Changes In Key Components Research Articles

Implementation of generative artificial intelligence technologies in creative activities: development of a structural model of design thinking

The subject of the study is systemic changes in the methodology of design thinking, taking place under the influence of the development and spread of generative artificial intelligence (AI) technologies in design and other creative industries. The purpose of the work is: analysis of modern research on the impact of generative AI technologies on creative industries, design and on design thinking; development of a structural model of design thinking to further explore the evolution of the methodology. The following tasks are set in the article: to analyze modern scientific publications regarding the essence, structure and content of design thinking; review research on the benefits and challenges of using generative AI in design processes; to develop a model that allows identifying and describing changes in key components of the design thinking methodology arising under the influence of widespread adoption of generative AI technologies. During the research, the following methods were used: analysis and synthesis of the content of technical, economic, philosophical, linguistic, historical scientific and methodical research on the problems of forming the conceptual apparatus of the design-thinking methodology and the use of generative AI in design processes; comparative-historical, retrospective methods; structural and logical analysis. The following results were achieved: the actualized need for a comprehensive research approach to analyze the multifaceted impact of AI technologies on design; the key advantages and challenges associated with the integration of AI into creative processes are identified; a structural model of presentation of the design-thinking methodology was developed in the form of four interconnected structural layers with subsequent decomposition of each of the layers into constituent elements. The conclusions highlight the depth and multifaceted nature of the changes taking place in design and other creative industries under the influence of generative AI and need further in-depth research. The developed structural model of the design-thinking methodology allows to decompose the complex creative process to a certain extent, laying the foundation for a comprehensive analysis of the evolution of the methodology and the systematic introduction of generative artificial intelligence technologies into design processes.

The disparate effects of omega-3 PUFAs on intestinal microbial homeostasis in experimental rodents under physiological condition

The health benefits of omega-3 polyunsaturated fatty acids (omega-3 PUFAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are linked to their regulatory effects on the composition of the gut microbiota. However, there is a lack of direct evidence on whether omega-3 PUFAs regulate the gut microbial homeostasis under physiological conditions. This study investigated the impact of equivalent doses of EPA, DHA, and fish oil (FO) with a DHA to EPA ratio of approximately 1:1 on the bacterial and fungal composition of normal young mice. This study also analyzed changes in key components of the gut microenvironment, including the colonic mucus barrier and short-chain fatty acids, to address the prebiotic potential of omega-3 PUFAs. The results showed that all three omega-3 PUFAs interventions induced significant fluctuations in the gut bacteria and fungi, leading to an increase in the abundance of some probiotics. Notably, DHA, EPA, and FO interventions significantly increased the abundance of the probiotic Lactobacillus, Bifidobacterium, and Akkermansia, respectively. Both DHA and fish oil interventions also significantly reduced the abundance of potentially pathogenic fungi, such as Aspergillus and Penicillium. Association analysis of the top 19 differential fungal and bacterial genera in abundance revealed a much more bacteria-bacteria and bacteria-fungi connections, but fewer fungi-fungi connections. This highlights the importance of bacteria in the gut microecological network. Furthermore, the levels of butyric acid and valeric acid in the colonic contents of DHA intervention group were significantly increased, and the colonic mucus layer thickness was increased in three treatment groups. In summary, DHA, EPA and FO interventions showed targeted enhancement of different probiotics and enhanced colon defense barrier (mucus barrier), showing potential prebiotic effects.

Extracellular Matrix Proteomics: The mdx-4cv Mouse Diaphragm as a Surrogate for Studying Myofibrosis in Dystrophinopathy.

The progressive degeneration of the skeletal musculature in Duchenne muscular dystrophy is accompanied by reactive myofibrosis, fat substitution, and chronic inflammation. Fibrotic changes and reduced tissue elasticity correlate with the loss in motor function in this X-chromosomal disorder. Thus, although dystrophinopathies are due to primary abnormalities in the DMD gene causing the almost-complete absence of the cytoskeletal Dp427-M isoform of dystrophin in voluntary muscles, the excessive accumulation of extracellular matrix proteins presents a key histopathological hallmark of muscular dystrophy. Animal model research has been instrumental in the characterization of dystrophic muscles and has contributed to a better understanding of the complex pathogenesis of dystrophinopathies, the discovery of new disease biomarkers, and the testing of novel therapeutic strategies. In this article, we review how mass-spectrometry-based proteomics can be used to study changes in key components of the endomysium, perimysium, and epimysium, such as collagens, proteoglycans, matricellular proteins, and adhesion receptors. The mdx-4cv mouse diaphragm displays severe myofibrosis, making it an ideal model system for large-scale surveys of systematic alterations in the matrisome of dystrophic fibers. Novel biomarkers of myofibrosis can now be tested for their appropriateness in the preclinical and clinical setting as diagnostic, pharmacodynamic, prognostic, and/or therapeutic monitoring indicators.

