the beam are assumed to vary continuously in the depth direction. The governing equations of the FGM beam are derived based on the Levinson beam theory, in which a quadratic variation of the transverse shear strain through the depth is included. By eliminating the axial displacement as well as the rotational angle in the governing equations, an ordinary differential equation in terms of the deflection of the FGM LBs is derived, the form of which is the same as that of HEBBs except for the definition of the load parameter. By solving the eigenvalue problem of ordinary differential equations under different boundary conditions clamped (C), simply-supported (S), roller (R) and free (F) edges combined, a uniform analytical formulation of buckling loads of FGM LBs with S-S, C-C, C-F, C-R and S-R edges is presented for those of HEBBs with the same boundary conditions. For the C-S beam the above-mentioned equation does not hold. Instead, a transcendental equation is derived to find the critical buckling load for the FGM LB which is similar to that for HEBB with the same ends. The significance of this work lies in that the solution of the critical buckling load of a FGM LB can be reduced to that of the HEBB and calculation of three constants whose values only depend upon the through-the-depth gradient of the material properties and the geometry of the beam. So, a homogeneous and classical expression for the buckling solution of FGM LBs is accomplished.

To detect potential mutations of the spastic ataxia of Charlevoix-Saguenay (SACS) gene in a pedigree affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).Genomic DNA was extracted from peripheral blood samples of the proband and her family members. All exons and flanking sequences of the SACS gene were analyzed by high-throughput sequencing. Suspected mutations were verified with Sanger sequencing.Next generation sequencing revealed novel compound heterozygous mutations of the SACS gene, namely c.13085T to G (p.I4362R) and c.5236dupA (p.T1746fs), in the proband, which were respectively derived from her parents. The mutations were confirmed by Sanger sequencing.The c.5236dupA (p.T1746fs) and c.13085T to G (p.I4362R) mutations of the SACS gene probably underlie the ocular symptoms and hearing loss in the proband.

To explore a new method to correct the whistle deformity in bilateral cleft lip.A lower lip bipedicle orbicularis oris musculomucosal island flap was designed to repair the upper vermilion defect.The pedicle of this flap was deepidermidalized and then embedded into the upper lip. The dry lip in the central was reserved to reconstruct the vermilion tubercle.From Aug.2013 to Aug.2015,10 cases were treated successfully with primary healing. With the follow-up period of 5-17 months, the appearance of upper lip was greatly improved with a balanced proportion and full lip tubercle.This lower lip bipedicle orbicularis oris musculomucosal island flap is an ideal method for the correction of whistle deformity in bilateral cleft lip.

