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Previous studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF-ADAMTS13 axis dysfunction. In total, 180 children with a confirmed diagnosis of SCD (hemoglobin SS) on hydroxycarbamide (n = 96) or blood transfusion (n = 84) were included. Despite disease-modifying treatment, plasma VWF and VWF propeptide were elevated in a significant proportion of children with SCD (33% and 47%, respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared with the blood transfusion cohort (P < .05). Additionally, increased levels of other Weibel-Palade body-stored proteins, including factor VIII (FVIII), angiopoietin-2, and osteoprotegerin were observed, indicated ongoing endothelial cell activation. Children treated with hydroxycarbamide also had higher FVIII activity and enhanced thrombin generation compared with those in the blood transfusion cohort (P < .001). Finally, hemolysis markers strongly correlated with VWF levels (P < .001) and were significantly reduced in the blood transfusion cohort (P < .001). Cumulatively, to our knowledge, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF-ADAMTS13 axis is present in a significant subgroup of pediatric patients with SCD, especially those treated with hydroxycarbamide., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: The aim of this study was to establish the utility of the NIH Toolbox as a cognitive screener of executive functions in the clinical context. Additionally, we aimed to investigate whether age and time on transfusion were related to executive function performance. Method: Twenty-eight children and adolescents with sickle cell anemia (SCA) between 8 and 18 years (M = 13.28, SD = 3.05) on transfusion treatment were included. Participants completed five NIH Toolbox tasks (three executive function tasks and two non-executive function control tasks). Results: Mean scores on one of the three executive function measures (inhibitory control) fell below the average range (M = 81.36, SD = 14.01) with approximately 70% of children from both groups below the average range. Scores for processing speed (M = 86.82, SD = 22.01) and cognitive flexibility (M = 85.75, SD = 12.67) were low averages. As expected, scores on non-executive measures (language and memory) fell within the average range. No significant differences were observed between children with silent stroke and no stroke on executive function measures. Older age (p <.01) and length of time on transfusion (p <.05) predicted lower inhibitory control scores. Conclusions: Findings provide evidence for poor development of inhibitory control with age in this patient population. As the NIH Toolbox successfully highlighted expected deficits in this patient population, this study supports the use of this tool as a brief screening measure for children with SCD. The clinical and theoretical implications of the findings are discussed. [ABSTRACT FROM AUTHOR]

Study Objective: The purpose of this study was to examine the feasibility, acceptability, and preliminary efficacy of a mindfulness-based healthy lifestyle self-management intervention with adolescents and young adults diagnosed with polycystic ovary syndrome (PCOS)., Design: A pilot randomized controlled trial using a pre-post design was used., Setting: Central Texas., Participants: Individuals aged 14-23 with a diagnosis of PCOS., Interventions: The PCOS Kind Mind Program integrates a manualized mindfulness training program (Taming the Adolescent Mind) with health education in 4 key areas of self-management and health promotion: (1) medication adherence, (2) nutrition, (3) physical activity, and (4) sleep., Main Outcome Measures: Psychological distress, mindfulness, physical activity strategies, nutrition, and exercise self-efficacy., Results: Linear regression models revealed that those in the PCOS Kind Mind condition reported significantly higher nutrition self-efficacy (β = 6.50, 95% CI, 1.71-11.28, P = 0.013, d = 0.48), physical activity strategies (β = 0.41, 95% CI, 0.04-0.79, P = 0.040, d = 0.67), and physical activity self-efficacy (β = 0.48, 95% CI, 0.07-0.88, P = 0.028, d = 0.46)., Conclusion: The PCOS Kind Mind Program improved self-efficacy in the key areas of nutrition and physical activity and increased physical activity strategies in adolescents and young people with PCOS. These findings are encouraging and suggest the need for larger-scale, randomized controlled trials with longer-term follow-up to more robustly evaluate the effects of the PCOS Kind Mind Program on the psychological and physiological health of adolescents and young people with PCOS., Competing Interests: Disclosure/Conflict of Interest Statement No authors report any conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: SCD patients experience declines in health-related quality of life (HRQOL) domains compared with healthy controls. Despite evidence supporting the benefits of hydroxyurea, medication non-adherence remains problematic, especially in adolescents and young adults (AYA). Adherence barriers include forgetfulness and lack of knowledge. Recently, increased interest in technology-based strategies to improve medication adherence has emerged. No data currently exists on hydroxyurea adherence, HRQOL or perceptions of technology-based tools in the Irish SCD population., Methods: In order to interrogate these domains among Irish AYA SCD patients we administered an anonymous survey at two tertiary referral centres in Dublin, Ireland, in July 2019., Results: Sixty-three patients participated; 63% female and 37% male, with a median and mean age of 17 and 19 years, respectively. Average monthly adherence was 76% using a visual analogue scale. Recall barriers were present in 62% while 26% omit hydroxyurea for reasons other than forgetting. Reviewing HRQOL; only 36.5% felt always physically able to engage in recreational activities, while 51% experienced disruption to school/college/work due to pain. Eighty-one percent reported that anxiety about health interferes with their lives and non-adherence correlated with worse HRQOL outcomes. Interest in a smartphone app was expressed by the majority, with daily medication reminders being the most popular feature. Sharing adherence data with doctors and discussion forums were less appealing., Conclusions: Representing over 10% of the Irish SCD population, our survey provides novel and valuable insights into medication adherence and HRQOL domains. Preferred app features may inform future technology-based interventions to improve medication adherence in SCD and other chronic health conditions., (© 2021. The Author(s).)

