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Background: Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. Materials and methods: Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. Results: Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3–67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1–6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. Conclusion: TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.Methods: Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.Results: At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean ± SEM: 0.118 ± 0.01 [n = 3] in Vegf-A mRNA transfected group (VEGF) vs 0.056 ± 0.01 [n = 3] in no RNA [p < 0.05] vs 0.063 ± 0.02 [n = 4] in Gfp mRNA transfected group (GFP) [p < 0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085 ± 0.02 [n = 4] in VEGF vs 0.030 ± 0.004 [n = 4] in no RNA [p < 0.05] vs 0.034 ± 0.01 [n = 5] in GFP [p < 0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048 ± 0.013 [n = 3] in VEGF vs 0.015 ± 0.0051 [n = 4] in no RNA [p < 0.01] vs 0.013 ± 0.0046 [n = 4] in GFP [p < 0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049 ± 0.0042 [n = 8] in VEGF vs 0.029 ± 0.0052 [n = 5] in no RNA [p < 0.05] vs 0.027 ± 0.0056 [n = 4] in GFP [p < 0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292 ± 0.0032 μl [n = 7] in VEGF vs 0.0178 ± 0.0021 μl [n = 5] in no RNA [p < 0.01] vs 0.0129 ± 0.0012 μl [n = 4] in GFP [p < 0.001]).Conclusions/interpretation: Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants. [ABSTRACT FROM AUTHOR]

Copyright of Kind en Adolescent is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Parental knowledge about adolescents' activities is an identified protective factor in terms of adolescent adjustment. While research on parental knowledge has focused on adolescents' offline behavior, there is little empirical understanding of parental knowledge about adolescents' online behavior. This study investigates parental knowledge about adolescents' online activities and experiences with online risks, as well as the correlates of such knowledge. Building on former research, open communication and knowledge-generating monitoring practices are investigated as potential correlates of parental knowledge. Use is made of triadic data, relying on reports from children aged 13 to 18, mothers and fathers within the same family ( N = 357 families; 54.9 % female adolescents). The results showed that parents have little knowledge about the occurrence of online risks and their children's online activities. While mothers did not have more accurate knowledge compared to fathers, they did perceive themselves to be more knowledgeable than fathers. Associations between parental knowledge and hypothesized correlates were tested by means of one-way ANOVA tests and stepwise logistic regression models. Limited evidence was found for associations with parents' accurate knowledge about the occurrence of online risks. Engagement in knowledge-generating monitoring practices was linked to mothers and fathers' self-perceived knowledge about their children's online activities. For mothers, open communication with the child was linked to self-perceived knowledge. The findings suggest that parents need to be more aware of the possibility that online risks might occur and that more research needs to be done in order to understand what parents can do to improve their accurate knowledge. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8 T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4 T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8 T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient. [ABSTRACT FROM AUTHOR]

Fast simulation (e.g., real-time) of flexible multibody systems is typically restricted by the presence of both differential and algebraic equations in the model equations, and the number of degrees of freedom required to accurately model flexibility. Model reduction techniques can alleviate the problem, although the classically used body-level model reduction and general-purpose system-level techniques do not eliminate the algebraic equations and do not necessarily result in optimal dimension reduction. In this research, Global Modal Parametrization, a model reduction technique for flexible multibody systems is further developed to speed up simulation of flexible multibody systems. The reduction of the model is achieved by projection on a curvilinear subspace instead of the classically used fixed vector space, requiring significantly less degrees of freedom to represent the system dynamics with the same level of accuracy. The numerical experiment in this paper illustrates previously unexposed sources of approximation error: (1) the rigid body motion is computed in a forward dynamical analysis resulting in a small divergence of the rigid body motion, and (2) the errors resulting from the transformation from the modal degrees of freedom of the reduced model back to the original degrees of freedom. The effect of the configuration space discretization coarseness on the different approximation error sources is investigated. The trade-offs to be defined by the user to control these approximation errors are explained. [ABSTRACT FROM AUTHOR]

The floating frame of reference techniques is an established technique to incorporate flexibility in multibody models. The model dimension of the body flexibility models can be reduced by model reduction techniques such as Component Mode Synthesis (CMS) or Krylov subspace-based techniques, but the efficiency of these techniques is limited by the number of interface nodes in which the flexible body is or can be loaded. A common solution to this problem is condensing the different nodes of a given interface surface into a single node, which represents the net motion of the interface surface. Commercial finite element packages offer two modeling techniques to condense interface surfaces: rigid multipoint constraints and interpolation multipoint constraints. Rigid multipoint constraints will typically result in stiffness overestimation, whereas interpolation multipoint constraints will lead to an underestimation. Which approximation of both is most suitable depends on the application. However, the default definition of interpolation multipoint constraints does not allow generation of reduced body flexibility models for multibody models. This paper gives a theoretical background of the problem cause, and offers a practical solution. The two modeling techniques result in significantly different approximations of the body flexibility dynamics, as is shown in a numerical example. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4 and CD8 T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8 T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM. [ABSTRACT FROM AUTHOR]

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature's adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543-555, ; Melief in Immunity 29:372-383, ; Palucka and Banchereau in Nat Rev Cancer 12:265-277, ; Vacchelli et al. in Oncoimmunology 2:e25771, ; Galluzzi et al. in Oncoimmunology 1:1111-1134, ). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications. [ABSTRACT FROM AUTHOR]