Introduction Multiple myeloma (MM) bone disease is characterized by the development of osteolytic bone lesions due to the over-activation of osteoclast and inhibition of osteoblast cells. MM cells secret pro-osteoclastogenic factors which lead to osteoclast (OCL) activation. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor which is highly secreted by MM cells. MMP-13 induces osteoclast fusion and bone-resorption by triggering the ERK1/2-dependent up-regulation of the cell fusogen, DC-STAMP. This process operates independently of the MMP-13 proteolytic activity. The fact that MMP-13 regulates OCL signaling via a proteolytic independent mechanism suggests that MMP-13 functions as a paracrine message protein mediating the crosstalk between MM cells and OCL. However, the mechanism is yet to be identified. Methods and Results To screen for MMP-13 cellular binding proteins/receptors, we performed a MMP-13 pull-down assay wherein recombinant MMP-13-His6 was incubated with mouse mononuclear bone marrow cells (BMCs) lysates and Ni-NTA magnetic beads were used to pull-down MMP-13- associated proteins. Following mass spectral analysis, programmed death-1 homolog (PD-1H) was identified as a major MMP-13-binding protein. PD-1H, also known as V-domain Ig suppressor of T cell activation (VISTA), is a critical negative checkpoint regulator expressed on myeloid cells and involved in immune responses. Binding of MMP-13 and PD-1H was confirmed by co-expressing both proteins in HEK293 cells and subsequent co-immunoprecipitation assay. Further, following PD-1H expression in HEK293 cells, an MMP-13-GFP fusion fluorescence protein docked to the cell surface where mutagenesis studies demonstrated that the PD-1H extracellular domain (ECD) mediates the specific binding interaction. Western blot and immunohistochemistry revealed that PD-1H was highly expressed in mononuclear BMCs, pre-OCL and mature OCL. ShRNA-mediated knockdown of PD-1H in mouse mononuclear BMCs blocked the ability of MMP-13 to induce osteoclast fusion and activation. These results were further confirmed by using BMCs from Pd-1h-/- mice and WT littermates for in vitro osteoclast differentiation. While MMP-13 induced WT OCL fusion and activation, these effects were completely blocked in Pd-1h-/-OCLs in tandem with a loss in MMP-13 induced ERK1/2 phosphorylation, NFATc1 and DC-STAMP upregulation. Conclusions Taken together, our study, for the first time, revealed that checkpoint inhibitor PD-1H is highly expressed in pre- and mature osteoclast. More importantly, we identified PD-1H as the critical receptor for MMP-13 in OCL, thereby mediating MMP-13-induced OCL fusion, activation and bone resorption. Hence, MMP-13 as a novel PD-1H ligand might not only induce bone disease, but also play a potential role in the regulation of T-cell activity in MM. As such, targeting MMP-13 and PD-1H interactions may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment. Disclosures Lentzsch: Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Introduction: Next-generation sequencing revealed frequent mutations of the RAS/mitogen-activated protein kinase (MAPK) pathway, with mutations in NRAS, KRAS or BRAF in up to 50% of newly diagnosed MM patients1. The majority of the NRAS, KRAS and BRAF mutations occur in hotspots causing constitutive activation of the corresponding pathways2. Given the upstream activator role of Germinal Center Kinase (GCK) in the MAPK pathway, GCK might be an attractive therapeutic target in MM. Indeed, we recently discovered the critical role of GCK, also named mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2), in MM cell survival and growth. Methods and Results: Our data show that GCK is higher expressed in RAS mutated MM cells compared to the wild type (WT) RAS MM cells. Silencing of GCK in RASmut MM cells (MM.1S and RPMI-8226) by using an inducible Tet-on-shGCK significantly decreased MM cell proliferation and induced cell death (Figure 1). In contrast, knockdown of GCK in RASwt MM cell lines (LP1 and U266) induced only modest inhibition of proliferation. The higher sensitivity to GCK knockdown in RASmut cells suggests that targeting GCK is especially effective in multiple myeloma which harbors RAS mutations. To exclude a potential off-target effect associated with GCK knockdown that led to the inhibition of MM proliferation, we set up an shGCK-resistant GCK allele (GCKshRNA-RES) by introducing mismatch mutations on the shRNA targeted sequences without changing the encoded amino acids. In the shGCK rescue experiment using GCKshRNA-RES we showed that all shRNA induced phenotypes (lack of growth, apoptosis and downstream effectors decrease) were corrected by the GCK resistant allele expression, ruling out the off-target hypothesis. Moreover, we expanded the in vivo studies of GCK knockdown on MM tumor progression. To monitor the tumor progression, we transduced MM.1S cells with firefly luciferase and established an inducible GCK knockdown system. Luciferase-expressing GCK inducible knockdown MM cells or non-targeting control shRNA (shCNTL) transduced MM cells were s.c. injected into SCID/Beige mice and the tumor progression was monitored by bioluminescence imaging. Doxycycline (for induction of shRNA) or vehicle treatment were started after the tumor was established on day 16 to induce shGCK and subsequently silence GCK expression. In contrast to the vehicle-treated MM.1S-Tet-on-shGCK or doxycycline-treated MM.1S-Tet-on-shCNTL tumors, doxycycline-treated animals bearing MM.1S-Tet-on-shGCK xenografts showed a significant inhibition (P Lysine 45 is critical for GCK kinase activity. Point mutation of K45A will completely abolish its kinase activity. We introduced K45A mutation into GCKshRNA-RES (GCKshRNA-RESK45A→ shGCK resistant and kinase dead GCK). Tet-on-shGCK with GCKshRNA-RES or GCKshRNA-RESK45A were co-transduced in MM.1S cells. As expected, the GCK knockdown effects were rescued by GCKshRNA-RES but not by the kinase-dead mutant GCKshRNA-RESK45A. In contrast to GCKshRNA-RES, GCKshRNA-RESK45A failed to stimulate MM cell proliferation, to suppress MM cells apoptosis and to restore the downstream effectors expression. Our findings demonstrated that GCK kinase activity is required for its function in myeloma cell physiology. Conclusion: Taken together, our findings provide a rationale for the clinical evaluation of targeting GCK in MM patients and the role of GCK in MM tumorigenesis as well as drug resistance. The subsequent development of small molecules inhibiting this pathway, such as GCK kinase inhibitors, will address the unmet need of developing targeted treatments for RASmut myeloma and potentially for other RASmut malignancies. References 1. Walker, B.A., et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J Clin Oncol33, 3911-3920 (2015). 2. Xu, J., et al. Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis6, e337 (2017). Disclosures Marcireau: Sanofi: Employment. Lentzsch:Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Bayer: Consultancy.

