Global Level Change Research Articles

Upscaling in socio-environmental systems modelling: Current challenges, promising strategies and insights from ecology

Sustainability challenges in socio-environmental systems (SES) are inherently multiscale, with global-level changes emerging from socio-environmental processes that operate across different spatial, temporal, and organisational scales. Models of SES therefore need to incorporate multiple scales, which requires sound methodologies for transferring information between scales. Due to the increasing global connectivity of SES, upscaling – increasing the extent or decreasing the resolution of a modelling study – is becoming progressively more important. However, upscaling in SES models has received less attention than in other fields (e.g., ecology or hydrology) and therefore remains a pressing challenge. To advance the understanding of upscaling in SES, we take three steps. First, we review existing upscaling approaches in SES as well as other disciplines. Second, we identify four main challenges that are particularly relevant to upscaling in SES: 1) heterogeneity, 2) interactions, 3) learning and adaptation, and 4) emergent phenomena. Third, we present an approach that facilitates the transfer of existing upscaling methods to SES, using two good practice examples from ecology. To describe and compare these methods, we propose a scheme of five general upscaling strategies. This scheme builds upon and unifies existing schemes and provides a standardised way to classify and represent existing as well as new upscaling methods. We demonstrate how the scheme can help to transparently present upscaling methods and uncover scaling assumptions, as well as to identify limits for the transfer of upscaling methods. We finish by pointing out research avenues on upscaling in SES to address the identified upscaling challenges.

Epigenetic Marks, DNA Damage Markers, or Both? The Impact of Desiccation and Accelerated Aging on Nucleobase Modifications in Plant Genomic DNA.

Modifications of DNA nucleobases are present in all forms of life. The purpose of these modifications in eukaryotic cells, however, is not always clear. Although the role of 5-methylcytosine (m5C) in epigenetic regulation and the maintenance of stability in plant genomes is becoming better understood, knowledge pertaining to the origin and function of oxidized nucleobases is still scarce. The formation of 5-hydroxymetylcytosine (hm5C) in plant genomes is especially debatable. DNA modifications, functioning as regulatory factors or serving as DNA injury markers, may have an effect on DNA structure and the interaction of genomic DNA with proteins. Thus, these modifications can influence plant development and adaptation to environmental stress. Here, for the first time, the changes in DNA global levels of m5C, hm5C, and 8-oxo-7,8-dihydroguanine (8-oxoG) measured by ELISA have been documented in recalcitrant embryonic axes subjected to desiccation and accelerated aging. We demonstrated that tissue desiccation induces a similar trend in changes in the global level of hm5C and 8-oxoG, which may suggest that they both originate from the activity of reactive oxygen species (ROS). Our study supports the premise that m5C can serve as a marker of plant tissue viability whereas oxidized nucleobases, although indicating a cellular redox state, cannot.

How knowledge and uncertainty affect strategic international business investment decisions: Implications for cross-border mergers and acquisitions

Changes in country-level and global economic conditions create numerous challenges for firms expanding internationally. Country-level changes such as volatility in GDP growth, increasing regulations, and/or inflation may influence temporal periods of static or declining markets and often drive an inward contraction of focus. Conversely, global-level changes such as expanding markets often drive an outward expansion of focus as firms adjust to opportunities created by changing conditions. However, given increasing technological interconnectedness and global economic interdependencies, firms may better leverage their knowledge of such factors to improve international business investment decisions. We hypothesize how firms seeking international expansion adjust based on changes in their environment through both the frequency and value of their cross-border M&A (CB M&A) activity. Our findings from a sample of pre- and post-CB M&A activity using data on the 2008–2009 financial crisis outline how firms’ strategic international business decisions incorporate knowledge and uncertainty regarding country and global economic fluctuations.

Abstract P499: Histone H4K20 Trimethylation Is Differentially Regulated In Heart Disease