Adaptive diversity in structure and function of C4 photosynthetic components.

Many tropical and subtropical plant lineages have independently evolved C4 photosynthesis. The convergent evolution of this complex functional trait from different ancestors is reflected in variations in the structural and biochemical characteristics of C4 components such as enzymes and cellular specializations. The mechanism of C4 carbon concentration mostly involves coordinated function of mesophyll and bundle sheath cells. Important adaptations of the C4 syndrome include increased vein density and the development of photosynthetic bundle sheath cells with low gas conductance. In addition, the enzymes and transporters of the C4 pathway evolved via the co-option of multiple genes, each derived from a specific lineage of isoforms present in nonC4-ancestors. In particular, the adaptation of C4 enzymes resulted in a variety of structural and biochemical modifications, generally leading to increased catalytic efficiency and regulation by metabolites and post-translational modifications. Differences in these adaptations are particularly evident in the C4-acid decarboxylation step, which can be catalyzed by three decarboxylases that define the C4 subtypes. Associated with the biochemical subtypes, there are also differences in the extend of grana staking and localization of bundle sheath cells chloroplasts. The presence of a suberin layer and symplastic connections also likely vary among the different C4-subtypes. This review examines the current understanding of the diversity of structural and functional changes in key components of the C4 carbon concentration mechanism. This knowledge is necessary not only to identify divergent solutions for convergent optimization of C4 components in different C4 lineages, but also to guide their creation for rational synthetic biology approaches.

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells

Inspired by the well-known phenomenon of stretch-induced airway dilation in normal lungs and the emerging stretch-responsive Piezo1 channels that can be chemically activated by specific agonists such as Yoda1, we attempted to investigate whether chemical activation of Piezo1 by Yoda1 can modulate the biomechanical behaviors of airway smooth muscle cells (ASMCs) so that it may be exploited as a novel approach for bronchodilation. Thus, we treated in vitro cultured rat ASMCs with Yoda1, and examined the cells for calcium signaling, cell stiffness, traction force, cell migration, and the mRNA expression and distribution of molecules relevant to cell biomechanics. The data show that ASMCs expressed abundant mRNA of Piezo1. ASMCs exposed to 1 µM Yoda1 exhibited a potent but transient Ca2+ signaling, and treatment with 1 µM Yoda1 for 24 h led to decreased cell stiffness and traction force, all of which were partially reversed by Piezo1 inhibitor GsMTx4 and Piezo1 knockdown, respectively. In addition, ASMCs treated with 1 µM Yoda1 for 24 h exhibited impaired horizontal but enhanced vertical cell migration, as well as significant changes in key components of cells' contractile machinery including the structure and distribution of stress fibers and alpha-smooth muscle actin (α-SMA) fibrils, the mRNA expression of molecules associated with cell biomechanics. These results provide the first evidence that chemical activation of Piezo1 by Yoda1 resulted in marked pro-relaxation alterations of biomechanical behaviors and contractile machinery of the ASMCs. These findings suggest that Piezo1-specific agonists may indeed have great potential as alternative drug agents for relaxing ASMCs.