The release of cytokines by T cells strongly defines their functional activity in vivo. The ability to produce multiple cytokines has been associated with beneficial immune responses in cancer and infectious diseases, while their progressive loss is associated with T-cell exhaustion, senescence and anergy. Consequently, strategies that enhance the multifunctional status of T cells are a key for immunotherapy. Dendritic cells (DCs) are professional antigen presenting cells that regulate T-cell functions by providing positive and negative co-stimulatory signals. A key negative regulator of T-cell activity is provided by binding of programmed death-1 (PD-1) receptor on activated T cells, to its ligand PD-L1, expressed on DCs. We investigated the impact of interfering with PD-L1/PD-1 co-stimulation on the multifunctionality of T cells, by expression of the soluble extracellular part of PD-1 (sPD-1) or PD-L1 (sPD-L1) in human monocyte-derived DCs during antigen presentation. Expression, secretion and binding of these soluble molecules after mRNA electroporation were demonstrated. Modification of DCs with sPD-1 or sPD-L1 mRNA resulted in increased levels of the co-stimulatory molecule CD80 and a distinct cytokine profile, characterized by the secretion of IL-10 and TNF-α, respectively. Co-expression in DCs of sPD-1 and sPD-L1 with influenza virus nuclear protein 1 (Flu NP1) stimulated Flu NP1 memory T cells, with a significantly higher number of multifunctional T cells and increased cytokine secretion, while it did not induce regulatory T cells. These data provide a rationale for the inclusion of interfering sPD-1 or sPD-L1 in DC-based immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Persistent activation of the transcription factor, signal transducer and activator of transcription 3 (Stat3) has been shown to mediate several oncogenic features in many types of cancers, including melanoma. In this study, we investigated whether lentiviral (LV) delivery of Stat3-targeting short hairpin RNA (shRNA; LV-shStat3) to K1735-C4 melanoma cells modulates antitumor immunity. Three shStat3 sequences, starting at the position 446, 830 and 1412, were cloned into a mir30 cassette. A shRNA with scrambled sequence served as a control. Transduction with LV-shStat3 resulted in downregulation of Stat3 in vitro. The latter coincided with low cell viability, a reduced expression of survivin and matrix metalloproteinase (MMP)-2. A single injection of LV-shStat3 in K1735-C4 tumors efficiently downregulated Stat3 in vivo and resulted in reduction of both vascular endothelial growth factor secretion and in myeloid-derived suppressor cell (MDSC) numbers. In contrast, we observed an increase in interleukin-6 and interferon-γ secretion, mature dendritic cells (DCs) and CD8+ T cells. Both DCs and CD8+ T cells displayed enhanced activity, whereas granulocytic MDSCs lost their suppressive capacity upon Stat3 downregulation. Importantly, a single injection of LV-shStat3 was sufficient to reduce tumor growth, hence prolong survival of tumor-bearing mice. These data demonstrate that Stat3 downregulation in melanoma reinvigorates existing antitumor immunity. [ABSTRACT FROM AUTHOR]

Lentiviral vectors (LVs) provide unique opportunities for the development of immunotherapeutic strategies, as they transduce a variety of cells in situ, including antigen-presenting cells (APCs). Engineering LVs to specifically transduce APCs is required to promote their translation towards the clinic. We report on the Nanobody (Nb) display technology to target LVs to dendritic cells (DCs) and macrophages. This innovative approach exploits the budding mechanism of LVs to incorporate an APC-specific Nb and a binding-defective, fusion-competent form of VSV.G in the viral envelope. In addition to production of high titer LVs, we demonstrated selective, Nb-dependent transduction of mouse DCs and macrophages both in vitro and in situ. Moreover, this strategy was translated to a human model in which selective transduction of in vitro generated or lymph node (LN)-derived DCs and macrophages, was demonstrated. In conclusion, the Nb display technology is an attractive approach to generate LVs targeted to specific cell types. [ABSTRACT FROM AUTHOR]

Many applications require fast and even real-time multibody simulations. Until recently, strongly simplified models were used in order to reach real-time constraints. A novel system-level model reduction technique, namely Global Modal Parameterization (GMP), enables the reduction of a complex mechanism, incorporating flexibility. This technique groups all computationally demanding tasks in a preprocessing phase, which allows the actual simulation to run at real-time. The main strength of the algorithm lies in the fact that the original system of differential-algebraic equations is transformed into a system of ordinary differential equations, which can easily be integrated with explicit methods. This work shortly reviews the GMP-method for systems undergoing 3D motion with multiple rigid DOFs. Furthermore the framework for hard real-time simulation with GMP is discussed. The novelty is the description of a simulation method for a GMP model with an explicit time integrator, which is deployable on hard real-time systems. One of the method's advantages is the a priori known computational load for each timestep, allowing hard real-time simulations. The method is benchmarked for a flexible spatial slider-crank mechanism, modeled in a commercial flexible multibody package. This is the first application of the GMP-approach on an original floating-frame-of-reference component mode synthesis model undergoing highly dynamical motion. [ABSTRACT FROM AUTHOR]

The early-age hydration (≤48 h) of a series of self-compacting concretes and corresponding mortars and one traditionally vibrated concrete and mortar is monitored in a continuous way using ultrasonic testing and isothermal calorimetry. The mixtures differ in type of mineral addition, superplasticizer, cement, cement-to-powder ratio and water-to-powder ratio. The influence of these different mixture compositions on the kinetics of the hydration during the first days of the hydration is characterized by the heat production rate q and the evolution of the p-wave velocity, which is a consequence of the microstructural changes. The variations in the acceleration caused by mineral additions and the deceleration caused by superplasticizers lead to a significantly different behavior. Separating the impact of each of the affecting factors is not always possible due to their combined actions. The nature of the acceleration due to limestone additions and the deceleration caused by polycarboxylate ether superplasticizers can be distinguished clearly, but cannot be quantified. The correlation between the ultrasonic and isothermal calorimetric results is investigated based on parameters related to the start and the end of the setting and reveals the meaningfulness of these parameters when assessing the hydration of self-compacting mixtures with continuous ultrasonic techniques. [ABSTRACT FROM AUTHOR]

