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In this paper, we prove that the ratio of the modulus of the iterates of two points in an escaping Fatou component could be bounded even if the orbit of the component contains a sequence of annuli whose moduli tend to infinity, and this cannot happen when the maximal modulus of the meromorphic function is uniformly large enough. In this way we extend certain related results for entire functions to meromorphic functions with infinitely many poles.

Purpose: To study the effect of traditional Chinese Medicine formula Taoren-Quyu decoction (TQD) on endometriosis. Method: Fifty female Wistar rats were randomly separated into five groups (10 rats/group): normal control, model (untreated) group, positive control (danazol), 200 mg/kg/day (low dose) or 400 mg/kg/day (high dose). All rats were prepared into endometriosis except for normal control rats. TDQ groups rats were orally administered of TQD for 5 weeks. After treatment, the rats were sacrificed by cervical dislocation. The number of total endometriotic lesions were counted. Serum levels of cancer antigen 125 (CA-125), interleukin 13 (IL-13), interleukin 18 (IL-18) and peritoneal fluid tumor necrosis factoralpha (TNF-α) were measured by ELISA kits. Result: Compared with control rats, TQD reduced the number of total endometriotic lesions significantly (12.7 ± 1.2, p < 0.01), as well as serum levels of CA-125 (6.4 ± 1.2 U/mL), IL-18 (118.6 ± 7.4 pg/mL), IL13 (6.3 ± 0.8 pg/mL) and peritoneal fluid TNF-α (231.5 ± 11.7 pg/mL) (p < 0.01). Conclusion: The results reveal that TQD exerts anti-endometriotic effect in rats by inhibiting inflammatory factors. Therefore, TQD has potentials for use in the treatment of endometriosis.

In this perspective, we outline that a space borne gravitational wave detector network combining LISA and Taiji can be used to measure the Hubble constant with an uncertainty less than 0.5% in ten years, compared with the network of the ground based gravitational wave detectors which can measure the Hubble constant within a 2% uncertainty in the next five years by the standard siren method. Taiji is a Chinese space borne gravitational wave detection mission planned for launch in the early 2030 s. The pilot satellite mission Taiji-1 has been launched in August 2019 to verify the feasibility of Taiji. The results of a few technologies tested on Taiji-1 are presented in this paper. Gravitational wave astronomy has opened the door to test general relativity and the effect of gravity in the Universe. The authors present the capabilities of an overlap between space gravitational wave detectors LISA and Taiji to constrain the Hubble constant to 0.5%, in 10 years, and what can be learned from the satellite pilot Taiji-1 launched in 2019.

Several studies have reported the prognostic value of ultrasound elastography (UE) in patients receiving neoadjuvant chemotherapy (NACT) for breast cancer. However, the assessment of parameters differed between shear-wave elastography and strain elastography in terms of measured elasticity parameter and mode of imaging. It is important, therefore, to assess the accuracy of the two modes of elastography.To assess the accuracy of UE for predicting the pathologic complete response (pCR) in breast cancer patients following NACT.A comprehensive and systematic search was performed in the databases of MEDLINE, EMBASE, SCOPUS, PubMed Central, CINAHL, Web of Science and Cochrane library from inception until December 2020. Meta-analysis was performed using STATA software "Midas" package.A total of 14 studies with 989 patients were included. The pooled sensitivities were 86% [95% confidence interval (CI): 76%-92%] for UE, 77% (95%CI: 68%-84%) for shear-wave elastography, and 92% (95%CI: 73%-98%) for strain-wave elastography. The pooled score specificities were 86% (95%CI: 80%-90%) for UE, 84% (95%CI: 72%-91%) for shear-wave elasticity, and 87% (95%CI: 81%-92%) for strain-wave elastography. A significant heterogeneity was found among studies based on the chi-square test results and anStrain-wave type of UE can accurately predict the pCR following NACT amongst breast cancer patients. Studies exploring its accuracy in different ethnic populations are required to strengthen the evidence.

The spherically convergent plasma fusion (SCPF) scheme is a robust approach to provide a high-brightness pulsed neutron source. The performance of the SCPF driven by the long-pulsed laser is investigated. The experiments, with the laser pulse duration in a range of 0.5 ns to 3 ns, were implemented on the ShenGuang-II Upgrade facility and a 100 kJ level laser facility. The intensity of the laser beam was about multiple 1014 W cm−2. The measured D–D reaction neutron yields were in a range of 7.3 × 108 to 1.01 × 1011, while the driven laser energies were in a range of 2.1 kJ to 100.5 kJ. The temporal self-emitted x-ray flux and image were measured. It showed that the plasma core could be maintained for a longer time in the long duration shots. The neutron reaction rate was measured on the 100 kJ level laser facility. The full width at half maximum reached about 1 ns in the shot with 2 ns duration laser. The scaling law of the measured yields with respect to the laser power and the pulse duration were presented. The neutron yield was able to be increased by increasing the power and extending the duration.