Hamiltonella defensa is well known for its protective roles against parasitoids for its aphid hosts, but its functional roles in insect‐plant interactions are less understood. Thus, the impact of H. defensa infections on life‐history characters and the underlying genetic variation for the grain aphid, Sitobion avenae (Fabricius), was explored on three plants (i.e., wheat, oat, and rye). Compared to cured lines, H. defensa infected lines of S. avenae had lower fecundity on wheat and oat, but not on rye, suggesting an infection cost for the aphid on susceptible host plants. However, when tested on rye, the infected lines showed a shorter developmental time for the nymphal stage than corresponding cured lines, showing some benefit for S. avenae carrying the endosymbiont on resistant host plants. The infection of H. defensa altered genetic variation underlying its host S. avenea’s life‐history characters, which was shown by differences in heritabilities and genetic correlations of life‐history characters between S. avenae lines infected and cured of the endosymbiont. This was further substantiated by disparity in G‐matrices of their life‐history characters for the two types of aphid lines. The G‐matrices for life‐history characters of aphid lines infected with and cured of H. defensa were significantly different from each other on rye, but not on oat, suggesting strong plant‐dependent effects. The developmental durations of infected S. avenae lines showed a lower plasticity compared with those of corresponding cured lines, and this could mean higher adaptability for the infected lines.Overall, our results showed novel functional roles of a common secondary endosymbiont (i.e., H. defensa) in plant‐insect interactions, and its infections could have significant consequences for the evolutionary ecology of its host insect populations in nature.

Background To compare the clinical characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL), to find out valuable, relevant indicators for differential diagnosis. Methods The clinical, endoscopic and pathological data of 67 cases (54 cases of Crohn’s disease and 13 cases of primary intestinal lymphoma) admitted by the PLA Army General Hospital in the last seven years were analysed retrospectively. Results The average age of CD was lower than that of PIL, but the course of CD was longer than that of PIL (p Abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy or intestinal resection), and multi-site lesions were more common in CD than in PIL (p The biopsy diagnosis rate of PIL was 92.3%, while 85.1% of CD’s pathological manifestations were non-specific inflammation. So the biopsy diagnosis rate of PIL was significantly higher than that of CD (p Two patients were initially diagnosed with CD based on the clinical comprehensive analysis. The clinical symptoms disappeared, and the colonoscopy achieved mucosal healing after treatment. But the patients‘ symptoms repeated, and they were eventually diagnosed as PIL. Conclusions The clinical and endoscopic characteristics of Crohn’s disease (CD) and primary intestinal lymphoma (PIL) are similar, but they have their own characteristics. Therefore, the differential diagnosis is difficult. The diagnosis of CD is more supported by young, long course of the disease, abdominal pain, oral ulcers, perianal lesions, history of surgery (appendectomy, resection), and multi-site lesions. Short disease duration, abdominal mass and single-site lesion are more common in PIL. Biopsy diagnosis rate of PIL is higher than that of CD. In the case of the diagnosis of PIL after CD treatment, misdiagnosis, a combination of the two and drug induction should be considered.