It has been well established that many cardiac pathologies result from dynamic changes in gene expression and conversely that modulating key epigenetic factors in murine models is capable of preventing or abrogating ischemic injury and pathological remodeling. One epigenetic mechanism is the post-translational modification of histones, which are reversibly methylated on lysine (K) residues and can accept up to three methyl groups (Me1, Me2 and Me3). In the heart, significant changes in global levels of histone H3K4Me3 and H3K9Me3 have been previously reported to be upregulated and downregulated, respectively, during hypertrophy and failure in mice. However, the majority of post-translational modifications on histones have never been examined to quantify global abundance in the heart during disease. In particular, histone H4K20Me3 is important in heterochromatin formation and gene repression in non-cardiac cells but has never been evaluated in the heart. Therefore, we utilized cardiac tissue from three animal models of cardiac stress and employed western blotting and mass spectrometry to quantify the global abundance of total histone H4 and H4K20 methylation. We specifically evaluated tissue from mice subjected to LAD ligation, transverse aortic banding and isoproterenol infusion (via mini-osmotic pump). In addition, we also utilized primary neonatal cardiomyocytes treated with the hypertrophic agonist phenylephrine to quantify H4K20 methylation. Our data show that global levels of histone H4K20Me3 are differentially regulated in some models of cardiac dysfunction, but not all (i.e. isoproterenol infusion). In addition, we measured the abundance of histone methyltransferases and demethylases (via western blotting and qPCR) which are responsible for adding or removing this methyl mark in mouse cardiac tissue, and compared this to published data from human heart failure patients. These analyses allowed us to identify two enzymes, the methyltransferase Smyd5 and demethylase KDM7B, which are also differentially expressed in cardiac tissue during disease. Together these results are the first analysis of histone H4K20 methylation in the heart and suggest a novel role for this methylation site in the pathophysiology of cardiovascular disease.

Psychostimulants and opioids differentially influence the epigenetic modification of histone acetyltransferase and histone deacetylase in astrocytes.

Illicit drugs are known to affect central nervous system (CNS). Majorly psychostimulants such as cocaine, methamphetamine (METH) and opioids such as morphine are known to induce epigenetic changes of histone modifications and chromatin remodeling which are mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Aberrant changes in histone acetylation-deacetylation process further exacerbate dysregulation of gene expression and protein modification which has been linked with neuronal impairments including memory formation and synaptic plasticity. In CNS, astrocytes play a pivotal role in cellular homeostasis. However, the impact of psychostimulants and opioid mediated epigenetic changes of HAT/HADCs in astrocytes has not yet been fully elucidated. Therefore, we have investigated the effects of the psychostimulants and opioid on the acetylation-regulating enzymes- HAT and HDACs role in astrocytes. In this study, Class I and II HDACs and HATs gene expression, protein changes and global level changes of acetylation of H3 histones at specific lysines were analyzed. In addition, we have explored the neuroprotective "nootropic" drug piracetam were exposed with or without psychostimulants and opioid in the human primary astrocytes. Results revealed that psychostimulants and opioid upregulated HDAC1, HDAC4 and p300 expression, while HDAC5 and GCN5 expression were downregulated. These effects were reversed by piracetam coexposure. Psychostimulants and opioid exposure upregulated global acetylation levels of all H3Ks, except H3K14. These results suggest that psychostimulants and opioids differentially influence HATs and HDACs.

Changes in \u03b3H2AX and H4K16ac levels are involved in the biochemical response to a competitive soccer match in adolescent players

The aim of this study was to examine novel putative markers of the response to the competitive soccer match in adolescent players, such as changes in global levels of γH2AX and H4K16ac in the chromatin of peripheral mononuclear blood cells (PMBCs) and a Fourier-transform infrared spectroscopy (FTIR)-based biochemical fingerprint of serum. These characteristics were examined with reference to the physiological and metabolic aspects of this response. Immediately post-match we noticed: (1) a systemic inflammatory response, manifesting as peaks in leukocyte count and changes in concentrations of IL-6, TNFα, and cortisol; (2) a peak in plasma lactate; (3) onset of oxidative stress, manifesting as a decline in GSH/GSSG; (4) onset of muscle injury, reflected in an increase in CK activity. Twenty-four hours post-match the decrease in GSH/GSSG was accompanied by accumulation of MDA and 8-OHdG, macromolecule oxidation end-products, and an increase in CK activity. No changes in SOD1 or GPX1 levels were found. Repeated measures correlation revealed several associations between the investigated biomarkers. The FTIR analysis revealed that the match had the greatest impact on serum lipid profile immediately post-game. In turn, increases in γH2AX and H4K16ac levels at 24 h post-match indicated activation of a DNA repair pathway.

ChIPseqSpikeInFree: a ChIP-seq normalization approach to reveal global changes in histone modifications without spike-in.