Abstract  New advances in reconfigurable optical interconnect technologies will allow the fabrication of low-cost, fast and run-time adaptable networks for connecting processors and memory modules in large distributed shared-memory multiprocessor machines. Since the switching times of these components are typically high compared to the memory access time, reconfiguration exploits low frequency dynamics in the network traffic patterns. These are however not easily reproduced using statistical traffic generation, a tool commonly used when doing a fast design space exploration. In this paper, we present a technique that can predict network performance, based on the traffic patterns obtained from simulating the execution of real benchmark applications, but without the need to perform these slow full-system simulations for every parameter set of interest. This again allows for a quick comparison of different network implementations with good relative accuracy, narrowing down the design space for more detailed examination. [ABSTRACT FROM AUTHOR]

The discovery of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, together with an improved insight in dendritic cell biology illustrating their key function in the immune system, have provided a rationale to initiate dendritic cell-based cancer immunotherapy trials. Nevertheless, dendritic cell vaccination is in an early stage, as methods for preparing tumor antigen presenting dendritic cells and improving their immunostimulatory function are continuously being optimized. In addition, recent improvements in immunomonitoring have emphasized the need for careful design of this part of the trials. Still, valuable proofs-of-principle have been obtained, which favor the use of dendritic cells in subsequent, more standardized clinical trials. Here, we review the recent developments in clinical DC generation, antigen loading methods and immunomonitoring approaches for DC-based trials. [ABSTRACT FROM AUTHOR]

Copyright of Materials & Structures is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The maturation state of dendritic cells (DCs) is an important determinant for the initiation and regulation of adaptive immune responses. In this study, we wanted to assess whether functional activation of human monocyte-derived DCs can be achieved by electroporation of an activation signal in the form of double-stranded (ds) RNA and whether simultaneous electroporation of the dsRNA with tumor antigen encoding mRNA can lead to the induction of a cytotoxic T-lymphocyte (CTL) response. Electroporation of immature DCs with poly(I:C12U), a dsRNA analogue, resulted in phenotypic as well as functional changes, indicative of DC maturation. Co-electroporation of DCs with both poly(I:C12U) and Melan-A/MART-1 encoding mRNA induced strong anti-Melan-A/MART-1 CD8+ T-cell responses in vitro. Higher numbers of Melan-A/MART-1-specific CTLs were consistently obtained with poly(I:C12U)-activated DCs compared to DCs matured in the presence of an inflammatory cytokine cocktail. These results indicate that DC co-electroporation with both dsRNA and tumor antigen encoding mRNA induces fully activated and antigen-loaded DCs that promote antigen-specific CTL responses and may provide the basis for future immunotherapeutic strategies.Gene Therapy (2006) 13, 1027–1036. doi:10.1038/sj.gt.3302750; published online 2 March 2006 [ABSTRACT FROM AUTHOR]

Ex vivo lentivirally transduced dendritic cells (DC) have been described to induce CD8+ and CD4+ T-cell responses against various tumor-associated antigens (TAAs) in vitro and in vivo. We report here that direct administration of ovalbumin (OVA) encoding lentiviral vectors caused in vivo transduction of cells that were found in draining lymph nodes (LNs) and induced potent anti-OVA cytotoxic T cells similar to those elicited by ex vivo transduced DC. The cytotoxic T-lymphocyte (CTL) response following direct injection of lentiviral vectors was highly effective in eliminating target cells in vivo up to 30 days after immunization and was efficiently recalled after a boost immunization. Injection of lentiviral vectors furthermore activated OVA-specific CD4+ T cells and this CD4 help was shown to be necessary for an adequate primary and memory CTL response. When tested in therapeutic tumor experiments with OVA+ melanoma cells, direct administration of lentiviral vectors slowed down tumor growth to a comparable extent with the highest dose of ex vivo transduced DC. Taken together, these data indicate that direct in vivo administration of lentiviral vectors encoding TAAs has strong potential for anticancer vaccination.Gene Therapy (2006) 13, 630–640. doi:10.1038/sj.gt.3302697; published online 15 December 2005 [ABSTRACT FROM AUTHOR]

Genetically modified dendritic cells (DC) constitute a promising approach in cancer immunotherapy. Viral gene delivery systems have been shown to be very efficient strategies, but safety concerns for their clinical use in immunotherapy remain an important issue. Recently, the technique of mRNA electroporation was described as a very efficient tool for the genetic modification of human monocyte-derived DC. Here, we show that transgene expression can be modulated by varying the amount of mRNA used for electroporation. We document that CD40 ligation leads to a significant production of IL-12 by the electroporated DC, although the level of IL-12 production is somewhat lower than for non- or mock-electroporated DC. Furthermore, we show that the electroporated DC can be frozen and thawed without loss of viability or function and that Influenza virus Matrix Protein 1 mRNA electroporated DC are capable of inducing a memory cytotoxic T lymphocyte response and are more potent in doing so than mRNA-pulsed DC. Similar results were obtained with MelanA/MART-1 mRNA electroporated DC. These results clearly indicate that mRNA-electroporated DC represent powerful candidates for use as tumor vaccines and could constitute an improvement compared with vaccines using peptide-pulsed DC.Cancer Gene Therapy (2003) 10, 696-706. doi:10.1038/sj.cgt.7700622 [ABSTRACT FROM AUTHOR]