Background To evaluate the efficacy and safety of Infliximab (IFX) in the management of refractory ulcerative colitis (UC) and UC with extra-intestinal manifestations. Methods The clinical data for 36 cases including refractory UC patients and UC patients with special extra-intestinal manifestations, who all accepted treatment with IFX, were analysed retrospectively. Results Among all the 36 cases, 33 were refractory UC (5 with extra-intestinal manifestations) and another 3 with special extra-intestinal manifestations (2 with perianal abscess and 1 with ankylosing spondylitis). After treatment with IFX, 13 patients achieved clinical remission, of whom 3 achieved mucosal healing, 15 achieved clinical response and 8 failed to respond. The total effective rate of IFX treatment was 77.78%, remission rate 36.11%; Among 8 cases with extra-intestinal manifestations, 5 patients‘ extra-intestinal manifestations improved and the efficacy rate was 62.5%. No serious adverse events occurred during observation. Conclusions IFX is effective and safe in the management of refractory UC and extra-intestinal manifestations.

Background Drought may become one of the greatest challenges for cereal production under future warming scenarios, and its impact on insect pest outbreaks is still controversial. To address this issue, life-history responses of the English grain aphid, Sitobion avenae (Fabricius), from three areas of different drought levels were compared under three water treatments. Results Significant differences were identified in developmental time, fecundity and adult weight among S. avenae clones from moist, semiarid and arid areas under all the three water treatments. Semiarid and arid area clones tended to have higher heritability for test life-history traits than moist area clones. We identified significant selection of water-deficit on the developmental time of 1st instar nymphs and adult weight for both semiarid and arid area clones. The impact of intermediate and severe water-stress on S. avenae’s fitness was neutral and negative (e.g., decreased fecundity and weight), respectively. Compared with arid-area clones, moist- and semiarid-area clones showed higher extents of adaptation to the water-deficit level of their respective source environment. Adult weight was identified as a good indicator for S. avenae’s adaptation potential under different water-stress conditions. After their exposure to intermediate water-deficit stress for only five generations, adult weight and fecundity tended to decrease for moist- and semiarid-area clones, but increase for arid-area clones. Conclusions It is evident from our study that S. avenae clones from moist, semiarid and arid areas have diverged under different water-deficit stress, and such divergence could have a genetic basis. The impact of drought on S. avenae’s fitness showed a water-level dependent pattern. Clones of S. avenae were more likely to become adapted to intermediate water-deficit stress than severe water-deficit stress. After continuous water-deficit stress of only five generations, the adaptation potential of S. avenae tended to decrease for moist and semiarid area clones, but increase for arid area clones. The rapid shift of aphids’ life-history traits and adaptation potential under drought could have significant implications for their evolutionary dynamics and outbreak risks in future climate change scenarios. Electronic supplementary material The online version of this article (10.1186/s12898-018-0173-0) contains supplementary material, which is available to authorized users.

