, 2012) Of the 71 compounds or classes encountered in this study

, 2012). Of the 71 compounds or classes encountered in this study, along with TPH and total PAH, the primary four classes of compounds noted above yielded the highest concentrations. We chose to focus on this set of compounds because we wanted to define broad-scale, robust geographic distribution patterns. Using compounds with higher concentrations allowed us to examine any subtle geographic shifts in that distribution which might have occurred. Such would not have been possible using compounds occurring in very low concentrations. We believe that the distribution

of these classes Talazoparib price of compounds is indicative of other classes as well. The objectives of this study were to define the distribution and abundance patterns of (1) TPH in the northern GOM, within the limits of our sampling regime; (2) PAH; (3) C1-benzo(a)anthracenes/chrysenes; (4 and 5) C2- and C-4 phenanthrenes/anthracenes; and (6) C3-naphthalenes. Selleck Sirolimus The other eight compounds mentioned above are also presented for comparative purposes. The six major classes of compounds were assessed in the following media: (a) seawater; (b) sediment; (c) marine fauna and flora; and (d) some commercial species. The patterns of concentrations were considered in the context of known general meso- and macro-scale

currents in the region. Field samples were collected from coastal waters between the Florida Keys and Galveston, Texas between May and November 2010 (Fig. 1). Sample codes and GIS locations of samples are shown in Table 1. Samples were taken in places and at times defined independently by individual investigators, and data were pooled and later analyzed. No attempt has been made to interpret the results in a temporal context,

only a spatial one. In addition, samples were pooled from several different investigators who were sampling from different regions at different times over a period of several months. The samples were designed to describe potentially affected regions and determine the distribution and abundance of the compounds under spill circumstances. Control samples were not collected because this was not designed a priori Carnitine dehydrogenase as an experimental study; i.e., it was not the purpose of this descriptive study to compare affected sites with control sites. All samples were sealed in plastic ziploc bags or amber jars, cooled to <4 °C, and transferred to refrigerators or freezers for storage at temperatures of <4 °C or −20 °C, respectively, until processed. Replicate samples were often collected. Holding times recommended by processing laboratories for individual media were respected. Samples were shipped in sealed coolers overnight to the laboratories for processing. Standard Chain of Custody procedures were followed regarding delivery of samples to the analytical labs. Processing of samples was similar between the laboratories of the investigators, although details varied in some cases.

It is very fortunate and gratified to announce

that the d

It is very fortunate and gratified to announce

that the dream of having our own journal see more is realized from this year of 2012. From perhaps the momentous birthday of the SGI in 2007, we have all dreamt of having the warehouse for our brilliant works of collaboration and open discussion between enthusiastic attendees, presenters and speakers. Six years’ hard work for building the house to preserve our creative ideas finally paid off. We had unique insights, from the SGI’s onset, about the power of collaboratively open debate over seeking the best way of managing gastrointestinal diseases among surgeons, physicians, and radiologists. The small number of the SGI’s architects had the firm belief that if we had focused on achieving our goal of interdisciplinary collaboration from a variety of the broadest group possible, the SGI can and must Caspase inhibitor continue flourishing as a platform for developing intelligently applicable ideas and pushing them to the edge of potential best treatment for gastrointestinal diseases. This is our shared common purpose which we believe is something none of us can

be neglectful about. Even though the SGI alone can not discuss and find out the very best solution to the gastrointestinal diseases, it can and will play a critical role in searching for it. That is because of annual growth of the number of participants and real passion of the SGI members who will not forget that we were very small, founded on little more than a good idea of collaboration.

Now time comes for all of us to bring our innovative results to fill up Gastrointestinal Intervention, which is our another goal of the SGI. Figure options Download full-size image Download as PowerPoint slide “
“The presence of pre-transplant anti-HLA antibody directed against the donor antigens (DSA) in the presence of a negative CDC crossmatch is associated with increased risk of antibody mediated rejection (AMR) and graft failure [1], [2] and [3]. HLA antibodies are formed as a consequence of cAMP prior transplantation, pregnancy and blood transfusion due to exposure to foreign HLA antigens [4], [5], [6], [7], [8] and [9]. However blood transfusion prior to transplant is immunomodulatory and appears to reduce the risk of acute allograft rejection and graft loss despite an increased risk of sensitisation [10], [11] and [12]. Historically it had been observed that large volumes of third-party red blood cell transfusion (RBCT) (up to 20 units) over a prolonged period are required to induce enduring antibodies, especially in males or nulliparous females [4], [13], [14] and [15]. However in the presence of another immune stimulating process such as pregnancy or transplantation, co-administration of third party RBCT results in broad HLA antibody production which is more potent and enduring [6], [16] and [17].