In this paper, in terms of the hyperbolic metric, we give a condition under which the image of a hyperbolic domain of an analytic function contains a round annulus centred at the origin. From this, we establish results on the multiply connected wandering domains of a meromorphic function that contain large round annuli centred at the origin. We thereby successfully extend the results of transcendental meromorphic functions with finitely many poles to those with infinitely many poles.

Background: The Food and Drug Administration recently announced that the use of morcellation may cause fibroids or pelvic dissemination and metastasis of uterine sarcoma; therefore, the use of morcellation is limited in the USA. A large sample study is necessary to assess the proportion of uterine malignant tumors found in patients with laparoscopic myomectomy. Methods: A national multicenter study was performed in China. From 2002 to 2014, 33,723 cases were retrospectively selected. We calculated the prevalence and recorded the clinical characteristics of the patients with malignancy after morcellation application. A total of 62 cases were finally pathologically confirmed as malignant postoperatively. Additionally, the medical records of the 62 patients were analyzed in details. Results: The proportion of postoperative malignancy after morcellation application was 0.18% (62/33,723) for patients who underwent laparoscopic myomectomy. Nearly 62.9% (39/62) of patients had demonstrated blood flow signals in the uterine fibroids before surgery. And, 23 (37.1%) patients showed rapid growth at the final preoperative ultrasound. With respect to the pathological types, 38 (61.3%) patients had detectable endometrial stromal sarcoma, 13 (21.0%) had detectable uterine leiomyosarcoma, only 3 (3.2%) had detectable carcinosarcoma, and 5 (8.1%) patients with leiomyoma had an undetermined malignant potential. Conclusions: The proportion of malignancy is low after using morcellation in patients who undergo laparoscopic myomectomy. Patients with fast-growing uterine fibroids and abnormal ultrasonic tumor blood flow should be considered for malignant potential, and morcellation should be avoided. Key words: Laparoscopic Myomectomy; Morcellation; Sarcoma

Background: While chimeric antigen receptor T cells (CAR T-cells) induce dramatic remissions of refractory or recurrent B cell malignancies, the durability of these remissions is frequently limited by subsequent reduction in circulating CAR T-cells and/or by diminution of their effector function. We hypothesized that we could overcome this therapeutic limitation and increase the functional activity and longevity of CAR T-cells by selectively deriving them from virus-specific effector memory T cells. We have developed biologics we termed synTacs (artificial immunological synapse for T-cell activation), which selectively activate and expand antigen-specific CD8+ T cells in vitro and in vivo by recapitulating signals delivered at the immunological synapse. The synTacs consist of dimeric Fc domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to virus-derived peptides. Treatment of PBMCs from CMV-exposed donors with synTacs presenting a CMV-derived peptide (pp65-NLVPMVATV) induce vigorous and selective ex vivo and in vivo expansion of highly functional CMV-specific CD8+ T cells, with potent antiviral activity. We used these synTacs to selectively generate CAR T-cells from CMV-specific effector memory CD8+ T cells, which could be further expanded by restimulation with the CMV-specific synTacs. Methods: We treated PBMCs from CMV-exposed donors in media supplemented with either IL-2 or IL-7/12/15 with a synTac containing the CMV-derived pp65 peptide presented by HLA-A2 MHC molecules linked to ligands capable of stimulating CD28- or 4-1BB-dependent costimulatory pathways. PBMCs activated either with anti-CD3/CD28 or the CMV-specific synTacs were transduced with lentivirus expressing an anti-CD19 CAR and a GFP reporter gene. CMV-specific CD8+ T cells were quantified by tetramer staining and CAR T-cells were detected by GFP expression determined by flow cytometric analysis. The functional activity of the CD19 CAR T-cells was determined by a B cell-specific cytotoxic assay. Results: After 7 days, treatment of PBMCs with CMV-specific synTacs rapidly induced robust activation and >50-fold expansion of CMV-specific CD8+ T cells expressing effector memory markers. Treatment of the PBMCs with CMV-specific synTacs selectively activated CMV-specific T cells and enabled them to be specifically transduced with a CD19-specific CAR lentivirus and converted into CD19 CAR T-cells. These CMV-specific CD19 CAR T-cells displayed potent dose-responsive cytotoxic activity targeting purified primary B cells. Furthermore, these CMV-specific CD19 CAR T-cells could be selectively expanded by in vitro treatment with CMV-specific synTacs. Conclusions: SynTacs are versatile immunotherapeutics capable of selective in vitro and in vivo activation and expansion of virus-specific CD8+ T cells with potent antiviral cytotoxic activity. After selective lentiviral transduction and conversion into CD19 CAR T-cells, their co-expression of the CMV-specific T cell receptor enabled them to be potently stimulated and activated by in vitro treatment with CMV synTacs. The modular design of synTacs facilitates efficient coupling of other costimulatory ligands - such as OX40 or GITRL - or cytokines, such as IL-2, IL-7, or IL-15, to enable the selective in vivo delivery of defined costimulatory signals or cytokines to the CAR T-cells expressing CMV-specific TCR. This strategy has the potential to boost the in vivo activity of tumor-specific CAR T-cells after infusion and enable more durable and potent treatment of refractory/recurrent B cell malignancies. Disclosures Almo: Cue Biopharma: Current equity holder in publicly-traded company, Patents & Royalties: Patent number: 62/013,715, Research Funding. Goldstein:Cue Biopharma: Research Funding.

Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4+ T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo-reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcRnull, suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcRnull-treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies.IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. ispartof: Journal of Virology vol:93 issue:6 ispartof: location:United States status: published

We consider a problem of whether a property of holomorphic curves on a subset $X$ of the complex plane can be extended to the whole complex plane. In this paper, the property we consider is uniqueness of holomorphic curves. We introduce the propagation set. Simply speaking, $X$ is a propagation set if linear relation of holomorphic curves on the part of preimage of hyperplanes contained in $X$ can be extended to the whole complex plane. If the holomorphic curves are of infinite order, we prove the existence of a propagation set which is the union of a sequence of disks (In fact, the method applies to the case of finite order). For a general case, the union of a sequence of annuli will be a propagation set. The classic five-value theorem and four-value theorem of R. Nevanlinna are established in such propagation sets., Comment: 32 pages

Curing HIV infection has been thwarted by the persistent reservoir of latently infected CD4(+) T cells, which reinitiate systemic infection after antiretroviral therapy (ART) interruption. To evaluate reservoir depletion strategies, we developed a novel preclinical in vivo model consisting of immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells (PBMC) from long-term ART-suppressed HIV-infected donors. In the absence of ART, these mice developed rebound viremia which, 2 weeks after PBMC injection, was 1,000-fold higher (mean = 9,229,281 HIV copies/ml) in mice injected intrasplenically than in mice injected intraperitoneally (mean = 6,838 HIV copies/ml) or intravenously (mean = 591 HIV copies/ml). One week after intrasplenic PBMC injection, in situ hybridization of the spleen demonstrated extensive disseminated HIV infection, likely initiated from in vivo-reactivated primary latently infected cells. The time to viremia was delayed significantly by treatment with a broadly neutralizing antibody, 10-1074, compared to treatment with 10-1074-FcR(null), suggesting that 10-1074 mobilized Fc-mediated effector mechanisms to deplete the replication-competent reservoir. This was supported by phylogenetic analysis of Env sequences from viral-outgrowth cultures and untreated, 10-1074-treated, or 10-1074-FcR(null)-treated mice. The predominant sequence cluster detected in viral-outgrowth cultures and untreated mouse plasma was significantly reduced in the plasma of 10-1074-treated mice, whereas two new clusters emerged that were not detected in viral-outgrowth cultures or plasma from untreated mice. These new clusters lacked mutations associated with 10-1074 resistance. Taken together, these data indicated that 10-1074 treatment depletes the reservoir of latently infected cells harboring replication competent HIV. Furthermore, this mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies. IMPORTANCE Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors. Reactivation and dissemination of HIV infection was visualized in the mouse spleens in parallel with the onset of viremia. The applicability of this model for evaluating reservoir depletion treatments was demonstrated by establishing, through delayed time to viremia and phylogenetic analysis of plasma virus, that treatment of these humanized mice with a broadly neutralizing antibody, 10-1074, depleted the patient-derived population of latently infected cells. This mouse model represents a new in vivo approach for the preclinical evaluation of new HIV cure strategies.

Epidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4 + T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4 + T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2 env -NLuc, which expresses an env gene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2 env -NLuc intravaginal challenge was increased ∼4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4 + T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract. IMPORTANCE Multiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4 + T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition.