Previous studies have demonstrated that total flavonoid extracts from

Objectives This study aims to explore the clinical profiles and onset age-related difference of executive dysfunctions and behavioral changes in early drug-naive patients with Parkinson's disease (PD). Methods A cross-sectional analysis on 419 early stage drug-naive PD patients was conducted. The frontal assessment battery (FAB) was used to assess executive functions and the frontal behavioral inventory (FBI) was used to assess behavioral changes. Results Executive dysfunctions were detected in 113 patients (27.0%), and 219 patients (52.3%) displayed varied degrees of behavioral changes. The most frequent affected domain for the FAB was lexical fluency (31.7%), while the three most frequent affected domains for the FBI were apathy (26.0%), irritability (24.3%) and inattention (20.8%). Compared to the early-onset PD (EOPD) patients, the late-onset PD (LOPD) patients exhibited significantly higher frequent damage in FAB especially similarities, motor series, and conflicting instructions as well as lower frequent damage in lexical fluency. The frequencies of FBI-abnormal were not different between the two groups. Multivariate analyses indicated that age at PD onset was independently associated with FAB total score and its subscores including lexical fluency, motor series, conflicting instructions and go-no go task, but it has no relationship with FBI total score and its subscores. Conclusions Executive deficits and behavioral changes are common in the early stage of PD. Age at PD onset is independently associated with the performance of executive functions. However, behavioral changes in PD may be not affected by onset age.

Additional file 1. Dynamics (from day 1 to day 15) of leaf water potential (SE) in wheat seedlings under three water treatments.

Keloid is an overgrowth of scar tissue that develops around a wound. The mechanisms of keloid formation and development still remain unknown, and no effective treatment is available. Searching for active natural resources may develop better prevention and treatment approaches for keloids. Aspidin PB is a natural resource with lower toxicity. We explored its effect on the regulation of TGF-β1-induced expression of type I collagen, CTGF, and α-SMA in keloid fibroblasts (KFs). Western blotting was used to detect the expression levels of type I collagen, CTGF, α-SMA, PI-3K/Akt and Smad-dependent and Smad-independent signaling pathway. The effect of aspidin PB on cell viability in human keloid fibroblasts was measured by MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide). The percentage of the apoptotic cells was studied by flow cytometry. Based on our results, we revealed that aspidin PB inhibited the production of type I collagen, CTGF, and α-SMA in TGF-β1-induced KFs by blocking PI-3K/Akt signaling pathway. The TGF-β1-mediated phosphorylated levels of Smad2/3 were inhibited by aspidin PB pretreatment. Conclusively, our study suggests that aspidin PB has an inhibitory effect on fibrogenesis in TGF-β1-induced KFs. Our findings imply that aspidin PB has a therapeutic potential to intervene and prevent keloids and other fibrotic diseases.

The exact relationship between the bending solutions of functionally graded material (FGM) beams based on the Levinson beam theory and those of the corresponding homogenous beams based on the classical beam theory is presented for the material properties of the FGM beams changing continuously in the thickness direction. The deflection, the rotational angle, the bending moment, and the shear force of FGM Levinson beams (FGMLBs) are given analytically in terms of the deflection of the reference homogenous Euler-Bernoulli beams (HEBBs) with the same loading, geometry, and end supports. Consequently, the solution of the bending of non-homogenous Levinson beams can be simplified to the calculation of transition coefficients, which can be easily determined by variation of the gradient of material properties and the geometry of beams. This is because the classical beam theory solutions of homogenous beams can be easily determined or are available in the textbook of material strength under a variety of boundary conditions. As examples, for different end constraints, particular solutions are given for the FGMLBs under specified loadings to illustrate validity of this approach. These analytical solutions can be used as benchmarks to check numerical results in the investigation of static bending of FGM beams based on higher-order shear deformation theories.

A subgroup A of a finite group G is called a TI-subgroup if either A ∩ A x = 1 or A ∩ A x = A holds for all x ∈ G. In this paper, finite group all of whose meta-cyclic subgroups are TI-subgroups are classified completely. In particular, such groups are solvable.