Business model innovation and firm performance: Exploring causal mechanisms in SMEs

Although research has shown that business model innovation (BMI) can create a firm's competitive advantage and enhance its performance, many small and medium-sized enterprises (SMEs) fail to obtain the expected outcomes when innovating their business model. Business Model Innovation (BMI) leads to irreversible fundamental changes in key components of a company's business model, which means it carries with it a high level of risk, ambiguity and uncertainty. Drawing on the data from a cross-industry sample of 563 European SMEs, we apply structural equation modelling to examine how a firm's performance is affected by innovating its business model. A conceptual model is developed to examine how organisational capabilities and implementation of a profit- or growth-oriented strategy, as materialised in BMI, affect a firm's overall performance. The results indicate that, while the direct link between BMI and firm performance is not significant, this path is fully mediated through efficiency growth, organisational capabilities and revenue growth. Furthermore, there are significant direct effects from efficiency growth, organisational capabilities and revenue growth on firm performance. These findings confirm the validity of the model and contribute to existing literature on BMI efforts in SMEs and provide guidelines to help company owners/managers implement informed decisions about the implementation of BMI based on their firm's strategies.

GRACE products and land surface models for estimating the changes in key water storage components in the Nile River Basin

The Nile River Basin (NRB) is facing extreme demand for its water resources due to an alarming increase in population and the changing climate. The NRB is not compatible with ground-based in-situ observations owing to its large basin area size and limited hydrological data access from basin countries. Thus, it lends itself to remotely sensed approaches with high spatial resolution and extended temporal coverage. The Gravity Recovery and Climate Experiment (GRACE) avails a unique opportunity to investigate the changes in key components of terrestrial water storage (TWS). GRACE TWS solutions have specific tuning parameters and processing strategies that result in regionally specific variations and error patterns. We explored the TWS time series spatiotemporal changes, trends, uncertainties, and signal-to-noise ratio among different GRACE TWS data. We had also investigated the key terrestrial water storage components such as surface water, soil moisture, and groundwater storage changes. The results show that GRACE spherical harmonic solutions' uncertainty is higher than the mass concentration (mascon) over the NRB, and the Center for Space Research-mascons had the best performance. The evapotranspiration correlation (R2 = 0.85) has the highest correlation with GRACE’s TWS, whereas the normalized difference vegetation index (R2 = 0.82) has the second highest correlation. Notably, significant long-term (2003–2017) negative groundwater and soil moisture trends demonstrate a potential depletion of the NRB. Despite an increase in precipitation and the TWS time series, the rate of decline increased rapidly after 2008, thereby indicating the possibility of human-induced change (e.g. for irrigation purposes). Therefore, the results of this study provide a guide for future studies related to hydro-climatic change over the NRB and similar basins.

The stress of Arctic warming on polar bears.

Arctic ecosystems are changing rapidly in response to climate warming. While Arctic mammals are highly evolved to these extreme environments, particularly with respect to their stress axis, some species may have limited capacity to adapt to this change. We examined changes in key components of the stress axis (cortisol and its carrier protein-corticosteroid binding globulin [CBG]) in polar bears (Ursus maritimus) from western Hudson Bay (N=300) over a 33year period (1983-2015) during which time the ice-free period was increasing. Changing sea ice phenology limits spring hunting opportunities and extends the period of onshore fasting. We assessed the response of polar bears to a standardized stressor (helicopter pursuit, darting, and immobilization) during their onshore fasting period (late summer-autumn) and quantified the serum levels of the maximum corticosteroid binding capacity (MCBC) of CBG, the serum protein that binds cortisol strongly, and free cortisol (FC). We quantified bear condition (age, sex, female with cubs or not, fat condition), sea ice (breakup in spring-summer, 1year lagged freeze-up in autumn), and duration of fasting until sample collection as well as cumulative impacts of the latter environmental traits from the previous year. Data were separated into "good" years (1983-1990) when conditions were thought to be optimal and "poor" years (1991-2015) when sea ice conditions deteriorated and fasting on land was extended. MCBC explained 39.4% of the variation in the good years, but only 28.1% in the poor ones, using both biological and environmental variables. MCBC levels decreased with age. Changes in FC were complex, but more poorly explained. Counterintuitively, MCBC levels increased with increased time onshore, 1year lag effects, and in poor ice years. We conclude that MCBC is a biomarker of stress in polar bears and that the changes we document are a consequence of climate warming.