Natural killer (NK) cells with anti-HIV-1 activity may inhibit HIV-1 replication and dissemination during acute HIV-1 infection. We hypothesized that the capacity of NK cells to suppress acute in vivo HIV-1 infection would be augmented by activating them via treatment with an interleukin-15 (IL-15) superagonist, IL-15 bound to soluble IL-15Rα, an approach that potentiates human NK cell-mediated killing of tumor cells. In vitro stimulation of human NK cells with a recombinant IL-15 superagonist significantly induced their expression of the cytotoxic effector molecules granzyme B and perforin; their degranulation upon exposure to K562 cells, as indicated by cell surface expression of CD107a; and their capacity to lyse K562 cells and HIV-1-infected T cells. The impact of IL-15 superagonist-induced activation of human NK cells on acute in vivo HIV-1 infection was investigated by using hu-spl-PBMC-NSG mice, NOD-SCID-IL2rγ −/− (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMCs) which develop productive in vivo infection after intrasplenic inoculation with HIV-1. IL-15 superagonist treatment potently inhibited acute HIV-1 infection in hu-spl-PBMC-NSG mice even when delayed until 3 days after intrasplenic HIV-1 inoculation. Removal of NK cells from human PBMCs prior to intrasplenic injection into NSG mice completely abrogated IL-15 superagonist-mediated suppression of in vivo HIV-1 infection. Thus, the in vivo activation of NK cells, integral mediators of the innate immune response, by treatment with an IL-15 superagonist increases their anti-HIV activity and enables them to potently suppress acute in vivo HIV-1 infection. These results indicate that in vivo activation of NK cells may represent a new immunotherapeutic approach to suppress acute HIV-1 infection. IMPORTANCE Epidemiological studies have indicated that NK cells contribute to the control of HIV-1 infection, and in vitro studies have demonstrated that NK cells can selectively kill HIV-1-infected cells. We demonstrated that in vivo activation of NK cells by treatment with an IL-15 superagonist that potently stimulates the antitumor activity of NK cells markedly inhibited acute HIV-1 infection in humanized mice, even when activation of NK cells by IL-15 superagonist treatment is delayed until 3 days after HIV-1 inoculation. NK cell depletion from PBMCs prior to their intrasplenic injection abrogated the suppression of in vivo HIV-1 infection observed in humanized mice treated with the IL-15 superagonist, demonstrating that activated human NK cells were mediating IL-15 superagonist-induced inhibition of acute HIV-1 infection. Thus, in vivo immunostimulation of NK cells, a promising therapeutic approach for cancer therapy, may represent a new treatment modality for HIV-1-infected individuals, particularly in the earliest stages of infection.

Antibodies bound to human immunodeficiency virus type 1 (HIV-1) envelope protein expressed by infected cells mobilize antibody-dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to a functional HIV-1 cure. The most effective antibodies for controlling and eradicating HIV-1 infection would likely have the dual capacities of potently neutralizing a broad range of HIV-1 isolates and effectively mobilizing HIV-1-specific ADCC to eliminate HIV-1-infected cells. For this purpose, we constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and simian-human immunodeficiency virus (SHIV) infection in humanized mouse and macaque models, respectively, including in vivo neutralization of HIV-1 strains resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. We developed a novel humanized mouse model to evaluate in vivo human NK cell-mediated elimination of HIV-1-infected cells by ADCC and utilized it to demonstrate that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir. IMPORTANCE Mobilization of antibody-dependent cellular cytotoxicity (ADCC) to eliminate reactivated latent HIV-1-infected cells is a strategy which may contribute to depleting the HIV-1 reservoir and achieving a functional HIV-1 cure. To more effectively mobilize ADCC, we designed and constructed LSEVh-LS-F, a broadly neutralizing, defucosylated hexavalent fusion protein specific for both the CD4 and coreceptor gp120-binding sites. LSEVh-LS-F potently inhibited in vivo HIV-1 and SHIV infection in humanized mouse and macaque models, respectively, including in vivo neutralization of an HIV-1 strain resistant to the broadly neutralizing antibodies VRC01 and 3BNC117. Using a novel humanized mouse model, we demonstrated that LSEVh-LS-F rapidly mobilized NK cells to eliminate >80% of HIV-1-infected cells in vivo 1 day after its administration. The capacity of LSEVh-LS-F to eliminate HIV-1-infected cells via ADCC combined with its broad neutralization activity supports its potential use as an immunotherapeutic agent to eliminate reactivated latent cells and deplete the HIV-1 reservoir.