Rationale: Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability. Objective: The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant. Methods: Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65-80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results: Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug-placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences >2.4 cm and those who had SDLP differences <−2.4 cm following suvorexant. Conclusions: There was no clinically meaningful residual effect of suvorexant 15 and 30 mg on next-morning driving (9 h after bedtime dosing) in healthy older adults, as assessed by mean changes in SDLP and by the number of participants on drug versus placebo that exceeded a predetermined threshold for clinically meaningful impairment. [ABSTRACT FROM AUTHOR]

Recently, human dendritic cells (DCs) pulsed with mRNA encoding a broad range of tumor antigens have proven to be potent activators of a primary anti–tumor-specific T-cell response in vitro. The aim of this study was to improve the mRNA pulsing of murine DC. Compared to a standard lipofection protocol and passive pulsing, electroporation was, in our hands, the most efficient method. The optimal conditions to electroporate murine bone marrow–derived DCs with mRNA were determined using enhanced green fluorescent protein and a truncated form of the nerve growth factor receptor. We could obtain high transfection efficiencies around 70–80% with a mean fluorescence intensity of 100–200. A maximal expression level was reached 3 hours after electroporation. A clear dose–response effect was seen depending on the amount of mRNA used. Importantly, the electroporation process did not affect the viability nor the allostimulatory capacity or phenotype of the DC. To study the capacity of mRNA-electroporated DCs to present antigen in the context of MHC classes I and II, we made use of chimeric constructs of ovalbumin. The dose-dependent response effect and the duration of presentation were also determined. Together, these results demonstrate that mRNA electroporation is a useful method to generate genetically modified murine DC, which can be used for preclinical studies testing immunotherapeutic approaches. Cancer Gene Therapy (2002) 9, 787–797 doi:10.1038/sj.cgt.7700499 [ABSTRACT FROM AUTHOR]

The signal transducer and activator of transcription 3 (STAT3) can be activated by the tyrosine kinase domain of the chimeric protein nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), and has a pivotal role in mediating NPM/ALK-related malignant cell transformation. Although the role of STAT3 and wild-type NPM in oncogenesis has been extensively investigated, the relationship between both molecules in cancer remains poorly understood. In the present study, we first demonstrate that STAT3 phosphorylation at tyrosine 705 is accompanied by a concomitant increase in the expression level of NPM. Nuclear co-translocation of phosphorylated STAT3 with NPM can be triggered by interferon-alpha (IFN-α) stimulation of Jurkat cells and phosphorylated STAT3 co-localizes with NPM in cancer cells showing constitutive STAT3 activation. We further demonstrate that STAT3 phosphorylation can transcriptionally mediate NPM upregulation in IFN-α-stimulated Jurkat cells and is responsible for maintaining its expression in cancer cells showing constitutive STAT3 activation. Inhibition of STAT3 phosphorylation or knockdown of NPM expression abrogates their simultaneous transnuclear movements. Finally, we found evidence for a physical interaction between NPM and STAT3 in conditions of STAT3 activation. In conclusion, NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. These observations might open novel opportunities for targeting the STAT3 pathway in cancer. [ABSTRACT FROM AUTHOR]

Purpose: Melanoma patients with a high risk of recurrence may benefit from immunotherapy with mRNA-electroporated autologous monocyte-derived dendritic cells (DCs). Further benefit may be found in combining DC-therapy with interferon alfa-2b. Patients and methods: The long-term clinical outcome of AJCC stage III/IV melanoma patients who had no evidence of disease at the time of treatment with autologous mRNA-electroporated DCs in a single-center pilot clinical trial was analyzed. Antigen loading was accomplished by co-electroporation of mRNA encoding a fusion protein between MAGE-A1, -A3, -C2, Tyrosinase, MelanA/MART-1, or gp100, and an HLA class II-targeting sequence. DCs were administered by 4-6 bi-weekly intradermal injections. IFN-α-2b (5 MIU TIW) was initiated either at recurrence (cohort 1), concomitant with DCs (cohorts 2 and 3), or following the fourth DC administration (cohort 4). Results: Thirty melanoma patients were recruited between April 2006 and June 2009. DC-related adverse events included grade 2 local injection site reactions in all patients, grade 2 fever and flu-like symptoms in one patient, and skin depigmentation in seven patients. After a median follow-up of over 6 years, the median relapse-free survival is 22 months (95 % CI 12-32 months). Twelve patients have died. The median overall survival has not been reached; the 2-year and 4-year survival rates are 93 and 70 %, respectively. Conclusions: Adjuvant therapy following the resection of melanoma metastases with autologous mRNA-electroporated DCs, combined with interferon alfa-2b, is tolerable and results in encouraging long-term overall survival rates justifying further evaluation in a randomized clinical trial. [ABSTRACT FROM AUTHOR]

This report summarizes our experimental data concerning the use of bispecific antibodies (bsAb) for the treatment of the murine BCL1 B cell lymphoma model. Initially we used a hybrid-hybridoma-derived bsAb with specificity for the TcR/CD3 complex on T cells and the idiotype of the membrane-bound IgM on the tumor cells. The bsAb used as a single agent could cure animals with a low tumor load (resembling minimal residual disease). However, in experiments aimed at increasing the therapeutic effect in animals with a higher tumor burden, we could demonstrate the importance of additional T-cell-costimulatory signals and the careful timing of the bsAb administration. Recently we have generated a bispecific single-chain Fv (bsscFv) fusion protein with the same dual specificity as the hybrid-hybridoma-derived bsAb. Immunotherapy with this smaller molecule also resulted in tumor elimination in BCL1-bearing mice. A second bsscFv (α-CDl9×α-CD3) with a broader applicability is now being characterized and tested in vivo. [ABSTRACT FROM AUTHOR]

Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8(+) T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4(+)CD8(+) double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8(+) T cells. Comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8(+) T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimer-reactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing. [ABSTRACT FROM AUTHOR]

Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8+ T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4+CD8+ double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8+ T cells. Comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8+ T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimer-reactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing. [ABSTRACT FROM AUTHOR]

Until now, studies utilizing mRNA electroporation as a tool for the delivery of tumor antigens to human monocyte-derived dendritic cells (DC) have focused on DC electroporated in an immature state. Immature DC are considered to be specialized in antigen capture and processing, whereas mature DC present antigen and have an increased T-cell stimulatory capacity. Therefore, the consensus has been to electroporate DC before maturation. We show that the transfection efficiency of DC electroporated either before or after maturation was similarly high. Both immature and mature electroporated DC, matured in the presence of an inflammatory cytokine cocktail, expressed mature DC surface markers and preserved their capacity to secrete cytokines and chemokines upon CD40 ligation. In addition, both immature and mature DC can be efficiently cryopreserved before or after electroporation without deleterious effects on viability, phenotype or T-cell stimulatory capacity including in vitro antigen-specific T-cell activation. However, DC electroporated after maturation are more efficient in in vitro migration assays and at least as effective in antigen presentation as DC electroporated before maturation. These results are important for vaccination strategies where an optimal antigen presentation by DC after migration to the lymphoid organs is crucial.Gene Therapy (2005) 12, 772-782. doi:10.1038/sj.gt.3302471 Published online 3 March 2005 [ABSTRACT FROM AUTHOR]

This paper studies the initial resources on which new organizations are based and how these resources interact with the institutional origin and market characteristics. Using a unique hand-collected data set of research-based startups (RBSUs), we empirically test how technological, financial and human resources relate to each other to form distinct starting resource configurations. We find four different starting configurations: ‘venture capital-backed start-ups,’ ‘prospectors,’ ‘product start-ups’ and ‘transitional startups’. The results show that VC-backed start-ups are a minority while half of the firms start as prospectors. Market complexity and growth prospects influence the probability of starting with venture capital. The unclearness of the product market at founding characterizes prospectors, while product start-ups mostly have an almost market-ready product targeted at an international niche market. Transitional starters initially commercialize technical know-how through consulting and become product oriented later on. This discussion contributes to the debate concerning the interplay of environment and firm resources. [ABSTRACT FROM AUTHOR]

Introduction: Unwanted exposure (UE) to sexual content may have important consequences on children/adolescents' psychosexual development. Our objective was to analyze UE to online pornography, parental filter use, type of sexual contents seen, emotional/behavioral reactions, and UE as positive/traumatic experience in Spanish adolescents and to examine these experiences and reactions depending on the type of sexual content. Methods: In 2020, 500 Spanish teenagers (13–18 years) completed an ad hoc questionnaire for the evaluation of different dimensions involved in UE to sexual contents, such as those mentioned in the study objectives. Results: A high frequency of UE (88.2%) is observed. Regarding the kind of scenes, naked people, straight porn, and people showing genitals are the most unexpectedly seen. Adolescents used to react to the UE closing the window and deleting sexual materials. A greater predominance of negative emotions was revealed, and another noteworthy result is related to the role played by type of sexual content and gender. Gay scenes and being woman increased the probability of living the experience as non-positive, and being woman and viewing naked people/BDSM scenes/under-age sex were associated with reactions of rejection. Conclusions: This study contributes significantly to the knowledge of UE to online pornography in adolescents. It provides valuable information about the role played by the type of sexual content seen and the gender in the diverse reactions/experiences derived from the UE to pornography. Policy Implications: This topic, that is, involuntary exposure to online sexual material in adolescents, should be included in affective-sexual education and prevention programs at early ages, so that children/adolescents are already trained in healthy sexuality when facing this type of content for the first time. These programs, adjusted to the reality of our adolescents, will minimize the negative impact that UE may have on their psychosexual development. [ABSTRACT FROM AUTHOR]

Co-delivery of different protein-encoding polynucleotide species with varying expression kinetics of their therapeutic product will become a prominent requirement in the realm of combined nucleic acid(NA)-based therapies in the upcoming years. The current study explores the capacity for time-staggered expression of encoded proteins by simultaneous delivery of plasmid DNA (pDNA) in the core and mRNA on the shell of the same nanocarrier. The core is based on a Gelatin Type A-pDNA coacervate, thermally stabilized to form an irreversible nanogel stable enough for the deposition of cationic coats namely, protamine sulfate or LNP-related lipid mixtures. Only the protamine-coated nanocarriers remained colloidally stable following mRNA loading and could successfully co-transfect murine dendritic cell line DC2.4 with fluorescent reporter mRNA(mCherry) and pDNA (pAmCyan1). Further investigation of the protamine-coated nanosystem only, the transfection efficiency (percentage of transfected cells) and level of protein expression (mean fluorescence intensity, MFI) of mRNA and pDNA, simultaneously delivered by the same nanocarrier, were compared and kinetically assessed over 48 h in DC2.4 using flow cytometry. The onset of transfection for both nucleotides was initially delayed, with levels < 5% at 6 h. Thereafter, mRNA transfection reached 90% after 24 h and continued to slightly increase until 48 h. In contrast, pDNA transfection was clearly slower, reaching approximately 40% after 24 h, but continuing to increase to reach 94% at 48 h. The time course of protein expression (represented by MFI) for both NAs essentially followed that of transfection. Model-independent as well as model-dependent kinetic parameters applied to the data further confirmed such time-staggered expression of the two NA's where mRNA's rate of transfection and protein expression initially exceeded those of pDNA in the first 24 h of the experiment whereas the opposite was true during the second 24 h of the experiment where pDNA displayed the higher response rates. We expect that innovative nanocarriers capable of time-staggered co-delivery of different nucleotides could open new perspectives for multi-dosing, pulsatile or sustained expression of nucleic acid-based therapeutics in protein replacement, vaccination, and CRISPR-mediated gene editing scenarios. [ABSTRACT FROM AUTHOR]