Objectives: Nonpharmacologic pain management strategies are needed because of the growing opioid epidemic. While studies have examined the efficacy of virtual reality (VR) for pain reduction, there is little research in adult inpatient settings, and no studies comparing the relative efficacy of standard animated computer-generated imagery (CGI) VR to Video Capture VR (360 degrees 3D/stereoscopic Video Capture VR). Here, we report on a randomized controlled trial of the relative efficacy of standard CGI VR versus Video Capture VR (matched for content) and also compared the overall efficacy of VR to a waitlist control group., Materials and Methods: Participants (N=103 hospitalized inpatients reporting pain) were randomized to 1 of 3 conditions: (1) waitlist control, (2) CGI VR, or (3) Video Capture VR. The VR and waitlist conditions were 10 minutes in length. Outcomes were assessed pretreatment, post-treatment, and after a brief follow-up., Results: Consistent with hypotheses, both VR conditions reduced pain significantly more relative to the waitlist control condition (d=1.60, P<0.001) and pain reductions were largely maintained at the brief follow-up assessment. Both VR conditions reduced pain by ∼50% and led to improvements in mood, anxiety, and relaxation. Contrary to prediction, the Video Capture VR condition was not significantly more effective at reducing pain relative to the CGI VR condition (d=0.25, P=0.216). However, as expected, patients randomized to the Video Capture VR rated their experience as more positive and realistic (d=0.78, P=0.002)., Discussion: Video Capture VR was as effective as CGI VR for pain reduction and was rated as more realistic., Competing Interests: This research was graciously funded by a University of Texas at Austin “Lift” grant (Austin, TX). M.B.P. reports grants from the National Institutes of Health (Bethesda, MD), Defense Advanced Research Projects Agency (Arlington County, VA), Department of Defense, National Institute on Disability Independent Living Rehabilitation and Research (Washington, DC), and book royalties from Oxford University Press (Oxford, UK) and Academic Press (Cambridge, MA). J.A.J.S. reports grants from the Cancer Prevention and Research Institute of Texas (Austin, TX) and National Institute on Drug Abuse (Bethesda, MD) and personal fees from Big Health Ltd. (San Francisco, CA), Aptinyx (Evanston, IL), Elsevier (Amsterdam, Netherlands), and the American Psychological Association (Worcester, MA), Oxford University Press (Oxford, UK). M.W.O. is a paid speaker and is further compensated as an Advisory Board member for Big Health (San Francisco, CA). The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In this paper, we summarize findings from the Tenth International Workshop on Tropical Cyclones (IWTC-10) subgroup on operational track forecasting techniques and capability. The rate of improvement in the accuracy of official forecast tracks (OFTs) appears to be slowing down, at least for shorter lead times, where we may be approaching theoretical limits. Operational agencies continue to use consensus methods to produce the OFT with most continuing to rely on an unweighted consensus of four to nine NWP models. There continues to be limited use of weighted consensus techniques, which is likely a result of the skills and additional maintenance needed to support this approach. Improvements in the accuracy of ensemble mean tracks is leading to increased use of ensemble means in consensus tracks. Operational agencies are increasingly producing situation-dependent depictions of track uncertainty, rather than relying on a static depiction of track forecast certainty based on accuracy statistics from the preceding 5 years. This trend has been facilitated by the greater availability of ensemble NWP guidance, particularly vortex parameter files, and improved spread in ensembles. Despite improving spread-skill relationships, most ensemble NWP systems remain under spread. Hence many operational centers are looking to leverage "super-ensembles" (ensembles of ensembles) to ensure the full spread of location probability is captured. This is an important area of service development for multi-hazard impactbased warnings as it supports better decision making by emergency managers and the community in the face of uncertainty. [ABSTRACT FROM AUTHOR]

Multiple theoretical frameworks have been proposed to provide a more comprehensive picture of the risk factors that influence anxiety-related developmental trajectories. Nonetheless, there remains a need for an integrative model that outlines: (1) which risk factors may be most pertinent at different points in development, and (2) how parenting may maintain, exacerbate, or attenuate an affective style that is characterized by high negative emotional reactivity to unfamiliar, uncertain, and threatening situations. A developmentally informed, integrative model has the potential to guide treatment development and delivery, which is critical to reducing the public health burden associated with these disorders. This paper outlines a model integrating research on many well-established risk mechanisms for anxiety disorders, focusing on (1) the developmental progression from emotional reactivity constructs early in life to those involving higher-level cognitive processes later in youth, and (2) potential pathways by which parenting may impact the stability of youth's cognitive-affective responses to threat-relevant information across development., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.