Profile of subpopulation composition of regulatory T lymphocytes and intestinal microbiota in patients with irritable bowel syndrome

The following specificcharacteristics of the composition of intestinal microbiota in patients with irritable bowel syndrome (IBS) were identified using a metagenomic analysis (16 S rRNA): 1) an increase in the representation of Actinobacteria, including Bifidobacterium spp., Firmicutes, including representatives of Streptococcaceae (Streptococcus), Lachnosperaceae (Dorea), Veillonellaceae (Dialister), Proteobacteria (Enterobacteriaceae and Desulfovibrionaceae families); 2) a decrease in the population of Bacteroidetes, including representatives of the families Prevotellacea (Prevotella spp.), Bacteroidaceae (Bacteroides spp.). Firmicutes belonging to the families Clostridiaceae and Ruminococcaceae (Fecalibacterium spp.). Flow cytometry in the study of the subpopulation composition of T regulatory (Treg) lymphocytes in patients with IBS revealed an increase in the number of CD45R0+CD62L+ central memory cells (CM), which can regulate the processes of maturation and differentiation of lymphocytes in lymphoid tissue. A decrease in the expression of exonucleases CD39 and CD73 was detected, which can have a significant effect on their activity. A reduction in effector memory cells (EM) Treg was observed. Changes in the expression level of exonucleases CD39 and CD73 were inversely correlated with the content of Proteobacteria and the representation of the genera Bifidobacterium spp. and Faecalibacterium spp. The content of СЫ Treg was directly correlated with the content of Dorea spp. The results may be indicative of impairment in the processes of Treg differentiation, which are closely related to changes in key components of intestinal microbiocenosis in IBS.

Microenvironment in classical Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is histologically characterized by aquantitatively dominating immune cell infiltrate. Its composition differs depending on the histological subtype and EBV (Epstein-Barr-Virus) status. Current pathogenic concepts postulate that the malignant cells, the so-called Hodgkin and Reed-Sternberg (HRS) cells, act as master recruiters, thereby actively shaping the microenvironment to support their proliferation and outgrowth. This view on the pathogenesis of cHL is further solidified by genetic studies, which have identified important mechanisms by which the HRS cells are enabled to escape immune surveillance. Besides an insufficient antigen presentation mediated by mutations and structural chromosomal changes in key components or regulators of major histocompatibility classI and II molecules, copy number gains of the 9p24.1 genomic locus encompassing JAK2 and the ligands of the programmed cell death protein1 (PD-1), PD-L1 and PD-L2, play an important role in the pathogenesis of this disease as the engagement of those ligands with their cognate receptor leads to suppression of the immune response. Of importance, the reversibility of this inhibitory receptor-ligand interaction is key to the clinical success that checkpoint inhibitors had and continue to have in cHL patients, especially in the relapse setting. In addition, comprehensive assessment of microenvironment composition, integration with results from genetic studies, and correlation with clinical outcomes have led to the development of prognostic models, which may assist in an improved risk stratification, informed selection of treatment regimens, and therefore better outcomes.

Integrating satellite observations and human water use data to estimate changes in key components of terrestrial water storage in a semi-arid region of North China

Sustainable management strategies for water resources rely on accurate knowledge about the dynamics of hydrological processes, especially in drylands, where freshwater is the limiting factor for the development of human society and ecosystems. The populated Loess Plateau (LP) in North China is a typical semi-arid region where competition for water between people and nature is worth noting because of afforestation promoted by the Grain to Green Program. In this study, changes in key components of terrestrial water storage (TWS) in the LP were explored using a multi-satellite approach, including Gravity Recovery and Climate Experiment (GRACE) observations and Earth observations of precipitation, evapotranspiration and soil moisture. By integrating data on human water use from different sources with satellite observations, we were able to examine the mechanisms driving these changes. The results demonstrated that, according to an evaluation based on reproducing TWS computed from the regional water balance in the LP, the mascon solution of the Center for Space Research (CSR) at University of Texas at Austin performed best out of the commonly used GRACE products. Regional TWS derived from the CSR mascon solution in the LP decreased significantly for the period 2003–2015. Significant decreases were also detected for regional ground water storage (GWS) estimated by decomposing the GRACE TWS using multi-sources remote sensing data. GWS made the greatest contribution to the changes in TWS. Increased plant transpiration was one reason for the decreasing trend of GWS. Because changes in precipitation, soil moisture and water consumed by irrigation were minor at regional scales, we concluded that the increase of transpiration is driven by deep-rooted trees planted, which use the part of precipitation that previously recharged groundwater. The findings from this study are valuable for water resource management and ecological restoration in semi-arid regions with high populations.

Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury: A Systematic Review.

Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group. Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response. Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice.

Differentiation-Associated Reprogramming of the Transforming Growth Factor β Receptor Pathway Establishes the Circuitry for Epithelial Autocrine/Paracrine Repair

Transforming growth factor (TGF) β has diverse and sometimes paradoxical effects on cell proliferation and differentiation, presumably reflecting a fundamental but incompletely-understood role in regulating tissue homeostasis. It is generally considered that downstream activity is modulated at the ligand:receptor axis, but microarray analysis of proliferative versus differentiating normal human bladder epithelial cell cultures identified unexpected transcriptional changes in key components of the canonical TGFβ R/activin signalling pathway associated with cytodifferentiation. Changes included upregulation of the transcriptional modulator SMAD3 and downregulation of inhibitory modulators SMURF2 and SMAD7. Functional analysis of the signalling pathway revealed that non-differentiated normal human urothelial cells responded in paracrine mode to TGFβ by growth inhibition, and that exogenous TGFβ inhibited rather than promoted differentiation. By contrast, in differentiated cell cultures, SMAD3 was activated upon scratch-wounding and was involved in promoting tissue repair. Exogenous TGFβ enhanced the repair and resulted in hyperplastic scarring, indicating a feedback loop implicit in an autocrine pathway. Thus, the machinery for autocrine activation of the SMAD3-mediated TGFβR pathway is established during urothelial differentiation, but signalling occurs only in response to a trigger, such as wounding. Our study demonstrates that the circuitry of the TGFβR pathway is defined transcriptionally within a tissue-specific differentiation programme. The findings provide evidence for re-evaluating the role of TGFβR signalling in epithelial homeostasis as an autocrine-regulated pathway that suppresses differentiation and promotes tissue repair. This provides a new paradigm to help unravel the apparently diverse and paradoxical effect of TGFβ signalling on cell proliferation and differentiation.

Suppression of Mir-93 May Regulate Anti-Oxidant Metabolism in Mesenchymal Stromal Cells Derived From Acute Myeloid Leukemia Patients.

Abstract 2354Though still in its infancy, increasing interest is focused on the role of metabolism in cancers and leukemias. At present, most of the studies addressing this question have centered on the malignant cells themselves and not on the cells that comprise the tumor microenvironment. The leukemia microenvironment in the bone marrow has been found to provide survival advantage to AML stem cells, and to protect against chemotherapy. The underlying mechanisms, however, are not well understood. Furthermore, it is not known how the leukemic microenvironment in AML patients differs from the hematopoietic microenvironment of healthy individuals. A better understanding of leukemia will be achieved when we determine if such differences exist and importantly, how these differences could impact the microenvironment’s ability to render cells resistant to therapy and possibly also support leukemogenesis. Mesenchymal stromal cells (MSC) are a key component of the bone marrow and play a key regulatory role in the leukemic niche. We have previously shown that co-cultured MSC can alter metabolism of leukemic cell lines by a mechanism involving mitochondrial uncoupling induced by the activation of Uncoupling Protein 2, to promote the Warburg Effect (Samudio et al Cancer Research, 2008; 68: 5198–5205). However, the metabolic nature of MSC from the leukemic microenvironment has not been investigated. In the present study, analysis of 352 known metabolites was performed on MSC from normal healthy donors (N = 15) and AML-derived MSC (N = 14) using Liquid Chromatography/Mass Spectrometry (LC/MS) and Gas Chromatography/Mass Spectrometry (GC/MS) (Metabolon, Durham, NC). Results indicated that metabolites involved in signaling and anti-oxidant rather than in energy regulation showed significant differences. AML derived MSC had significantly elevated levels of both reduced and oxidized glutathione compared to healthy donor MSC. Homocysteine, 5-methyltetrahydrofolate, and opthalmate levels were higher in AML MSC which is consistent with increased glutathione synthesis. The antioxidants α- and γ-tocopherol (components of vitamin E) were also significantly increased in AML MSC. These changes in key components of cellular redox homeostasis may reflect a cellular response that leads to the upregulation of glutathione synthesis and tocopherol uptake to protect the MSC cells from a more oxidative environment. In addition to metabolic analysis, we conducted miR profiling on MSC from normal healthy donors (N = 15) and AML derived MSC (N = 28). Eighteen miRs showed significant differences in expression between the 2 groups. AML derived MSC were found to express 2.3 fold less miR-93 compared to MSC from healthy donors. Previous analysis of miRs in AML cells by our groups indicated that miR-93 levels were lower in AML blast cells compared to normal counterparts (Garzon et al Blood, 2008; 111: 3183–3189). Mir-93 is a member of the miR-106b-25 cluster that comprises a group of three miRNAs on human chromosome 7q22. A recent report by Li and colleagues (Mechanisms of Ageing and Development, 2011; 132: 75–85) demonstrated in a mouse model that the aging liver is subject to damage by oxidative stress due to increased levels of miR-93. MiR-93 targets microsomal glutathione S-transferase 1 (MGST1) and the potential increase in MGST1 and the higher abundance of gluthathione support a model in which leukemia MSC could have increased xenobiotic (chemotherapy) detoxifying capacity. Future studies will include analysis of MGST1 protein expression to determine if this enzyme is indeed elevated in AML-derived MSC. In conclusion, AML-derived MSC exhibit lower expression of miR-93 that could support production of anti-oxidant metabolites to protect the cells from oxidative stress damage in the leukemic microenvironment. Disclosures:No relevant conflicts of interest to declare.