Functional analysis of T-cell responses in HIV-infected individuals has indicated that virus-specific CD8 + T cells with superior antiviral efficacy are well represented in HIV-1 controllers but are rare or absent in HIV-1 progressors. To define the role of individual T-cell receptor (TCR) clonotypes in differential antiviral CD8 + T-cell function, we performed detailed functional and mass cytometric cluster analysis of multiple CD8 + T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 epitope KK10 (KRWIILGLNK). Effective and ineffective CD8 + T-cell clones segregated based on responses to HIV-1-infected and peptide-loaded target cells. Following cognate peptide stimulation, effective HIV-specific clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained nonlytic cytokine and chemokine secretion than ineffective clones. To evaluate the TCR clonotype contribution to CD8 + T-cell function, we cloned the TCR α and β chain genes from one effective and two ineffective CD8 + T-cell clones from an elite controller into TCR-expressing lentivectors. We show that Jurkat/MA cells and primary CD8 + T cells transduced with lentivirus expressing TCR from one of the ineffective clones exhibited a level of activation by cognate peptide and inhibition of in vitro HIV-1 infection, respectively, that were comparable to those of the effective clonotype. Taken together, these data suggest that the potent antiviral capacity of some HIV-specific CD8 + T cells is a consequence of factors in addition to TCR sequence that modulate functionality and contribute to the increased antiviral capacity of HIV-specific CD8 + T cells in elite controllers to inhibit HIV infection. IMPORTANCE The greater ex vivo antiviral inhibitory activity of CD8 + T cells from elite controllers than from HIV-1 progressors supports the crucial role of effective HIV-specific CD8 + T cells in controlling HIV-1 replication. The contribution of TCR clonotype to inhibitory potency was investigated by delineating the responsiveness of effective and ineffective CD8 + T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 Gag-derived peptide, KK10 (KRWIILGLNK). KK10-stimulated “effective” CD8 + T-cell clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained cytokine and chemokine secretion than “ineffective” CD8 + T-cell clones. However, TCRs cloned from an effective and one of two ineffective clones conferred upon primary CD8 + T cells the equivalent potent capacity to inhibit HIV-1 infection. Taken together, these data suggest that other factors aside from intrinsic TCR-peptide-major histocompatibility complex (TCR-peptide-MHC) reactivity can contribute to the potent antiviral capacity of some HIV-specific CD8 + T-cell clones.

The finite element model of electric stop valve with flange bolts preload and valve stem force was established to improve the valve stress calculation method which was based only on action of fluid pressure, thermal stresses and pipe reaction forces. The principle and application of pretension load elements were expounded. By ANSYS, the stresses of this valve with preload and valve stem force were calculated, and the Mises equivalent stresses contour and some values of key position of whole valve were obtained. The results indicate the influence of the stresses on the valve caused by preload of bolt mounted on the flange and valve stem force can not be ignored.

In the paper, uniaxial compression creep tests were carried out at 25°C after the asphalt concrete corroded by different chloride solution concentrations, suffering different times of diurnal temperature variation cycle. Creep stiffness module and the ratio of residual strain were employed to evaluate the viscoelastic properties of asphalt concrete. According to the winter in Wuhan district, the viscoelastic properties of asphalt concrete under the action of chloride corrosion together with day-night cycle were preliminarily studied, and the corresponding viscoelastic parameters were determined with the help of Burgers model. The results show that chloride corrosion and day-night cycle can separately affect the viscoelastic properties of asphalt concrete, and the influence becomes severer while they act together.

Let $f$ be an entire function and denote by $f^\#$ be the spherical derivative of $f$ and by $f^n$ the $n$-th iterate of $f$. For an open set $U$ intersecting the Julia set $J(f)$, we consider how fast $\sup_{z\in U} (f^n)^\#(z)$ and $\int_U (f^n)^\#(z)^2 dx\:dy$ tend to $\infty$. We also study the growth rate of the sequence $(f^n)^\#(z)$ for $z\in J(f)$., 20 pages

Mice cannot be used as a model to evaluate HIV-1 therapeutics because they do not become infected by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 replication. This has limited their use for in vivo assessment of anti-HIV-1 therapeutics and the mechanism by which cofactors, such as illicit drug use accelerate HIV-1 replication and disease course in substance abusers. Here, we describe the development and application of two in vivo humanized mouse models that are highly sensitive and useful models for the in vivo evaluation of candidate anti-HIV therapeutics. The first model, hu-spl-PBMC-NSG mice, uses NOD-SCID IL2rγ(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMC) which develop productive splenic HIV-1 infection after intrasplenic inoculation with a replication-competent HIV-1 expressing Renilla reniformis luciferase (HIV-LucR) and enables investigators to use bioluminescence to visualize and quantitate the temporal effects of therapeutics on HIV-1 infection. The second model, hCD4/R5/cT1 mice, consists of transgenic mice carrying human CD4, CCR5 and cyclin T1 genes, which enables murine CD4-expressing cells to support HIV-1 entry, Tat-mediated LTR transcription and consequently develop productive infection. The hCD4/R5/cT1 mice develop disseminated infection of tissues including the spleen, small intestine, lymph nodes and lungs after intravenous injection with HIV-1-LucR. Because these mice can be infected with HIV-LucR expressing transmitted/founder and clade A/E and C Envs, these mouse models can also be used to evaluate the in vivo efficacy of broadly neutralizing antibodies and antibodies induced by candidate HIV-1 vaccines. Furthermore, because hCD4/R5/cT1 mice can be infected by vaginal inoculation with replication-competent HIV-1 expressing NanoLuc (HIV-nLucR)-, this mouse model can be used to evaluate the mechanisms by which substance abuse and other factors enhance mucosal transmission of HIV-1.