Ireland has seen a steady increase in paediatric sickle cell disease (SCD). In 2005, only 25% of children with SCD were referred to the haemoglobinopathy service in their first year. A non-funded screening programme was implemented. This review aimed to assess the impact screening has had. All children referred to the haemoglobinopathy service born in Ireland after 2005 were identified. Data was collected from the medical chart and laboratory system. Information was analysed using Microsoft Excel. 77 children with SCD were identified. The median age at antibiotic commencement in the screened group was 56 days compared with 447 days in the unscreened group, p = < 0.0003. 22 (28%) of infants were born in centre's that do not screen and 17 (81%) were over 6 months old at referral, compared with 14 (21%) in the screened group. 6 (27%) of those in the unscreened group presented in acute crisis compared with 2 (3%) in the screened population. The point prevalence of SCD in Ireland is 0.2% in children under 15 yr of African and Asian descent. We identified delays in referral and treatment, which reflect the lack of government funded support and policy. We suggest all maternity units commence screening for newborns at risk of SCD. It is a cost effective intervention with a number needed to screen of just 4 to prevent a potentially fatal crisis.

Article 12 of the United Nations Convention of the Rights of the Child (UNCRC) (1989) sets out the right for all children to be heard and for their opinions to be given due weight. However, the voices of children with disabilities often remain silenced as their perspectives are rarely consulted. This paper describes how a visual, participatory research method called Photovoice was used to elicit the voices of students with Intellectual Disabilities (ID) in mainstream post-primary schools in the Republic of Ireland. Thirteen students with ID in four schools across Ireland participated by taking photographs of aspects of their school life that were meaningful to them. Photographs focused on places, spaces, objects and examples of learning, including their role in decision making. This paper details the stages of the Photovoice method which was adapted to support students to participate in the research process. It provides guidance on how to address the ethical and methodological concerns which arise when researching with children. It outlines a two-step approach to analysis, where participating students interpreted and created meaning which was further developed by the Principal Investigator. Employing Photovoice repositions students in this study as co-researchers and co-creators of meaning. Its use operationalises Lundy's Model of Participation (2007) by providing space, voice, audience and influence which are necessary for children to express their views and have their voices heard in an ethical and inclusive manner. [ABSTRACT FROM AUTHOR]

As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted. [ABSTRACT FROM AUTHOR]

In this review, the process of extracting precise values for NMR interaction tensors from single crystal samples is systematically explored. Starting with a description of the orientation dependence of the considered interactions, i.e., chemical shift, dipolar, and quadrupole interaction, the techniques for acquiring and analysing single-crystal spectra are outlined. This includes the 'classical' approach, which requires the acquisition of three rotation patterns around three rotation axes that are orthogonal to each other, as well as more recent strategies aimed at reducing the number of required NMR spectra. One such strategy is the 'single-rotation method', which exploits the symmetry relations between tensors in the crystal structure to reduce the necessary amount of orientation-dependent data. This concept may be extended to additionally include the orientation of the goniometer axis itself in the data fit, which may be termed the 'minimal-rotation method'. Other, more exotic schemes, such as the use of specialised probe designs or the investigation of single crystals under magic-angle-spinning, are also briefly discussed. Actual values of NMR interaction tensors as determined from the various single-crystal methods have been collected and are provided in tables for spin I = 1 / 2 , I = 1 , and half-integer spins with I > 1 / 2 . [ABSTRACT FROM AUTHOR]