The traditional reads per million normalization method is inappropriate for the evaluation of ChIP-seq data when treatments or mutations have global effects. Changes in global levels of histone modifications can be detected with exogenous reference spike-in controls. However, most ChIP-seq studies overlook the normalization that must be corrected with spike-in. A method that retrospectively renormalizes datasets without spike-in is lacking. ChIPseqSpikeInFree is a novel ChIP-seq normalization method to effectively determine scaling factors for samples across various conditions and treatments, which does not rely on exogenous spike-in chromatin or peak detection to reveal global changes in histone modification occupancy. Application of ChIPseqSpikeInFree on five datasets demonstrates that this in silico approach reveals a similar magnitude of global changes as the spike-in method does. St. Jude Cloud (https://pecan.stjude.cloud/permalink/spikefree) and St. Jude Github ( https://github.com/stjude/ChIPseqSpikeInFree). Supplementary data are available at Bioinformatics online.

Prediction and Validation of Rainfall Classes for Vaigai River Catchment using El Nino

Extraordinary weather patterns are being observed globally during the past 30 years due to climate change resulting in variations in temperature and rainfall. Studies on long-term trend pattern of temperature and rainfall since 1980 distinctly shows a rise in mean temperature and declining rainfall trend. Due to change of climate at global level change, forecasting of rainfall with the conventional statistical analysis could not predict satisfactory results. Among the available processes, the El Niño Southern Oscillation (ENSO) cycle is considered efficient. Statistical analysis was carried out in this study so as to investigate the implication of rainfall data in seven rain gauge stations located in Vaigai River Catchment through the period from 1959 to 2016. ENSO Cycle was used also to predict rainfall for Vaigai River catchment of the Tamil Nadu State, India. Quadratic discrimination analysis (QDA) and Neural Network models are used to identify the class of rainfall classes with reference to ENSO cycle. The patterns recognized on the study area offer constructive information to administrators of water resource management, to implement the same for agriculture, water supply and power generation.

Age, but Not Amyloidosis, Induced Changes in Global Levels of Histone Modifications in Susceptible and Disease-Resistant Neurons in Alzheimer's Disease Model Mice.

There is increasing interest in the role of epigenetic alterations in Alzheimer’s disease (AD). The epigenome of every cell type is distinct, yet data regarding epigenetic change in specific cell types in aging and AD is limited. We investigated histone tail modifications in neuronal subtypes in wild-type and APP/PS1 mice at 3 (pre-pathology), 6 (pathology-onset) and 12 (pathology-rich) months of age. In neurofilament (NF)-positive pyramidal neurons (vulnerable to AD pathology), and in calretinin-labeled interneurons (resistant to AD pathology) there were no global alterations in histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac) or histone 3 lysine 27 trimethylation (H3K27me3) in APP/PS1 compared to wild-type mice at any age. Interestingly, age-related changes in the presence of H3K27ac and H3K27me3 were detected in NF-labeled pyramidal neurons and calretinin-positive interneurons, respectively. These data suggest that the global levels of histone modifications change with age, whilst amyloid plaque deposition and its sequelae do not result in global alterations of H3K4me3, H3K27ac and H3K27me3 in NF-positive pyramidal neurons or calretinin-labeled interneurons.

Chronic over-expression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice.

Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1-4) receptor expression without affecting the levels of NMDA (GRIN) or GABAA receptors. Ubiquitin over-expression also negatively impacted hippocampus-dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3-CA1 synapses. These changes occurred in a dose-dependent manner in that mice with the highest levels of ubiquitin over-expression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress-induced changes observed in neurological disorders.

Regionalism in a globalised multipolar economy

This paper focuses on regional organisations, looking at how they are studied in international relations and especially in international political economy. Regions are considered to occupy a place midway between the state and the global order. This paper mainly assesses how regions are affected by systemic factors. One key issue is how global-level changes are shaping regional organisations. A second issue is the regions’ capacity to meet the challenges and difficulties resulting from global events. In terms of regionalism, the two systemic factors studied here are globalisation and multipolarity.

Evidence for the importance of post-transcriptional regulatory changes in ovarian cancer progression and the contribution of miRNAs

High-throughput technologies have identified significant changes in patterns of mRNA expression over cancer development but the functional significance of these changes often rests upon the assumption that observed changes in levels of mRNA accurately reflect changes in levels of their encoded proteins. We systematically compared the expression of 4436 genes on the RNA and protein levels between discrete tumor samples collected from the ovary and from the omentum of the same OC patient. The overall correlation between global changes in levels of mRNA and their encoding proteins is low (r = 0.38). The majority of differences are on the protein level with no corresponding change on the mRNA level. Indirect and direct evidence indicates that a significant fraction of the differences may be mediated by microRNAs.

Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape

Deposition of replication-independent histone variant H3.3 into chromatin is essential for many biological processes, including development and reproduction. Unlike replication-dependent H3.1/2 isoforms, H3.3 is expressed throughout the cell cycle and becomes enriched in postmitotic cells with age. However, lifelong dynamics of H3 variant replacement and the impact of this process on chromatin organization remain largely undefined. Using quantitative middle-down proteomics we demonstrate that H3.3 accumulates to near saturation levels in the chromatin of various mouse somatic tissues by late adulthood. Accumulation of H3.3 is associated with profound changes in global levels of both individual and combinatorial H3 methyl modifications. A subset of these modifications exhibit distinct relative abundances on H3 variants and remain stably enriched on H3.3 throughout the lifespan, suggesting a causal relationship between H3 variant replacement and age-dependent changes in H3 methylation. Furthermore, the H3.3 level is drastically reduced in human hepatocarcinoma cells as compared to nontumoral hepatocytes, suggesting the potential utility of the H3.3 relative abundance as a biomarker of abnormal cell proliferation activity. Overall, our study provides the first quantitative characterization of dynamic changes in H3 proteoforms throughout lifespan in mammals and suggests a role for H3 variant replacement in modulating H3 methylation landscape with age.

How to Approach Real Mathematical Modeling in Surge Capacity: Clinical Review

Objectives: Science of surge is one of most important topics in the realm of disaster preparedness. Since 2006, after Academic Emergency Medicine (AEM) Consensus Conference, few articles with quantitative data address decision making in surge capacity. The aim of this article is looking forward to the facts about mathematical modeling and proposes real modeling in decision making to have better outcome. Methods: Literature Research was performed on database for the last ten years (2007-2017). Articles with mathematical modeling were separated and classified based on the usage of them in the field. Results: All current mathematical studies compared based on pre-hospital and hospital setting and flexibility in change of global level of care in time. Integrated model of sigmoid curve and HASC (Hospital Acute Care Surge Capacity) with name B-H integrated modeling in two-hour interval proposed. Conclusion: This study shows dynamic process of disaster planning based on outcome and reality. The proposed model makes surge capacity more predictable and adjustable.

Global and gene-specific DNA methylation alterations in the adolescent amygdala and hippocampus in an animal model of caregiver maltreatment

Epigenetic mechanisms such as DNA methylation are part of an emerging story on how early-life experiences can alter behavioral trajectories and lead to the development of disease and psychological disorders. Previous work from our laboratory has demonstrated alterations in methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) gene within the amygdala and hippocampus of infant and adult rats that were repeatedly exposed to caregiver maltreatment outside the home cage during their first week of life. In the current study we examine changes in global levels of DNA methylation (5-mC) and hydroxymethylation (5-hmC), as well as gene-specific changes in methylation patterns of the candidate gene bdnf (at exons I and IV) within the adolescent amygdala and hippocampus resulting from exposure to maltreatment. While adolescent females exposed to maltreatment showed no significant alterations in global 5-mC or 5-hmC levels, examination of bdnf DNA methylation revealed that maltreated females had greater methylation of exon IV DNA in the amygdala and ventral hippocampus. While adolescent males exposed to maltreatment showed no significant alterations in bdnf DNA methylation, maltreated males had significantly higher 5-mC levels in the dorsal hippocampus and lower 5-hmC levels in the amygdala. These findings demonstrate that the effects of the early caregiving environment are detectable in the adolescent brain at the level of the epigenome, with brain-region specific and sexually-dimorphic epigenetic consequences that could have relevance to adolescent mental health and behavior.