Evidence for Enhanced Land–Atmosphere Feedback in a Warming Climate

Abstract Global simulations have been conducted with the European Centre for Medium-Range Weather Forecasts operational model run at T1279 resolution for multiple decades representing climate from the late twentieth and late twenty-first centuries. Changes in key components of the water cycle are examined, focusing on variations at short time scales. Metrics of coupling and feedbacks between soil moisture and surface fluxes and between surface fluxes and properties of the planetary boundary layer (PBL) are inspected. Features of precipitation and other water cycle trends from coupled climate model consensus projections are well simulated. Extreme 6-hourly rainfall totals become more intense over much of the globe, suggesting an increased risk for flash floods. Seasonal-scale droughts are projected to escalate over much of the subtropics and midlatitudes during summer, while tropical and winter droughts become less likely. These changes are accompanied by an increase in the responsiveness of surface evapotranspiration to soil moisture variations. Even though daytime PBL depths increase over most locations in the next century, greater latent heat fluxes also occur over most land areas, contributing a larger energy effect per unit mass of air, except over some semiarid regions. This general increase in land–atmosphere coupling is represented in a combined metric as a “land coupling index” that incorporates the terrestrial and atmospheric effects together. The enhanced feedbacks are consistent with the precipitation changes, but a causal connection cannot be made without further sensitivity studies. Nevertheless, this approach could be applied to the output of traditional climate change simulations to assess changes in land–atmosphere feedbacks.

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

BackgroundDopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).ResultsGene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-O-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.ConclusionsWe find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

Abstract 4088: Targeting glutamine metabolism in breast cancer

Abstract Background: Unlike normal cells, most cancer cells primarily metabolize glucose by glycolysis rather than oxidative phosphorylation (Warburg effect). The cancer cells are reprogrammed to acquire these fundamental metabolic alterations during malignant transformation via different mechanisms. These mechanisms include mitochondrial defects and malfunction, adaptation to a hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Cancer cells also rely on glutamine for anabolism and ATP synthesis. Recent studies have shown that inhibiting glycolytic pathways leads to a significant inhibition of growth of tumor xenografts. Our group has previously shown the MYC oncogene activates glutamine metabolism which serves as a major energy source in transformed cells. Objective: Examine the antitumor effect of a glutamine metabolic inhibitor, aminooxyacetate (AOA; aminotransferases/malate-aspartate shuttle inhibitor), alone and in combination with chemotherapy (doxorubicin and carboplatin) in a breast cancer xenograft model. Methods: Immunodeficient mice bearing MDA-MB-231 breast cancer cells were treated with AOA alone, doxorubicin or carboplatin alone, or AOA in combination with the chemotherapeutic agent for four weeks. The tumors were evaluated for histopathological and molecular alterations. Statistical analysis: Tumor growth was analyzed using a mixed-effects model for repeated measures data to account for dependence among observations within the same animal. Results: We observed a significant inhibition of tumor volume in mice treated with AOA in combination with doxorubicin or carboplatin compared to groups receiving single drugs (p&amp;lt;0.01). Western blot analysis of tumors treated with drug combinations showed decreased cyclin D1 level and increased p21 levels. Changes in key components of the glycolytic pathway are being examined. Conclusion: Our results suggest that targeting the metabolic pathway results in significant tumor inhibition in preclinical models of breast cancer and potentially could serve as attractive therapeutic targets for breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4088. doi:10.1158/1538-7445.AM2011-4088

Liver Glucokinase(A456V) Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase.