Background: Despite significant advancements in the development of anticancer therapies over the past few decades, the clinical management of colorectal cancer remains a challenging task. This study aims to investigate the inhibitory effects of cancer-targeting liposomes against colorectal cancer. Materials and Methods: Liposomes consisting of 3β-[N-(N′, N′-dimethylamino ethane)carbamoyl]-cholesterol (DC-CHOL), cholesterol (CHOL), and dioleoylphosphatidylethanolamine (DOPE) at a molar ratio of 1:1:0.5 were created and used as carriers to deliver an apoptosis-inducing plasmid encoding the tumor necrosis factor-related apoptosis-inducing ligand (pTRAIL) gene, along with the toll-like receptor (TLR7) agonist Rsiquimod (R848). The rationale behind this design is that pTRAIL can trigger cancer cell apoptosis by activating the DR4/5 receptor, while R848 can stimulate the immune microenvironment. Results: Experimental results demonstrated the synergistic effects of R848 and pTRAIL encapsulated by liposomes (RTL) in suppressing the proliferation of colorectal cancer cells. Moreover, further in vivo investigations revealed the strong anti-tumor efficacy of RTL in xenograft and orthotropic in situ models of colorectal cancer. Conclusions: These findings collectively highlight the therapeutic potential of R848/pTRAIL-loaded liposomes in the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Active immunotherapy and cancer vaccines that promote host antitumor immune responses promise to be effective and less toxic alternatives to current cytotoxic drugs for the treatment of cancer. However, the success of tumor immunotherapeutics and vaccines is dependent on identifying approaches for circumventing the immunosuppressive effects of regulatory T (Treg) cells induced by the growing tumor and by immunotherapeutic molecules, including Toll-like receptor (TLR) agonists. Here, we show that tumors secrete high concentrations of active TGF-β1, a cytokine that can convert naive T cells into Foxp3+ Treg cells. Silencing TGF-β1 mRNA using small interfering RNA (siRNA) in tumor cells inhibited active TGF-β1 production in vitro and restrained their growth in vivo. Prophylactic but not therapeutic administration of TGF-β1 siRNA reduced the growth of CT26 tumors in vivo. Furthermore, suppressing TGF-β1 expression at the site of a tumor, using siRNA before, during and after therapeutic administration of a TLR-activated antigen-pulsed dendritic cell vaccine significantly reduced the growth of B16 melanoma in mice. The protective effect of co-administering TGF-β1 siRNA with the DC vaccine was associated with suppression of CD25+ Foxp3+ and CD25+ IL-10+ T cells and enhancement of tumor infiltrating CD4 and CD8 T cells. Our findings suggest that transient suppression of TGF-β1 may be a promising approach for enhancing the efficacy of tumor vaccines in humans.

Macrophage migration inhibitory factor (MIF) was the original cytokine, described almost 50 years ago and has since been revealed to be an important player in pro-inflammatory diseases. Recent work using MIF mouse models has revealed new roles for MIF. In this review, we present an increasing body of evidence implicating the key pro-inflammatory cytokine MIF in specific biological activities related directly to cancer growth or contributing towards a microenvironment favouring cancer progression.

Background: Self-management (SM) programs are effective for some chronic conditions, however the evidence for arthritis SM is inconclusive. The aim of this case series project was to determine whether a newly developed specific self-management program for people with osteoarthritis of the knee (OAK), implemented by health professionals could achieve and maintain clinically meaningful improvements., Participants: 79 participants enrolled; mean age 66, with established osteoarthritis of the knee. People with coexisting inflammatory joint disease or serious co-morbidities were excluded., Intervention: 6-week disease (OA) and site (knee) specific self-management education program that included disease education, exercise advice, information on healthy lifestyle and relevant information within the constructs of self-management. This program was conducted in a community health care setting and was delivered by health professionals thereby utilising their knowledge and expertise., Measurements: Pain, physical function and mental health scales were assessed at baseline, 8 weeks, 6 and 12 months using WOMAC and SF-36 questionnaires. Changes in pain during the 8-week intervention phase were monitored with VAS., Results: Pain improved during the intervention phase: mean (95% CI) change 15 (8 to 22) mm. Improvements (0.3 to 0.5 standard deviation units) in indices of pain, mental health and physical functioning, assessed by SF-36 and WOMAC questionnaires were demonstrated from baseline to 12 months., Conclusion: This disease and site-specific self-management education program improved health status of people with osteoarthritis of the knee in the short and medium term.

Prophylactic immunization of mice with autologous tumor-derived heat shock proteins (Hsp) generates effective anti-tumor immunity. However, this approach is ineffective when used therapeutically, partly due to the immunosuppressive effects of the growing tumor. Here we sought to overcome this problem by therapeutic vaccination with dendritic cells (DC) pulsed with Hsp70 and a COX-2 inhibitor. We found that Hsp70 induces IL-6 and IL-10 production and suppressed expression of CD40 on DC. Incubation of DC with tumor-conditioned medium attenuated Hsp70-induced expression of CD80 and induced expression of COX-2. Inhibition of COX-2 partially reversed the stimulatory effect of Hsp70 on DC IL-6 and IL-10 production and enhanced expression of CD80 and MHC classes I and II. Therapeutic administration of DC pulsed in vitro with Hsp70 in the presence of a COX-2 inhibitor significantly reduced progression of B16 tumors in mice and significantly enhanced survival. This was associated with a reduction in the frequency of IL-10-producing CD4(+) T cells and enhancement of IFN-gamma-producing CD8(+) T cells. Our findings provide a novel immunotherapeutic approach against cancer based on attenuation of COX-2-mediated immunosuppression using in vitro modulated DC.