SOD catalyzes the dismutation of superoxide into oxygen and hydro

SOD catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. Measurement of SOD activity is an indirect method of detecting ROS, since SOD activity reflects superoxide production in SCH727965 in vitro cells. Nrf2 is a transcription factor that is activated during oxidative stress and translocated from the cytoplasm to the nucleus to bind the antioxidant response element (ARE), activating transcription of antioxidant and xenobiotic

response genes (Venugopal and Jaiswal, 1996). The increase in SOD activity and Nrf2 activation in this study confirmed that oxidative stress was caused by CdTe-QD exposure. Compared to CdCl2, CdTe-QDs caused greater oxidative stress as demonstrated by a lower GSH/GSSG ratio, increased SOD activity and Nrf2 activation, suggesting that cadmium learn more from CdTe-QDs cannot account for the entire effect. However, other

factors such as the intrinsic nanoscale properties of QDs and ROS generated from the NPs may contribute to the observed oxidative stress. The glutathione S-transferases (GSTs) are a family of antioxidant enzymes important for detoxification of xenobiotics and peroxidation products (Hayes and McLellan, 1999). Under oxidative stress, GST activity is expected to increase from elevated levels of organic and non-organic peroxides, which act as substrates for the enzyme (Hayes and McLellan, 1999). Treatment of HepG2 cells with CdTe-QDs resulted in decreased GST activity, but unchanged GST protein abundance.

This revealed that decreased GST activity was not caused by cell death and that CdTe-QDs might have an inhibitory action on GST itself. Similar to GST, CAT, which is an antioxidant, catalyzes the decomposition of H2O2 to oxygen and water and is well known as an important antioxidant enzyme (Chelikani et al., 2004). Treatment of HepG2 cells with CdTe-QDs resulted in decreased CAT activity. Although CAT protein level was not measured in this study, lowered CAT activity was probably also related Carnitine palmitoyltransferase II to the activity inhibition of CdTe-QDs, but not from cell death. Cadmium has previously been reported to inhibit GST and CAT activity in vitro and in vivo ( Dierickx, 1982 and Pruell and Engelhardt, 1980). By inhibiting GST and CAT activities, CdTe-QDs appear to impair cellular antioxidant defenses, leading to oxidative stress. The inhibition of the activities of these antioxidant enzymes by CdTe-QDs suggests that cadmium might have a role in the effects of these NPs. Oxidative stress is an important factor for triggering apoptosis (Buttke and Sandstrom, 1994). Our results showed that CdTe-QDs caused an increase in certain apoptotic hallmarks. Caspase-3 is a protease catalyzing the specific cleavage of many key cellular proteins. The increase in caspase-3 activity was confirmed with the increased cleavage of PARP, the action of which is catalyzed by the protease caspase-3.


may then bind reactivated content to current


may then bind reactivated content to current experience, resulting in an integrated trace. Following integration in hippocampus, memory models may be updated with new content as needed through direct hippocampal inputs Epacadostat to mPFC [18]. Through this process, mPFC may come to represent integrated memories that have been abstracted away from individual episodes (i.e., schema) over time 18 and 25. A number of studies suggest that memory integration persists into post-encoding rest [26] and sleep [27], with offline consolidation processes facilitating generalization across episodes. Specifically, hippocampus-driven reactivation during slow-wave sleep is thought to transform memories, allowing connections to be formed among representations co-activated in neocortex [28]. This

process is thought to promote both the integration of new information into existing memories and abstraction across episodes in neocortical regions, particularly mPFC [28]. Memory integration has largely positive effects on behavior (though see Box 2 for examples of negative behavioral consequences). Below, we review recent work highlighting these benefits across a number selleck inhibitor of cognitive domains. While the effects of integration on behavior are largely beneficial, a few studies have uncovered negative consequences of integration. For example, integration may lead to false memories (i.e., through overgeneralization) [59•], and memory misattributions 5, 22•, 55 and 56. Interestingly, patients with ventral mPFC lesions show reduced false memories relative to healthy control participants for words that were never seen but are thematically related to a studied word list