Earthquakes and tsunamis are natural phenomena that have strongly affected communities located along the Chilean active plate margin. Large-magnitude megathrust earthquakes produced at the plate interface of the subduction zone and their associated tsunamis have repeatedly impacted the Chilean coast, leaving a sedimentary record at particular sites from historic and prehistoric times. Here we assess paleoseismic sites related to late Holocene (< 1.5 ka) earthquakes and tsunamis that occurred along the Pacific coastline of south-central Chile (38°-42°S), which record critical information for the study of megathrust earthquakes. We focus on sites along the Valdivia segment that were affected by the great earthquake and tsunami of 1960 (Mw = 9.5; the largest recorded by modern seismology), which host geologic evidence of coseismic land-level changes found in tidal marshes and wetlands. We present an inventory of seven paleoseismic geosites composed mainly of different layers of buried soils and sand deposits, and a quantitative assessment of their scientific value, their potential touristic and educational value, and their degradation risk. These sites are considered part of the paleoseismic heritage of Chile and are relevant globally. Our inventory contributes to the establishment of management strategies for geoconservation of the coastal area of south-central Chile, and the mitigation of the effects of seismological hazards through the promotion of educational, touristic and outreach activities. [ABSTRACT FROM AUTHOR]

Since its first use in organisational research, nearly five decades ago, imprinting has gained recognition in entrepreneurship studies. Accordingly, this study utilises the behavioural concept to develop new theorisations to account for the entrepreneurial processes of immigrant entrepreneurs. It pays attention on its effects on immigrant entrepreneurs, particularly when it comes to their decision–making and behaviours towards business creation in Canada. A comprehensive analysis of a dataset generated from a systematically selected group of immigrant entrepreneurs revealed the complexity of their imprints at various stages of their entrepreneurial cycle in the North American country. It emerged that imprinting not only modified their behaviours, attitudes and cognition, but also shaped the trajectory of their entrepreneurial processes. That is, their imprints had an effect on how they identified business opportunities, the types of businesses they pursued, their level of entrepreneurial drive, and the types of resources they acquired or accessed in their new environment. Notably, following a period of normalisation in their new surroundings, their original imprints changed due to diminishing affinity with their country-of-origin. This holds research and policy implications as it uncovers an unfolding but less-understood entrepreneurship phenomenon. [ABSTRACT FROM AUTHOR]

Biomedical research is fundamental in developing preventive and therapeutic vaccines, serving as a cornerstone of global public health. This review explores the key concepts, methodologies, tools, and challenges in the vaccine development landscape, focusing on transitioning from basic biomedical sciences to clinical applications. Foundational disciplines such as virology, immunology, and molecular biology lay the groundwork for vaccine creation, while recent innovations like messenger RNA (mRNA) technology and reverse vaccinology have transformed the field. Additionally, it highlights the role of pharmaceutical advancements in translating lab discoveries into clinical solutions. Techniques like CRISPR-Cas9, genome sequencing, monoclonal antibodies, and computational modeling have significantly enhanced vaccine precision and efficacy, expediting the development of vaccines against infectious diseases. The review also discusses challenges that continue to hinder progress, including stringent regulatory pathways, vaccine hesitancy, and the rapid emergence of new pathogens. These obstacles underscore the need for interdisciplinary collaboration and the adoption of innovative strategies. Integrating personalized medicine, nanotechnology, and artificial intelligence is expected to revolutionize vaccine science further. By embracing these advancements, biomedical research has the potential to overcome existing challenges and usher in a new era of therapeutic and prophylactic vaccines, ultimately improving global health outcomes. This review emphasizes the critical role of vaccines in combating current and future health threats, advocating for continued investment in biomedical science and technology. [ABSTRACT FROM AUTHOR]

With the extensive use of manufactured sand and admixtures, it has been observed that as the shear rate increases, the shear rate–shear stress curve of some fresh wet shotcrete materials increasingly deviates from a linear correlation. It is necessary to study the rheological properties of wet shotcrete using a nonlinear model due to the large error when utilizing the Bingham model to describe the concrete. The torque-velocity curve of wet shotcrete was determined using an ICAR rheometer in this study. The experimental data was fitted using the Bingham model, Herschel-Bulkley (H-B) model, and modified Bingham (M-B) model, resulting in the determination of the associated rheological parameters. The M-B model exhibits the most optimal fitting effect, followed by the H-B model and the Bingham model. As the shear rate reaches a specific value, the M-B model consistently represents a higher degree of divergence from linearity compared to the H-B model. Furthermore, considering the limitations of the H-B model which includes varying dimension parameters, this study enhanced the calculation approach for determining the equivalent plastic viscosity based on Larrard et al.'s (Mat Struct 31:494–498, 1998) research. Ultimately, the impact of the mix parameters on the yield stress and plastic viscosity of the three rheological models was analyzed through the range approach. This study is beneficial for enhancing the comprehension of the rheological characteristics of wet shotcrete. [ABSTRACT FROM AUTHOR]