Recent reports point out the importance of the complex GK-GKRP in controlling glucose and lipid homeostasis. Several GK mutations affect GKRP binding, resulting in permanent activation of the enzyme. We hypothesize that hepatic overexpression of a mutated form of GK, GKA456V, described in a patient with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and could provide a model to study the consequences of GK-GKRP deregulation in vivo. GKA456V was overexpressed in the liver of streptozotocin diabetic mice. Metabolite profiling in serum and liver extracts, together with changes in key components of glucose and lipid homeostasis, were analyzed and compared to GK wild-type transfected livers. Cell compartmentalization of the mutant but not the wild-type GK was clearly affected in vivo, demonstrating impaired GKRP regulation. GKA456V overexpression markedly reduced blood glucose in the absence of dyslipidemia, in contrast to wild-type GK-overexpressing mice. Evidence in glucose utilization did not correlate with increased glycogen nor lactate levels in the liver. PEPCK mRNA was not affected, whereas the mRNA for the catalytic subunit of glucose-6-phosphatase was upregulated ~4 folds in the liver of GKA456V-treated animals, suggesting that glucose cycling was stimulated. Our results provide new insights into the complex GK regulatory network and validate liver-specific GK activation as a strategy for diabetes therapy.

Critical vulnerabilities of marine and sea ice–based ecosystems in the high Arctic

The objectives of this paper are to summarise: (1) observed 20th-century and projected 21st-century changes in key components of the Arctic climate system and (2) probable impacts on the Arctic marine environment, with emphasis on the vulnerabilities of marine and sea ice–based ecosystems. Multi-decadal to century-scale observational data sets of surface air temperature (SAT) and sea ice indicate that the two pronounced 20th-century warming events, both amplified in the Arctic, were linked to sea-ice variability. Arctic sea-ice coverage has decreased ~8% in the past quarter century, with record- and near-record low summer ice in observed recent years. A set of coupled atmosphere–ice–ocean global model simulations quantifies the expected changes in Arctic temperature and sea ice through the twenty-first century. Projected are polar-amplified increases in SAT and reductions in sea ice, with a predominantly ice-free Arctic Ocean in summer projected before the end of this century. A range of potential consequences of Arctic warming and a shrinking ice cover are foreseen. First, exposure of vast areas of the Arctic Ocean would greatly alter the coastal and shelf marine environment. Second, broad changes in the marine and sea ice–based ecosystem—e.g. changes in plankton due to less ice and greater inflow of melt water—could negatively impact Arctic and sub-Arctic marine biodiversity, not least the vulnerable ice-based mammals such as polar bears. Third, there would be a larger open area for potential Arctic fisheries, as well as increased offshore activities and marine transportation, including the Northern Sea Route north of Siberia. Changes in the physical environment of the Arctic Ocean are thus expected to be dramatic, and although projecting ecosystem changes several decades into twenty-first century is challenging, the impact of diminishing sea ice on Arctic marine and sea ice–based ecosystems will certainly be transformative.

Can we explain airport performance? A case study of selected New York airports using a stochastic frontier model

This paper uses stochastic frontier models to assess whether technical efficiency at Newark Liberty International, New York John F. Kennedy International, and New York LaGuardia airports improved from June to August 2008 compared with the summers of 2000 and 2007. An airport is efficient if it can handle operations on-time by minimizing overall demand and maximizing available airport capacity. Granger-causality tests determined the factors that may cause changes in key components and indicators of airport performance. Compared with the other airports, JFK experienced the greatest improvement in technical efficiency. The Granger-causality tests stressed the significance of airport operations and en route factors in supporting efficiency.