[59•], consistent with the notion that ventral mPFC constructs generalized memory representations. Integration may also explain the phenomenon of memory misattribution, in which an episodic experience is incorrectly attributed to a different encoding Demeclocycline context than the one in which it occurred (e.g., as measured by intrusions; Box 1). Misattributions may occur when prior knowledge is reactivated and updated with the current experience to the detriment of memory accuracy. One fMRI study [5] used neural decoding to quantify the neural reinstatement of the context associated with prior memories (List 1) during new learning (List 2). Results showed that greater evidence for reactivation of the List 1 context was associated with more misattributions of List 2 words to List 1. Another study [22•] showed that when participants reactivated a prior experience during new encoding, ventral mPFC and hippocampal engagement was associated with later memory misattributions, consistent with a role for these regions in linking experiences across time. Perhaps the most familiar and widely studied form of memory integration stems from Tolman’s seminal work on cognitive maps [7].

, 1996) The rotational diffusion rate, Rbar, obtained from NLLS

, 1996). The rotational diffusion rate, Rbar, obtained from NLLS was converted to the rotational correlation time, τc, through the relationship τc = 1/6 Rbar ( Schneider and Freed, INK 128 in vitro 1989). Similar to previous studies ( Alonso et al., 2001, Alonso et al., 2003 and Queirós et al., 2005), the magnetic parameters were determined based on the global analysis of the

overall spectra obtained in this work, and all of the EPR spectra were simulated using the same predetermined parameters. The magnetic g and A tensors are defined in a molecule-fixed frame, where the constants of rotational diffusion rates around the x, y and z axes are included. The input parameters of tensors g and A were: gxx = 2.0088; gyy = 2.0060; gzz = 2.0026; Axx = 6.1; Ayy = 6.3 G; Azz = 36.5 G. Data from the microtiter plate reader were transferred to a spreadsheet template GraphPad Prism® to determine the cell viability, calculate the IC50 values using linear interpolation, and perform the statistical analyses. Concentration–response curves were constructed and fitted in ®Origin 8.0 using parametric nonlinear regression. IC50 values were computed using the fitted Hill equation and presented as the mean ± standard deviation (SD) of at least

three independent experiments with 4 repetitions in each experiment (12 experimental values for selleck compound each compound). IC50 data were compared by one-way analysis of variance (ANOVA) followed by Tukey’s multiple range test for statistically significant differences at P < 0.05. In the present study we used the 3T3 NRU to evaluate the cytotoxicity of eight terpenes. The results were obtained for different concentrations of terpenes in a Balb/c 3T3-A31 NRU cytotoxicity assay after incubation for 48 h. Fig. 2 shows the concentration Astemizole dependence of cell viability for the terpenes of higher and lower cytotoxicity. The IC50 values for the eight tested terpenes are presented in Table 1. The hemolytic effects of the terpenes on human erythrocytes were evaluated after 1.5 h incubation. Ethanol was used as a vehicle to optimize the incorporation of terpenes into the RBC membranes;

the hemolytic effect of ethanol was previously characterized. The levels of ethanol-induced hemolysis measured at 50% hematocrit (Fig. 3A) indicate that damage occurs only at an ethanol concentration above 10% (v/v). The hemolytic potential can be used to indicate the toxicity of molecules on human erythrocytes (Benavides et al., 2004). In Fig. 3B was plotted the concentration dependence of the most hemolytic terpene (nerolidol) and a less hemolytic terpene (1,8-cineole). Nerolidol is hemolytic at very low concentrations, whereas 1,8-cineole shows significant levels of hemolysis only for concentrations above 10 mM. For the other terpenes used in this work, hemolysis occurs at concentrations between 1.0 and 6.0 mM.