We aimed to evaluate the association of preoperative plasma fibrinogen levels with the clinicopathological parameters, disease-free survival, and overall survival in patients with renal cell carcinoma. We retrospectively studied 286 patients with renal cell carcinoma who underwent radical nephrectomy from 2000 to 2003 at one center. The plasma fibrinogen was routinely determined before operation in all patients. The correlation of preoperative plasma fibrinogen levels with clinicopathological findings was evaluated by t-test or analysis of variance (ANOVA) methods. As well, univariate and multivariate analyses were used to determine the association between the preoperative level of plasma fibrinogen and survival duration. An elevated level of plasma fibrinogen was positively related to the Fuhrman grade (P

A finite-difference numerical model is used to study the influence of surface textures configuration and depth on lubrication performance of hydrodynamic journal bearing. Reynolds equation is adopted to calculate the bearing dimensionless load carrying capacity, friction force and friction coefficient under different eccentricity ratio, textures configuration and depth. Results show that partial texturing in the inlet zone with shallow dimples and in the cavitation zone with deep dimples could improve bearing performance appreciably. The effect of the textures on bearing tribological performance was influenced by the eccentricity ratio. The advantage of partial textures decreases when the eccentricity ratio increases.

We investigate in which cases the boundary of a multiply connected wandering domain of an entire function is uniformly perfect. We give a general criterion implying that it is not uniformly perfect. This criterion applies in particular to examples of multiply connected wandering domains given by Baker. We also provide examples of infinitely connected wandering domains whose boundary is uniformly perfect., Comment: 19 pages

Based on the nonlinear dynamical model of the gear system considering friction, the system periodic motion is studied by the Shooting algorithm, also the stability and bifurcation properties of the system periodic motion is obtained by Floquet multipliers. The system's evolvement properties are presented under different frictional coefficients. The conclusions are indicated that friction can influence the properties of periodic motion, which improves the stability of periodic motion on a certain extent, but produces new instability periodic motion. The conclusions provide a theoretical reference for designing of this system.

A finite-difference numerical model is used to study the influence of surface texture on lubrication performance of hydrodynamic journal bearing. Reynolds equation is adopted to calculate the bearing load carrying capacity, friction force and friction coefficient under different width-diameter ratio, different eccentricity ratio and different texture location. Results show that partial texture along the circumferential direction on the bearing with small width-diameter ratio will increase bearing performance appreciably. Partial texture along the axial direction will decrease friction coefficient effectively, especially at the film inlet zone or the position of film pressure trending to zero.

The reutilization of waste concrete and fly ash produced by power plant is one way to develop green concrete. The addition of fly ash in recycled aggregate concrete has two methods, named equivalent replace and super-substitute technique. The workability of fresh concrete, compression strength, spilt and flexural strength of recycled aggregate concrete with different content of fly ash at different curing age are tested. Durability performance index such as sulfate attack, drying shrinkage and wear resistance is acquired base on the corresponding test. The result shows that the fluidity of fresh concrete is improved by the addition of fly ash. Before the age of 28d, the compression and flexural strength of recycled aggregate concrete with the contain of fly ash is lower than concrete without fly ash, after the age of 60d, the compression and flexural strength for FRC-10, FRC-10-2, FRC-10-4 are even higher than that of concrete without fly ash. The optimum equivalent replace ratio is 10%, and super-substitute ratio is 20% according to the compression and flexural strength. The performance of sulfate attack resistance, drying shrinking and wearing resistance of recycled aggregate concrete are significant improved as the containing of fly ash.