TLR ligands are potent adjuvants and promote Th1 responses to coadministered Ags by inducing innate IL-12 production. We found that TLR ligands also promote the induction of IL-10-secreting regulatory T (Treg) cells through p38 MAPK-induced IL-10 production by dendritic cells (DC). Inhibition of p38 suppressed TLR-induced IL-10 and PGE(2) and enhanced IL-12 production in DC. Incubation of Ag-pulsed CpG-stimulated DC with a p38 inhibitor suppressed their ability to generate Treg cells, while enhancing induction of Th1 cells. In addition, inhibition of p38 enhanced the antitumor therapeutic efficacy of DC pulsed with Ag and CpG and this was associated with an enhanced frequency of IFN-gamma-secreting T cells and a reduction of Foxp3(+) Treg cells infiltrating the tumors. Furthermore, addition of a p38 inhibitor to a pertussis vaccine formulated with CpG enhanced its protective efficacy in a murine respiratory challenge model. These data demonstrate that the adjuvant activity of TLR agonists is compromised by coinduction of Treg cells, but this can be overcome by inhibiting p38 signaling in DC. Our findings suggest that p38 is an important therapeutic target and provides a mechanism to enhance the efficacy of TLR agonists as vaccine adjuvants and cancer immunotherapeutics.

Apoptosis is an important cellular response to viral infection. In this study, we identified activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) as a positive regulator of apoptosis triggered by double-stranded (ds)RNA. Depletion of AMBRA1 by gene editing significantly reduced dsRNA-induced apoptosis, which was largely restored by trans-complementation of AMBRA1. Mechanistically, AMBRA1 interacts with mitochondrial antiviralsignaling protein (MAVS), a key mitochondrial adaptor in the apoptosis pathway induced by dsRNA and viral infection. Further co-immunoprecipitation analysis demonstrated that the mitochondrial localization of MAVS was essential for their interaction. The impact of AMBRA1 on dsRNA-induced apoptosis relied on the presence of MAVS and caspase-8. AMBRA1 was involved in the stabilization of MAVS through preventing its dsRNA-induced proteasomal degradation. Consistently, AMBRA1 upregulated the apoptosis induced by Semliki Forest virus infection. Taken together, our work illustrated a role for AMBRA1 in virus-induced apoptosis through interacting with and stabilizing MAVS. [ABSTRACT FROM AUTHOR]

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Marek's disease (MD), caused by the Marek's disease virus, is a lymphoproliferative disease in chickens that can be controlled by vaccination. However, the current vaccines can limit tumor growth and death but not virus replication and transmission. The present study aimed to evaluate host responses following intramuscular injection of an mRNA vaccine encoding gB and pp38 proteins of the MDV within the first 36 h. The vaccine was injected in low and high doses using prime and prime-boost strategies. The expression of type I and II interferons (IFNs), a panel of interferon-stimulated genes, and two key antiviral cytokines, IL-1β and IL-2, were measured in spleen and lungs after vaccination. The transcriptional analysis of the above genes showed significant increases in the expression of MDA5, Myd88, IFN-α, IFN-β, IFN-γ, IRF7, OAS, Mx1, and IL-2 in both the spleen and lungs within the first 36 h of immunization. Secondary immunization increased expression of all the above genes in the lungs. In contrast, only IFN-γ, MDA5, MyD88, Mx1, and OAS showed significant upregulation in the spleen after the secondary immunization. This study shows that two doses of the MDV mRNA vaccine encoding gB and pp38 antigens activate innate and adaptive responses and induce an antiviral state in chickens. [ABSTRACT FROM AUTHOR]