Epidermal stem cells could contribute to skin repair through the migration of cells from the neighboring uninjured epidermis, infundibulum, hair follicle, or sebaceous gland. However, little is known about the factors responsible for the complex biological processes in wound healing. Herein, we will show that the attracting chemokine, SDF-1/CXCR4, is a major regulator involved in the migration of epidermal stem cells during wound repair. We found that the SDF-1 levels were markedly increased at the wound margins following injury and CXCR4 expressed in epidermal stem cells and proliferating epithelial cells. Blocking the SDF-1/CXCR4 axis resulted in a significant reduction in epidermal stem cell migration toward SDF-1 in vitro and delayed wound healing in vivo, while an SDF-1 treatment enhanced epidermal stem cell migration and proliferation and accelerated wound healing. These results provide direct evidence that SDF-1 promotes epidermal stem cell migration, accelerates skin regeneration, and makes the development of new regenerative therapeutic strategies for wound healing possible.

Background In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. Methods Primary and advanced (relapsed from parental) University of Michigan squamous cell carcinoma cell lines were tested for sensitivity to cisplatin and gene expression profiles were compared between primary (cisplatin sensitive) and the relapsed (cisplatin resistant) cell lines by using Agilent microarrays. Additionally, differentially expressed genes phosphorylated AKT, and BAG-1, and BCL-xL were evaluated for expression using HNSCC tissue arrays. Results Advanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phosphorylated AKT, BAG-1, and BCL-xL were observed in advanced HNSCC compared to in that of primary HNSCC. Conclusion Increased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1289-2) contains supplementary material, which is available to authorized users.

We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34

Exosomes, as potential cancer diagnostic markers have received close attention in recent years. However, there is still a lack of simple and convenient methods to detect and quantitate exosomes. Herein, we used a simple paper-supported aptasensor based on luminescence resonance energy transfer (LRET) from upconversion nanoparticles (UCNPs) to gold nanorods (Au NRs) for the accessible determination of exosomes. When exosomes are present, the two sections of the aptamer can combine with the CD63 protein on the surface of exosomes and form a conjugation to close the distance between UCNPs and Au NRs, which initiates the LRET and promotes luminescence quenching. These variations can be monitored by the homemade image system, and the green channel intensities of obtained colored images were extracted with photoshop software to quantify the luminescence. As a result, the quenching of the luminescence of the UCNPs is linearly correlated to the concentration of the exosomes (in the range of 1.0 × 104 ~ 1.0 × 108 particles/μL), enabling the detection and quantification of the exosomes. Such approach can reach a low detection limit of exosomes (1.1 × 103 particles/μL) and effectively reduce the background signal by using UCNPs as a luminescent material. This study provides an efficient and practical approach to the detection of exosomes, which should lead to point-of-care testing in clinical applications.

BACKGROUND The aim of this study was to use a three-dimensional (3D) visualization technology to illustrate and describe the anatomical features of the penile suspensory ligamentous system based on the Visible Human data sets and to explore the suspensory mechanism of the penis for the further improvement of the penis-lengthening surgery. MATERIAL AND METHODS Cross-sectional images retrieved from the first Chinese Visible Human (CVH-1), third Chinese Visible Human (CVH-3), and Visible Human Male (VHM) data sets were used to segment the suspensory ligamentous system and its adjacent structures. The magnetic resonance imaging (MRI) images of this system were studied and compared with those from the Visible Human data sets. The 3D models reconstructed from the Visible Human data sets were used to provide morphological features of the penile suspensory ligamentous system and its related structures. RESULTS The fundiform ligament was a superficial, loose, fibro-fatty tissue which originated from Scarpa's fascia superiorly and continued to the scrotal septum inferiorly. The suspensory ligament and arcuate pubic ligament were dense fibrous connective tissues which started from the pubic symphysis and terminated by attaching to the tunica albuginea of the corpora cavernosa. Furthermore, the arcuate pubic ligament attached to the inferior rami of the pubis laterally. CONCLUSIONS The 3D model based on Visible Human data sets can be used to clarify the anatomical features of the suspensory ligamentous system, thereby contributing to the improvement of penis-lengthening surgery.