Quantification of Histone H3 Lys27 Trimethylation (H3K27me3) by High-Throughput Microscopy Enables Cellular Large-Scale Screening for Small-Molecule EZH2 Inhibitors

EZH2 inhibition can decrease global histone H3 lysine 27 trimethylation (H3K27me3) and thereby reactivates silenced tumor suppressor genes. Inhibition of EZH2 is regarded as an option for therapeutic cancer intervention. To identify novel small-molecule (SMOL) inhibitors of EZH2 in drug discovery, trustworthy cellular assays amenable for phenotypic high-throughput screening (HTS) are crucial. We describe a reliable approach that quantifies changes in global levels of histone modification marks using high-content analysis (HCA). The approach was validated in different cell lines by using small interfering RNA and SMOL inhibitors. By automation and miniaturization from a 384-well to 1536-well plate, we demonstrated its utility in conducting phenotypic HTS campaigns and assessing structure-activity relationships (SAR). This assay enables screening of SMOL EZH2 inhibitors and can advance the mechanistic understanding of H3K27me3 suppression, which is crucial with regard to epigenetic therapy. We observed that a decrease in global H3K27me3, induced by EZH2 inhibition, comprises two distinct mechanisms: (1) inhibition of de novo DNA methylation and (II) inhibition of dynamic, replication-independent H3K27me3 turnover. This report describes an HCA assay for primary HTS to identify, profile, and optimize cellular active SMOL inhibitors targeting histone methyltransferases, which could benefit epigenetic drug discovery.

The Drosophila Ortholog of MLL3 and MLL4, trithorax related, Functions as a Negative Regulator of Tissue Growth

The human MLL genes (MLL1 to MLL4) and their Drosophila orthologs, trithorax (trx) and trithorax related (trr), encode proteins capable of methylating histone H3 on lysine 4. MLL1 and MLL2 are most similar to trx, while MLL3 and MLL4 are more closely related to trr. Several MLL genes are mutated in human cancers, but how these proteins regulate cell proliferation is not known. Here we show that trr mutant cells have a growth advantage over their wild-type neighbors and display changes in the levels of multiple proteins that regulate growth and cell division, including Notch, Capicua, and cyclin B. trr mutant clones display markedly reduced levels of H3K4 monomethylation without obvious changes in the levels of H3K4 di- and trimethylation. The trr mutant phenotype resembles that of Utx, which encodes a H3K27 demethylase, consistent with the observation that Trr and Utx are found in the same protein complex. In contrast to the overgrowth displayed by trr mutant tissue, trx clones are underrepresented, express low levels of the antiapoptotic protein Diap1, and exhibit only modest changes in global levels of H3K4 methylation. Thus, in Drosophila eye imaginal discs, Trr, likely functioning together with Utx, restricts tissue growth. In contrast, Trx appears to promote cell survival.

The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects

The precise mechanisms by which nickel and arsenic compounds exert their carcinogenic properties are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of compounds of these two metals. In vitro exposure to certain nickel or arsenic compounds induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males when compared with females in the arsenic population. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.

Abstract 138: The effects of microRNA transfections on global patterns of gene expression are functionally coordinated

Abstract A current challenge in the application of miRNAs in cancer therapeutics is the inability to accurately predict the functional consequences of exogenous perturbations in the levels of potentially therapeutic miRNAs. To systematically address this issue, two miRNAs (miR-7 and miR-128) were separately transfected into a well characterized ovarian cancer cell line (HEY) and global changes in levels of gene expression were monitored. While ∼20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA-mRNA interactions, the majority of the changes were indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression. The pathways most significantly affected by miR-7 transfection are involved with cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions (EMT) and other processes linked with metastasis. In contrast, the pathways most significantly affected by miR-128 transfection are more focused on cell cycle control and other processes commonly linked with cellular replication. These computational predictions were experimentally verified. Our results indicate that changes in patterns of gene expression induced by exogenous expression of miRNAs are not random but functionally coordinated and that different families of miRNAs may regulate distinct cellular functions related to cancer. Our findings suggest that miRNAs may be of unique therapeutic value by providing clinicians with a strategy to treat cancer from a systems rather than a single gene perspective. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 138. doi:1538-7445.AM2012-138

2-Heptyl-4-quinolone, a precursor of the Pseudomonas quinolone signal molecule, modulates swarming motility in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an opportunistic pathogen capable of group behaviors, including biofilm formation and swarming motility. These group behaviors are regulated by both the intracellular signaling molecule c-di-GMP and acylhomoserine lactone quorum-sensing systems. Here, we show that the Pseudomonas quinolone signal (PQS) system also contributes to the regulation of swarming motility. Specifically, our data indicate that 2-heptyl-4-quinolone (HHQ), a precursor of PQS, likely induces the production of the phenazine-1-carboxylic acid (PCA), which in turn acts via an as-yet-unknown downstream mechanism to repress swarming motility. We show that this HHQ- and PCA-dependent swarming repression is apparently independent of changes in global levels of c-di-GMP, suggesting complex regulation of this group behavior.