Inflammasomes comprise a group of protein complexes with fundamental roles in the induction of inflammation. Upon sensing stress factors, their assembly induces the activation and release of the pro-inflammatory cytokines interleukin (IL)-1β and -18 and a lytic type of cell death, termed pyroptosis. Recently, CARD8 has joined the group of inflammasome sensors. The carboxy-terminal part of CARD8, consisting of a function-to-find-domain (FIIND) and a caspase activation and recruitment domain (CARD), resembles that of NLR family pyrin domain containing 1 (NLRP1), which is recognized as the main inflammasome sensor in human keratinocytes. The interaction with dipeptidyl peptidases 8 and 9 (DPP8/9) represents an activation checkpoint for both sensors. CARD8 and NLRP1 are activated by viral protease activity targeting their amino-terminal region. However, CARD8 also has some unique features compared to the established inflammasome sensors. Activation of CARD8 occurs independently of the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), leading mainly to pyroptosis rather than the activation and secretion of pro-inflammatory cytokines. CARD8 was also shown to have anti-inflammatory and anti-apoptotic activity. It interacts with, and inhibits, several proteins involved in inflammation and cell death, such as the inflammasome sensor NLRP3, CARD-containing proteins caspase-1 and -9, nucleotide-binding oligomerization domain containing 2 (NOD2), or nuclear factor kappa B (NF-κB). Single nucleotide polymorphisms (SNPs) of CARD8, some of them occurring at high frequencies, are associated with various inflammatory diseases. The molecular mechanisms underlying the different pro- and anti-inflammatory activities of CARD8 are incompletely understood. Alternative splicing leads to the generation of multiple CARD8 protein isoforms. Although the functional properties of these isoforms are poorly characterized, there is evidence that suggests isoform-specific roles. The characterization of the functions of these isoforms, together with their cell- and disease-specific expression, might be the key to a better understanding of CARD8's different roles in inflammation and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Adenylate cyclase toxin (CyaA) of Bordetella pertussis belongs to the repeat in toxin family of pore-forming toxins, which require posttranslational acylation to lyse eukaryotic cells. CyaA modulates dendritic cell (DC) and macrophage function upon stimulation with LPS. In this study, we examined the roles of acylation and enzymatic activity in the immunomodulatory and lytic effects of CyaA. The adenylate cyclase activity of CyaA was necessary for its modulatory effects on murine innate immune cells. In contrast, acylation was not essential for the immunomodulatory function of CyaA, but was required for maximal caspase-3 activation and cytotoxic activity. The wild-type acylated toxin (A-CyaA) and nonacylated CyaA (NA-CyaA), but not CyaA with an inactive adenylate cyclase domain (iAC-CyaA), enhanced TLR-ligand-induced IL-10 and inhibited IL-12, TNF-alpha, and CCL3 production by macrophages and DC. In addition, both A-CyaA and NA-CyaA, but not iAC-CyaA, enhanced surface expression of CD80 and decreased CpG-stimulated CD40 and ICAM-1 expression on immature DC. Furthermore, both A-CyaA and NA-CyaA promoted the induction of murine IgG1 Abs, Th2, and regulatory T cells against coadministered Ags in vivo, whereas iAC-CyaA had more limited adjuvant activity. In contrast, A-CyaA and iAC-CyaA induced caspase-3 activation and cell death in macrophages, but these effects were considerably reduced or absent with NA-CyaA. Our findings demonstrate that the enzymatic activity plays a critical role in the immunomodulatory effects of CyaA, whereas acylation facilitates the induction of apoptosis and cell lysis, and as such, NA-CyaA has considerable potential as a nontoxic therapeutic molecule with potent anti-inflammatory properties.

Members of the caspase family of cysteine proteases have been firmly established to play key roles in signal transduction cascades that culminate in apoptosis (programmed cell death). Caspases are normally expressed as inactive precursor enzymes (zymogens) that become activated during apoptosis and proceed to dismantle the cell from within. To date, three major apoptosis-associated pathways to caspase activation have been elucidated. Certain caspases, such as caspase-1, also occupy important positions in signaling pathways associated with immune responses to microbial pathogens. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-18, and not apoptosis per se. Here, we discuss the current understanding of how caspases are activated during apoptosis and inflammation and the roles these proteases play in either context.

The transmembrane proto-oncogene receptor tyrosine kinase (RTK) ROS is an orphan receptor that is aberrantly expressed in neoplasms of the central nervous system. Here, we report the fusion of its carboxy-terminal kinase domain to the amino-terminal portion of a protein called FIG (Fused in Glioblastoma) in a human glioblastoma multiforme (GBM). By characterizing both FIG and ROS genes in normal and in U118MG GBM cells, we determined that an intra-chromosomal homozygous deletion of 240 kilobases on 6q21 is responsible for the formation of the FIG-ROS locus. The FIG-ROS transcript is encoded by 7 FIG exons and 9 ROS-derived exons. We also demonstrate that the FIG-ROS locus encodes for an in-frame fusion protein with a constitutively active kinase activity, suggesting that FIG-ROS may act as an oncogene. This is the first example of a fusion RTK protein that results from an intra-chromosomal deletion, and it represents the first fusion RTK protein isolated from a human astrocytoma., (Copyright 2003 Wiley-Liss, Inc.)

Proteins possessing the caspase recruitment domain (CARD) motif have been implicated in pathways leading to activation of caspases or NF-kappaB in the context of apoptosis or inflammation, respectively. Here we report the identification of a novel protein, CARDINAL, that contains a CARD motif and also exhibits a high degree of homology to the C terminus of DEFCAP/NAC, a recently described member of the Apaf-1/Nod-1 family. In contrast with the majority of CARD proteins described to date, CARDINAL failed to promote apoptosis or NF-kappaB activation. Rather, CARDINAL potently suppressed NF-kappaB activation associated with overexpression of TRAIL-R1, TRAIL-R2, RIP, RICK, Bcl10, and TRADD, or through ligand-induced stimulation of the interleukin-1 or tumor necrosis factor receptors. Co-immunoprecipitation experiments revealed that CARDINAL interacts with the regulatory subunit of the IkappaB kinase (IKK) complex, IKKgamma (NEMO), providing a molecular basis for CARDINAL function. Thus, CARDINAL is a novel regulator of NF-kappaB activation in the context of pro-inflammatory signals.