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kδ inhibitors, inhibited casein kinase-1 ε (CK1ε). Targeting CK1ε using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3Kδ/CK1ε inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1ε should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.

Additional file 1: Table S1. Information of Seven pairs of UMSCC cell lines. These pairs of cell lines were established from the same individual HNSCC patient. A represents the cell line was established from primary or first time excision, B represents the cell line was established from advanced or secondary excision.

Objective Epidermal stem cells (ESCs) play a critical role in wound healing, but the mechanism underlying ESC proliferation is not well defined. Here, we explore the effects of RhoA on ESC proliferation and the possible underlying mechanism. Methods Human ESCs were enriched by rapid adhesion to collagen IV. RhoA(+/+)(G14V), RhoA(-/-)(T19N) and pGFP control plasmids were transfected into human ESCs. The effect of RhoA on cell proliferation was detected by cell proliferation and DNA synthesis assays. Induction of PKN1 activity by RhoA was determined by immunoblot analysis, and the effects of PKN1 on RhoA in terms of inducing cell proliferation and cyclin D1 expression were detected using specific siRNA targeting PKN1. The effects of U-46619 (a RhoA agonist) and C3 transferase (a RhoA antagonist) on ESC proliferation were observed in vivo. Results RhoA had a positive effect on ESC proliferation, and PKN1 activity was up-regulated by the active RhoA mutant (G14V) and suppressed by RhoA T19N. Moreover, the ability of RhoA to promote ESC proliferation and DNA synthesis was interrupted by PKN1 siRNA. Additionally, cyclin D1 protein and mRNA expression levels were up-regulated by RhoA G14V, and these effects were inhibited by siRNA-mediated knock-down of PKN1. RhoA also promoted ESC proliferation via PKN in vivo. Conclusion This study shows that the effect of RhoA on ESC proliferation is mediated by activation of the PKN1-cyclin D1 pathway in vitro, suggesting that RhoA may serve as a new therapeutic target for wound healing.

A novel magnetic nanocomposite of carbonized bacterial cellulose (CBC) modified by CoFe2O4 nanocrystals with different contents were synthesized successfully using an effective solvothermal method. Scanning electron microscopy and transmission electron microscopy revealed that the CBC fibers were intertwined and networks were loaded with well-distributed CoFe2O4 nanoparticles. With a CBC/CoFe2O4 ratio of 10 wt%, the optimal reflection loss (RL) of −45 dB at 8.6 GHz with a thickness of 2.0 mm because of the enhanced interfacial polarization related to the developed ɛ″. This novel electromagnetic nanocomposite material is believed to have potential applications in terms of microwave-absorbing performance.

In this paper, we characterize finite groups G satisfying that, for every prime power divisor p n of the order of G, there exists a subgroup H of index p n (of order p n ) in G such that H is normal or abnormal in G.

Suppose that \(G\) is a finite group and \(H\), \(K\) are subgroups of \(G\). We say that \(H\) is weakly closed in \(K\) with respect to \(G\) if, for any \(g \in G\) such that \(H^{g}\le K\), we have \(H^{g}=H\). In particular, when \(H\) is a subgroup of prime-power order and \(K\) is a Sylow subgroup containing it, \(H\) is simply said to be a weakly closed subgroup of \(G\) or weakly closed in \(G\). In the paper, we investigate the structure of finite groups by means of weakly closed subgroups.