The Notch signaling pathway plays an important role in the stem cell signaling network and contributes to tumorigenesis. However, the functions of Notch signaling in ovarian cancer stem cells (OCSCs) are not well understood. We aimed to investigate the effects of Notch blockade on self-renewal and stemness maintenance of OCSCs.Ovarian cancer stem-like cells were enriched from ovarian cancer cell lines in serum-free medium. A γ-secretase inhibitor, (DAPT), was used to block Notch signaling. MTT assays were performed to assess self-renewal and proliferation inhibition, flow cytometry was performed to analyze cell surface marker and immunofluorescence, Western Blot and Real-time RT-PCR assays were performed to detect Oct4 and Sox2 protein and mRNA expression of the Ovarian cancer stem-like cells treated with DAPT.Notch blockade markedly inhibits self-renewal and proliferation of ovarian cancer stem-like cells, significantly downregulates the expression of OCSCs-specific surface markers, and reduces protein and mRNA expression of Oct4 and Sox2 in OCSC-like cells.Our results suggest that Notch signaling is not only critical for the self-renewal and proliferation of OCSCs, but also for the stemness maintenance of OCSCs. The γ-secretase inhibitor is a promising treatment targeting OCSCs.

The bearing capacity property of large-diameter bored cast-in-situ deep and post-grouting pile is analyzed on the basis of measuring data of static load test and axial stress measure data. The study indicates that the large-diameter bored cast-in-situ deep and post-grouting pile show the characteristics of the friction when the bearing course at pile end is sand, when the pile top load is greater than 18000kN, the pile end begin to resistance and the share proportion is small, only 1% to 10%; the load settlement cure is gradual decline, no inflection point, the settlement of pile compression only accounted for about 15%, The developing degree of side resistance is well corresponding to the relative displacement between pile and soil. The side resistances significantly enhance effect, the measured value of the soil side resistance is 1.3 to 1.5 times of survey report recommended.

Squeezed branch pile is based on the traditional uniform pile in development of a new type of pile, with a high bearing capacity, settlement of small features widely used in the engineering. Based on the actual project site static test, analyzed the vertical bearing capacity characteristics of two adjacent squeezed branch piles; By means of testing of the pile stress gauge steel embedded in different parts of piles, the axial force transfer characteristics of the body, support plate side resistance drag and play characteristics of the squeezed branch pile were analyzed. The results showed that: the branch pile Q-S curve is slowly varying type, the three branch share of the load ratio increases with the pile top load increases and then decreases, load sharing ratio of 12% or so. The side resistance increased with the pile top displacement, the curve showed significant enhancement traits. Measured friction value of two test piles is too conservative under the existing norms, the actual measured value of 1.2～1.6 times of the standardized value.

Following the definition of parabolic rational functions and in view of the behavior of transcendental meromorphic functions, we give the definition of parabolic transcendental meromorphic functions. We discuss their dynamical behavior and prove the existence of conformal measures and invariant measures over their Julia sets, thus extending Denker and Urba ´ nski’s work on parabolic rational functions. However, our method for proving the existence of the conformal measures differs in that we use the Perron‐ Frobenius‐Ruelle operator.

The theory of value distribution of meromorphic functions is developed in two directions: module distribution and argument distribution. This article is a survey on two aspects of the value distribution of meromorphic functions with respect to arguments and it also includes some new results. The first part is to survey a characterization of growth of a transcendental meromorphic function for which the number of a-points in certain curvilinear sectors, specially in angular domains, is restricted. The second part is devoted to the discussion of singular directions: the Julia, Borel directions and T-directions. In the final section, some problems will be given for further discussion.

In recent years, the rapid development of the national economy has leaded to a variety of social and environmental problems, among which the waste of resources and environmental pollution caused by food packaging can’t be ignored. Basing on the existing food packaging problems in Chinese market and the consumers’ attitudes and ideas, this paper will explore the food packaging designs methods upon the green concept, and analyze their future development trends.

The primary aim of this study is to evaluate the clinical significance of E-cadherin protein expression and the methylation status in CDH1 promoter in endometrial cancer. The expression of E-cadherin and methylation in its promoter region was analyzed, retrospectively, in 152 clinical tissue samples from patients with endometrial lesions. We found that the hypermethylation of CDH1 promoter, which caused low expression of E-cadherin in endometrial cancer, was associated with not only clinicopathological progress of endometrial cancer but also with the overall 5-year clinical survival rate. The findings provide the potential therapeutic and prognostic target molecule for patients with endomethrial cancer.