Polycystic Ovary Syndrome (PCOS) presents multifaceted challenges affecting women's reproductive, metabolic, and psychological systems, consequently impacting their psychological and emotional well-being. The utilization of meditation and mindfulness interventions (MMIs) is found to be increasing for the management of PCOS. This scoping review systematically explored the current literature to identify the type and application of MMIs for PCOS management. A systematic search of literature was conducted using CINAHL, PsycINFO, Scopus, MEDLINE, and PubMed databases for identifying studies conducted on the usage of MMIs in women diagnosed with PCOS, irrespective of age. The comprehensive search identified 14 trials (comprising 17 citations) meeting inclusion criteria, involving 723 participants across various age groups. Among these, nine were randomized controlled trials (RCTs), while the remaining comprised non-RCTs. Several types of MMIs, including Rajayoga of Brahmakumaris, Yoga Nidra, OM cyclic meditation, unspecified forms of meditation, mindfulness-based stress reduction programs, mindful yoga, and mindfulness-based activities, were used. Outcomes were predominantly assessed in psychological domains (n=11), followed by anthropometric (n=9), quality of life (n=7), and metabolic metrics (n=7). The review findings suggest the integration of meditation with conventional treatment modalities. Preliminary data indicate that MMIs have the potential to improve psychosocial well-being and quality of life among PCOS-affected women. However, adequately powered studies with extended follow-up periods are required to investigate the mechanisms and therapeutic efficacy of MMIs, particularly concerning reproductive outcomes and weight management. Furthermore, diligent monitoring and reporting of adverse events and adherence are essential for a comprehensive understanding of MMI utilization in PCOS management. [ABSTRACT FROM AUTHOR]

3D micro-nano devices are expected to become the mainstay of multi-color solid-state lighting in the future because of their broad-band characteristic and the advantage of integrating the monolithic light-emitting diode on a single chip. In this work, InGaN/GaN micro-truncated pyramid arrays with six equivalent (10 1 ̄ 1) semi-polar facets and one (0001) polar facet were successfully prepared by the metal-organic chemical vapor deposition technology. The average diameter of the obtained uniform micro-truncated pyramids was 6.8 µm with a height of 2.4 µm. According to the results of micro-photoluminescence performed, the InGaN/GaN micro-truncated pyramid arrays can achieve multi-color emission from blue to red. The luminescent positions corresponding to different wavelengths were detected by the cathode luminescence spectrum. The multi-color emission was related to the quantum hybrid structures apart from the discrepancy of In composition in different positions. The developed microstructure can create multi-color emission by combining distinct luminescence modes, which can aid in the design of future optoelectronic devices. [ABSTRACT FROM AUTHOR]

Caspase (CASP) is a protease family that plays a vital role in apoptosis, development, and immune response. Herein, we reported the identification and characterization of two CASPs, AjCASPX1 and AjCASPX2, from the sea cucumber Apostichopus japonicus, an important aquaculture species. AjCASPX1/2 share similar domain organizations with the vertebrate initiator caspases CASP2/9, including the CARD domain and the p20/p10 subunits with conserved functional motifs. However, compared with human CASP2/9, AjCASPX1/2 possess unique structural features in the linker region between p20 and p10. AjCASPX1, but not AjCASPX2, induced marked apoptosis of human cells by activating CASP3/7. The recombinant proteins of AjCASPX2 and the CARD domain of AjCASPX2 were able to bind to a wide range of bacteria, as well as bacterial cell wall components, and inhibit bacterial growth. AjCASPX1, when expressed in Escherichia coli, was able to kill the host bacteria. Under normal conditions, AjCASPX1 and AjCASPX2 expressions were most abundant in sea cucumber muscle and coelomocytes, respectively. After bacterial infection, both AjCASPX1 and AjCASPX2 expressions were significantly upregulated in sea cucumber tissues and cells. Together, these results indicated that AjCASPX1 and AjCASPX2 were initiator caspases with antimicrobial activity and likely functioned in apoptosis and immune defense against pathogen infection. [ABSTRACT FROM AUTHOR]