Free vibration of functionally graded beams with a through-width delamination is investigated. It is assumed that the material property is varied in the thickness direction as power law functions and a single through-width delamination is located parallel to the beam axis. The beam is subdivided into three regions and four elements. Governing equations of the beam segments are derived based on the Timoshenko beam theory and the assumption of ‘constrained mode’. By using the differential quadrature element method to solve the eigenvalue problem of ordinary differential equations governing the free vibration, numerical results for the natural frequencies of the beam are obtained. Natural frequencies of delaminated FGM beam with clamped ends are presented. Effects of parameters of the material gradients, the size and location of delamination on the natural frequency are examined in detail.

A subgroup H of a group G is said to be an SS-quasinormal (Supplement-Sylow-quasinormal) subgroup if there is a subgroup B of G such that HB = G and H permutes with every Sylow subgroup of B. A subgroup H of a group G is said to be S-quasinormally embedded inGif for every Sylow subgroup P of H, there is an S-quasinormal subgroup K in G such that P is also a Sylow subgroup of K. Groups with certain SS-quasinormal or S-quasinormally embedded subgroups of prime power order are studied.

Poly(L-lactic acid) (PLLA) foams for tissue engineering were prepared via thermally induced phase separation of a ternary system PLLA/dioxane/tetrahydrofuran (THF) followed by double solvent exchange (water and ethyl alcohol) and drying. An extension to solidification from solution of a previously developed method for solidification from the melt was adopted. The technique is based on a continuous cooling transformation (CCT) approach, consisting in recording the thermal history experienced by rapidly cooled samples and then analyzing the resulting sample morphology. Different foams were produced by changing the relative amount of dioxane and THF in the starting solution while the amount of polymer was kept constant. Results show that the final morphology and crystallinity (measured by DSC) depend on solvent power, which in its turn was determined by the ratio dioxane/THF, and a minimum of pore size, optimum final crystallinity and crystallization rate were achieved for a system containing 70 % of dioxane. Under this condition, a higher bulk density (evaluated by Hg intrusion porosimetry) and a larger specific surface area (measured by BET N2 sorption technique) was achieved. Copyright © 2004 Society of Chemical Industry

A subgroup H of a finite group G is said to be Hall subnormally embedded in G if H is a Hall subgroup of the subnormal closure H S G . In this paper, some new characterizations for finite groups are obtained based on the assumption that some subgroups are Hall subnormally embedded.

In abnormal skin wound healing, hypertrophic scars (HS) are characterized by excessive fibroblast hypercellularity and an overproduction of collagen, leading to atypical extracellular matrix (ECM) remodeling. Although the exact mechanisms of HS remain unclear, decreased HS fibroblast (HSFB) apoptosis and increased proliferation are evident in the development of HS. In this study, the contribution of the second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein (IAP)-binding protein with a low isoelectric point (pI) (Smac/DIABLO), an apoptosis-promoting protein released from the mitochondria, was investigated in human normal skin and HSFB cultures. The expression of Smac/DIABLO is usually decreased in many malignant tumors compared with normal tissues. Immunohistochemical analysis of skin tissues and the western blot analyses of fibroblasts revealed that the expression of Smac/DIABLO was lower in HS tissues compared with normal skin tissues. Of note, adenovirus-mediated Smac/DIABLO overexpression in the cultured HSFBs significantly reduced cell proliferation, as detected by the cell counting kit-8, and increased caspase-3 and -9 activity, as detected by spectrofluorimetry. In addition, it increased apoptosis, as detected by fluorescence-activated cell sorting (FACS). Furthermore, we found that the silencing of Smac with siRNA in the HSFBs induced a noticeable decrease in caspase-3 and -9 activity, leading to a significant reduction in apoptosis. In addition, the mRNA expression of type I and III pro-collagen detected in the HSFBs was significantly increased following the silencing of Smac with siRNA and was inhibited following Smac/DIABLO overexpression, as shown by real-time RT-PCR. In conclusion, Smac/DIABLO decreases the proliferation and increases the apoptosis of HSFBs. To our knowledge, the data from our study suggest for the first time that Smac/DIABLO is a novel therapeutic target for HS.