In the world of high-performance computing, it is known that it can be beneficial to leave a small number of CPU cores unused, a practice termed undersubscription. However, undersubscription is rarely implemented in scientific applications of high-performance computing. We demonstrate the importance of calibrated undersubscription in Computational Fluid Dynamics simulations through the aggregated results of 1844 benchmarks. These benchmarks measured three hardware configurations and five different CFD models. On average, performance increased by 14% (weighted by node count). Performance improvements were most significant at large node counts, particularly when nearing a regime of negative scalability. We found that undersubscription could increase maximum performance by up to 50%; this advantage diminished as node count decreased but remained as much as 13% with a single node. In some cases, maximum performance was achieved with large numbers of free cores—nearly half of the cores in one case. Producing a regression from our dataset, we universally predict the optimal number of free cores as a function of cells per core. This regression achieves a 15% speed increase on average (again weighted by node count). [ABSTRACT FROM AUTHOR]

Cyberbullying is a disturbing form of behavior associated with the use of communication technologies among adolescents. Many studies have been devoted to cyberbullies and cyber victims, neglecting an important growing group: cyberbullies who are also cyber victims. Moreover, few studies refer to all cyberbullying roles and factors associated with them. Therefore, the goal of this study is to examine differences in family climate, peers' engagement in cyberbullying, and perception of academic achievements among involvements in cyberbullying roles. Data are collected by telephone or face-to-face from a sample of 277 eleventh- to twelfth-grade students in Israel who are asked to participate in the survey. Cyberbullying roles are composed of two variables—cyberbullies and cyber victims, creating four groups: cyberbullies, cyber victims, cyberbullies-and-victims, and non-involved. Three types of family climate are measured: warmth, order and supervision, and conflict. Respondents report their perceptions of peers' engagement in cyberbullying. At the personal level, gender, perception of academic achievements, and school absence are measured. Multinomial logistic regression findings show that boys are more likely to be cyberbullies and cyberbullies-victims than are girls; family conflicts increase the odds of being cyberbullies and cyber victims; and family warmth decreases the odds of being cyber victims and cyberbullies-cyber victims. Perception of peers' engagement in cyberbullying increases the odds of being cyberbullies and cyberbullies-victims. Perception of academic achievements and school absence have opposite effects on cyber victims, the former increasing the odds of being cyber victims and the latter decreasing them. The results emphasize the role of family and peers in adolescents' cyber behavior. Limitations and conclusions are discussed. [ABSTRACT FROM AUTHOR]

One of the main challenges for small deformation flexible multibody simulations is the a priori selection of the required modal basis. Often, to guarantee the accuracy of the component mode synthesis, an excessive amount of mode shapes are accounted for in the model basis. Hence, to address this problem, the variable modal basis for small deformation flexible multibody formulations is introduced. It allows truncation of the initial modal basis to minimize the required amount of active mode shapes while maintaining accurate results. Furthermore, the proposed framework is independent of the chosen small deformation flexible multibody formulation. The modal variation is achieved by neglecting mode shapes based on their individual energy content. Hence, the corresponding set of dynamic and constraint equations, as well as the generalized coordinates and Lagrangian parameters, reduce accordingly. Once mode shapes are neglected, their energy content is no longer evaluated. Therefore, reintroducing these mode shapes is based on the change in total flexible energy of a flexible body. To validate the accuracy of this approach, a comparison is made between the results obtained from implementing a variable modal basis and those obtained from a regular constant modal basis. [ABSTRACT FROM AUTHOR]

This paper focuses on the value drivers of innovative start-ups (ISUs). Few companies can overcome the start-up stage; often, the early performance is insufficient, and the potential contribution of innovation to economic development is very poor. Studies based on a firm-level perspective show mixed results on the factors affecting the growth of ISUs. Most studies emphasize the role of "external" drivers of ISUs growth, while more knowledge is required of "internal" drivers. Consequently, this research focuses on the relationship between the features of the founding teams and the early performance of ISUs. Specifically, it concentrates on education heterogeneity and analyzes whether the heterogeneity of the founding team in terms of educational level (vertical heterogeneity) and field of studies (horizontal heterogeneity) affects the Italian ISUs performance. Growth regression and unconditional quantile regression models confirm the prior literature: the educational level affects the performance and the vertical heterogeneity in the composition of the founding team is relevant for ISUs performance. However, the results also suggest interesting denials: horizontal heterogeneity does not play any role, and no moderating effect of heterogeneity is shown. These findings are strongly attractive for new ventures and policymakers. [ABSTRACT FROM AUTHOR]

To investigate the impact of different 5ʹ untranslated regions (UTRs) on mRNA vaccine translation efficiency, five dual-reporter gene expression plasmids with different 5ʹUTRs were constructed. The corresponding mRNA transcripts were transcribed and capped in vitro. By comparing the expression levels of reporter genes with different 5ʹUTRs, we identified the 5ʹUTR associated with the highest expression level. Subsequently, HIVgp145 mRNA vaccines containing various 5ʹUTRs were constructed and verified. The results demonstrated that mRNA 3 (β-globin 5ʹUTR) displayed the greatest number of green fluorescence-positive cells and the highest luciferase fluorescence intensity in the reporter gene expression system. Further, among the HIVgp145 mRNA vaccines with different 5ʹUTRs, mRNA 7 (β-globin 5ʹUTR) exhibited the highest level of expression. These findings indicate that it is feasible to use the 5ʹUTR of β-globin in an mRNA vaccine, laying the foundation for animal immunogenicity testing. [ABSTRACT FROM AUTHOR]