Due to the inherent immune evasion properties of the HIV envelope, broadly neutralizing HIV-specific antibodies capable of suppressing HIV infection are rarely produced by infected individuals. We examined the feasibility of utilizing genetic engineering to circumvent the restricted capacity of individuals to endogenously produce broadly neutralizing HIV-specific antibodies. We constructed a single lentiviral vector that encoded the heavy and light chains of 2G12, a broadly neutralizing anti-HIV human antibody, and that efficiently transduced and directed primary human B cells to secrete 2G12. To evaluate the capacity of this approach to provide protection from in vivo HIV infection, we used the humanized NOD/SCID/γ c null mouse model, which becomes populated with human B cells, T cells, and macrophages after transplantation with human hematopoietic stem cells (hu-HSC) and develops in vivo infection after inoculation with HIV. The plasma of the irradiated NOD/SCID/γ c null mice transplanted with hu-HSC transduced with the 2G12-encoding lentivirus contained 2G12 antibody, likely secreted by progeny human lymphoid and/or myeloid cells. After intraperitoneal inoculation with high-titer HIV-1 JR-CSF , mice engrafted with 2G12-transduced hu-HSC displayed marked inhibition of in vivo HIV infection as manifested by a profound 70-fold reduction in plasma HIV RNA levels and an almost 200-fold reduction in HIV-infected human cell numbers in mouse spleens, compared to control hu-HSC-transplanted NOD/SCID/γ c null mice inoculated with equivalent high-titer HIV-1 JR-CSF . These results support the potential efficacy of this new gene therapy approach of using lentiviral vectors encoding a mixture of broadly neutralizing HIV antibodies for the treatment of HIV infection, particularly infection with multiple-drug-resistant isolates.

In this paper we make a further discussion of a relationship between the number of fixed-points and distribution of singular values along the round annuli centered at the origin of a transcendental meromorphic function. To attain our purpose we first establish a fundamental inequality for the modulus of derivative of a holomorphic covering mapping whose image is an annulus by virtue of the hyperbolic metric. The inequality is of independent significance. We make a simple survey on some domain constants for hyperbolic domains.

In this paper we characterize the relation between two entire functions which are permutable and satisfy certain algebraic differential equations.

The effectiveness of genetic engineering with lentivectors to protect transplanted cells from allogeneic rejection was examined using, as a model, type 1 diabetes treatment with beta-cell transplantation, whose widespread use has been limited by the requirement for sustained immunosuppressive treatment to prevent graft rejection. We examined whether lentivectors expressing select immunosuppressive proteins encoded by the adenoviral genome early region 3 (AdE3) would protect transplanted beta-cells from an alloimmune attack. The insulin-producing beta-cell line beta TC-tet (C3HeB/FeJ-derived) was transduced with lentiviruses encoding the AdE3 proteins gp19K and RID alpha/beta. The efficiency of lentiviral transduction of beta TC-tet cells exceeded 85%. Lentivector expression of gp19K decreased surface class I major histocompatibility complex expression by over 90%, whereas RID alpha/beta expression inhibited cytokine-induced Fas upregulation by over 75%. beta TC-tet cells transduced with gp19K and RID alpha/beta lentivectors, but not with a control lentivector, provided prolonged correction of hyperglycemia after transplantation into diabetic BALB/c severe combined immunodeficient mice reconstituted with allogeneic immune effector cells or into diabetic allogeneic BALB/c mice. Thus, genetic engineering of beta-cells using gp19K- and RID alpha/beta-expressing lentiviral vectors may provide an alternative that has the potential to eliminate or reduce treatment with the potent immunosuppressive agents necessary at present for prolonged engraftment with transplanted islets.

Inflammatory mediators and viral products produced by human immunodeficiency virus (HIV)-infected microglia and astrocytes perturb the function and viability of adjacent uninfected neuronal and glial cells and contribute to the pathogenesis of HIV-associated neurocognitive disorders (HAND). In vivo exposure to lipopolysaccharide (LPS) activates parenchymal microglia and astrocytes and induces cytokine and chemokine production in the brain. HIV-infected individuals display increased circulating LPS levels due to microbial translocation across a compromised mucosa barrier. We hypothesized that HIV-infected microglia and astrocytes display increased sensitivity to the proinflammatory effects of LPS, and this combines with the increased levels of systemic LPS in HIV-infected individuals to contribute to the development of HAND. To examine this possibility, we determined the in vivo responsiveness of HIV-infected microglia and astrocytes to LPS using our mouse model, JR-CSF/human cyclin T1 (JR-CSF/hu-cycT1) mice, which are transgenic for both an integrated full-length infectious HIV type 1 (HIV-1) provirus derived from the primary R5-tropic clinical isolate HIV-1JR-CSFregulated by the endogenous HIV-1 long terminal repeat and the hu-cycT1 gene under the control of a CD4 promoter. In the current report, we demonstrated that in vivo-administered LPS more potently activated JR-CSF/hu-cycT1 mouse microglia and astrocytes and induced a significantly higher degree of monocyte chemoattractant protein production by JR-CSF/hu-cycT1 astrocytes compared to that of the in vivo LPS response of control littermate mouse microglia and astrocytes. These results indicate that HIV infection increases the sensitivity of microglia and astrocytes to inflammatory stimulation and support the use of these mice as a model to investigate various aspects of the in vivo mechanism of HIV-induced neuronal dysfunction.