In the modern world, dams and the artificial reservoirs behind them serve the increasing demand for water across diverse needs such as agriculture, energy production, and drinking water. As dams continue to proliferate, monitoring water availability influenced by reservoir operations is now of paramount importance. The Reservoir Assessment Tool (RAT) is a data-driven software platform that integrates satellite remote sensing with hydrological models, enabling the estimation of key reservoir parameters such as inflow, outflow, surface area, evaporation, and storage changes. The earliest version of RAT (version 1.0) was set up for 1598 reservoirs around the world with limitations in functional robustness, updating frequency, and scalability. Some of these limitations on updating frequency and functional robustness were addressed in version 2.0 that was later made operational for the intergovernmental agency of the Mekong River Commission. Recognizing the need for scalability to mobilize the global water management community to benefit from satellite remote sensing, we hereby introduce RAT version 3.0. This version is optimized for accelerating open collaboration among users for continuous improvement and customization of RAT to enable reservoir management breakthroughs. RAT 3.0 represents a wholesale overhaul from the previous versions to empower the global community of users and developers in the spirit of the open-source movement. RAT 3.0 allows reservoir monitoring advancements and new functional developments that can be freely exchanged and seamlessly integrated for continuous evolution of the software. A centralized web application has also been established to facilitate the storage and dissemination of global reservoir monitoring information along with comprehensive training resources. RAT 3.0 aspires to bridge the traditional practices of water management community with the capabilities of satellite remote sensing. The global impact of the software can be expected to increase as uptake spreads, enabling a more sustainable and equitable utilization of our planet's water resources. [ABSTRACT FROM AUTHOR]

In Australia, dental caries are observed in almost half of children starting school. Oral health promotion programs are being implemented in early childhood education and care (ECEC) settings to promote oral health. This study examined children's perceptions of one such program, the Bright Smiles Bright Futures (BSBF) program in ECEC settings in New South Wales, Australia. Data were collected using focus group discussions from 15 children aged 3–5 years, transcribed verbatim, and analysed through inductive thematic analysis. Three themes were identified as follows: (i) oral health knowledge of children, (ii) oral hygiene practices routine and skills development, and (iii) evaluation of the oral health promotion kit and opportunities for improvement. Children's perspectives highlight the BSBF program's success in communicating key messages to promote oral health. The integration of family-centric approaches, acknowledgement of children's preferences, and the use of interactive tools collectively enhance the overall effectiveness of the oral health promotion program. [ABSTRACT FROM AUTHOR]

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The dry root of the soybean plant Astragalus membranaceus (Fisch) Bge. var. mongholicus (Bge) Hsiao or A. membranaceus (Fisch) Bge, Astragali Radix (AR) has a long medicinal history. Astragalus polysaccharide (APS), the natural macromolecule that exhibits immune regulatory, anti-inflammatory, antitumor, and other pharmacological activities, is an important active ingredient extracted from AR. Recently, APS has been increasingly used in cancer therapy owing to its anti-tumor ability as it prevents the progression of prostate, liver, cervical, ovarian, and non-small-cell lung cancer by suppressing tumor cell growth and invasion and enhancing apoptosis. In addition, APS enhances the sensitivity of tumors to antineoplastic agents and improves the body's immunity. This macromolecule has prospects for broad application in tumor therapy through various pathways. In this article, we present the latest progress in the research on the anti-tumor effects of APS and its underlying mechanisms, aiming to provide novel theoretical support and reference for its use in cancer therapy. [ABSTRACT FROM AUTHOR]

Lung cancer is often triggered by genetic alterations that result in the expression of oncogenic tyrosine kinases. Specifically, ALK, RET, and ROS1 chimeric receptor tyrosine kinases are observed in approximately 5–7%, 1–2%, and 1–2% of NSCLC patients, respectively. The presence of these fusion genes determines the response to tyrosine kinase inhibitors. Thus, accurate detection of these gene fusions is essential in cancer research and precision oncology. To address this need, we have developed a multiplexed RT-qPCR assay using xeno nucleic acid (XNA) molecular clamping technology to detect lung cancer fusions. This assay can quantitatively detect thirteen ALK, seven ROS1, and seven RET gene fusions in FFPE samples. The sensitivity of the assay was established at a limit of detection of 50 copies of the synthetic template. Our assay has successfully identified all fusion transcripts using 50 ng of RNA from both reference FFPE samples and cell lines. After validation, a total of 77 lung cancer patient FFPE samples were tested, demonstrating the effectiveness of the XNA-based fusion gene assay with clinical samples. Importantly, this assay is adaptable to highly degraded RNA samples with low input amounts. Future steps involve expanding the testing to include a broader range of clinical samples as well as cell-free RNAs to further validate its applicability and reliability. [ABSTRACT FROM AUTHOR]

The present study builds a regional urban resilience index model through ecological density, spatial distance, and social division based on the Density, Distance and Division (3D) theory of new economic geography. In total, 41 cities in the Yangtze River Delta, China, were used as the research object, and the characteristics of the urban resilience index and the driving effect of factors were investigated. The results show that: (1) the Yangtze River Delta urban agglomerations are at the primary level of resilience, which presents a spatial development pattern of one core and two belts; (2) there is a significant positive correlation between external resistance and internal restoration, and the restoration lags behind the resistance in most cities because of the lack of internal density effects; and (3) the driving effects of ecological density, spatial distance, and social division elements on the urban resilience level are different at the regional and district scales. Ecological density and social division are stronger at the district scale, and the spatial distance is stronger at the regional scale. [ABSTRACT FROM AUTHOR]