The long-term interaction between the environment and humans has significantly shaped contemporary landscapes worldwide. As a heritage landscape, the polder is essential for understanding the impact of the past human activities on contemporary landscape on low-lying area of land. In this case study, we reconstructed the regional spatial distribution of the polders in the early twentieth century and examined their coherence over the past century using historical maps and other materials in the Jianghan Plain. The results revealed several key findings: (1) In the early twentieth century, there were 1571 polders covering an area of 11,826.1 km2 with a perimeter of 17,035.9 km. (2) These polders exhibited a J-shaped distribution, with few large-scale polders despite their substantial areas. (3) The shape of these polders reflected an ability to balance human needs and the natural environment. (4) Considerable regional differences in these polders were attributed to centuries-old interactions between humans and the environment. (5) The remnants of these early twentieth century polders have had a lasting influence on the contemporary landscape, particularly in rural areas. This case study underscores how taking into account a broader historical perspective can enhance our understanding of present-day landscapes and, more importantly, the role that past human actions have played in shaping them. [ABSTRACT FROM AUTHOR]

This paper investigates the durability performance of mortars with varying replacement levels of dolostone or limestone filler (0–30% by mass) and the stability of mortars with dolostone filler for 2 years. Compressive strength, total porosity, capillary water absorption, and chloride migration coefficients were determined. Results show that compressive strength decreases and the total porosity increases with increasing filler content due to a dilution effect, regardless of the filler composition. The capillary water absorption and the chloride migration coefficients rise significantly for mortars with 20–30% filler. However, the dolostone filler cements have lower chloride coefficients than those with limestone blended cement. Volumetric stability assessments reveal no significant expansion, and XRD and FT-IR analyses suggest the formation of hydrotalcite-like phases. [ABSTRACT FROM AUTHOR]

Influencer advertising has emerged as an integral part of social media marketing. Within this realm, consumer engagement is a critical indicator for gauging the impact of influencer advertisements, as it encompasses the proactive involvement of consumers in spreading advertisements and creating value. Therefore, investigating the mechanisms behind consumer engagement holds significant relevance for formulating effective influencer advertising strategies. The current study, grounded in self-determination theory and employing a stimulus-organism-response framework, constructs a general model to assess the impact of influencer factors, advertisement information, and social factors on consumer engagement. Analyzing data from 522 samples using structural equation modeling, the findings reveal: (1) Social media influencers are effective at generating initial online traffic but have limited influence on deeper levels of consumer engagement, cautioning advertisers against overestimating their impact; (2) The essence of higher-level engagement lies in the ad information factor, affirming that in the new media era, content remains 'king'; (3) Interpersonal factors should also be given importance, as influencing the surrounding social groups of consumers is one of the effective ways to enhance the impact of advertising. Theoretically, current research broadens the scope of both social media and advertising effectiveness studies, forming a bridge between influencer marketing and consumer engagement. Practically, the findings offer macro-level strategic insights for influencer marketing. [ABSTRACT FROM AUTHOR]

To accelerate green development and promote harmonious coexistence between man and nature, China has vigorously promoted investment in green food production. In China, farmers are the core unit of grain production, and China's green food production is inseparable from the strong support of farmers. Based on the theory of planned behavior, the structural equation model and multi-group comparative analysis method were used to investigate the investment intention of 435 farmers in green grain production in Zhengzhou, Zhoukou, and Shangqiu, Henan Province, from the perspective of farmers' micro- and psychological levels. The results show that attitude and perceived behavioral control among farmers can significantly boost their intention to invest in green production through two different channels. Subjective norms, on the other hand, only indirectly affect farmers' intentions to make such an investment. At the same time, through multi-group comparative analysis, the study also verified that different variables such as gender, age, educational background, and family labor force have different degrees of influence on different hypothetical paths. Therefore, this study provides suggestions for sustainable green production investment development and has certain guiding significance for the follow-up work of government departments, relevant companies, farmers, scholars, and other relevant personnel. [ABSTRACT FROM AUTHOR]

This article reports on one of the objectives of a larger study aiming at the development of an adolescent risk-behavior management program for foster parents. The objective relevant to this article entailed the exploration of parenting behaviors and attitudes of parents fostering adolescents presenting with risk behavior. The respondents were recruited from the clientele of designated welfare organizations in the North West Province of South Africa. A quantitative survey using the multi-dimensional Parental Style Dimension Questionnaire (PSDQ) was administered to a purposive sample of 150 respondents. A response rate of 64.5% was achieved, with only foster mothers participating in the study. Data analysis was done by the Statistical Consultation Services of the North-West University (Potchefstroom Campus) using IBM SPSS Statistics Version 25, Release 25.0 SPSS. In addition, T-Tests and ANOVAs were used to test the hypothesis at a 0.05 level of significance and Spearman's correlations examine correlations between sub-scale scores and biographical data. Sub-scales of the PSDQ were tested for internal consistency reliability and reasonable coefficients were rendered, except for the permissive parenting style scale that was excluded from analysis. The results showed a significant, positive correlation between authoritative and authoritarian parenting styles amongst the respondents. Parental attitudes and responses to risk behavior significantly affected their actual behavior towards fostered adolescents presenting with risk behavior. The researchers concluded that consideration of parenting styles in the foster care relationship context will greatly determine the nature of further interventions. [ABSTRACT FROM AUTHOR]