The objective of this research is to identify scenarios and locat

The objective of this research is to identify scenarios and locations that are particularly vulnerable to high-volume withdrawals of water and may require further evaluation should water permits be requested. A simulated range of development scenarios demonstrate how varying well pad density, water

source, and water volume might affect the groundwater–surface water systems in the Southern Tier of New York. The importance of this research lies in its application to all stakeholders in the HVHF controversy currently underway in New York. Not only will policy makers and regulators benefit from the predictive capacity of computer modeling, but industry, community members and interest groups can better understand how a water quantity perspective is valuable for sustainable energy development. Hydraulic fracturing is a AZD2281 process that involves the injection of water into the subsurface in order to fracture tight geologic formations. Fracturing creates pathways through which trapped natural gas flows freely into a well and is subsequently harnessed for energy. The combination of hydraulic fracturing and horizontal drilling has led to the growing viability of unconventional shale plays (U.S. Department of Energy, 2009). Horizontal drilling refers to the lateral drilling of a well bore through a target formation. This allows access to a greater volume of gas-bearing rock,

making such drilling ventures economically feasible (Soeder, 2010). In HVHF, large volumes of water in addition to proppants and other additives serve as the fracturing www.selleckchem.com/products/Etopophos.html fluid. The fluid injection and fracturing process progresses in stages along the horizontal extent of the well, with each horizontal clonidine well requiring between 1 and 5 million gallons of water (Gregory et al., 2011). Only a fraction of injected fluid actually returns to the surface – referred to as flowback – with the unreturned volume remaining in the subsurface. This fraction can vary greatly

between wells, company, and target formation with an estimated average of 10–40% flowback (Maloney and Yoxtheimer, 2012, NYSDEC, 2011 and Rassenfoss, 2011). In arid climates, where freshwater supply is limited, the quantity of water use associated with HVHF is of concern (Nicot and Scanlon, 2012). In humid climates, where freshwater supply is less emphasized in water resource management, increased water demand associated with HVHF is only beginning to receive recognition (Rahm and Riha, 2012). This is in part due to mass balance or water budget approaches in quantifying the impacts of HVHF water demands. Nicot and Scanlon (2012) estimate water use associated with HVHF is less than 1% of water use in Texas, but may account for larger fractions of water use at the county scale. For example, within the Barnett Shale play in Texas, the 2008 fraction of shale gas water use in the counties of Denton, Johnson, Parker, Tarrant, and Wise was 2.8%, 29%, 10%, 1.4%, and 19%, respectively (Nicot and Scanlon, 2012).

“Clozapine, a tricyclic dibenzodiazepine, is an atypical a

“Clozapine, a tricyclic dibenzodiazepine, is an atypical antipsychotic drug that is very efficacious in treating psychosis, particularly in patients refractory to other agents [1]. It has a strong antagonistic activity on D4-dopaminergic receptors [2] serotonergic, noradrenergic [3], histamine

[4] and cholinergic M2 receptors [5]. It differs from traditional antipsychotic drugs in that it has relatively weak D2-receptor activity and few extrapyramidal side effects, and it is effective in treating resistant schizophrenia [6]. Clozapine appears to be particularly beneficial in patients with schizophrenia who are suicidal and those with substance use disorder [7]. However, some adverse effects of clozapine have limited its clinical use [8]. A common and serious adverse effect requiring regular monitoring is cardiotoxicity [7]. Several cases showing clozapine-induced RG7420 price myocarditis (including deaths) have been reported internationally, 85% of which developed in the first 2 months of therapy [8]. Most of the patients in the reported cases were under 50 years of age. Clinical studies showed potentially fatal myocarditis, pericarditis, heart failure and eventually death associated with clozapine treatment [9]. The

mechanism of clozapine-induced cardiotoxicity is not yet clearly understood. Previous studies showed the presence of cardiac and peripheral blood eosinophilia associated with clozapine cardiotoxicity, indicating a possible IgE-mediated hypersensitivity reaction [10]. buy Ipilimumab In addition, clozapine treatment has been associated with increased levels of the catecholamines, norepinephrine and epinephrine [11]. Hyper-catecholaminergic states can significantly exacerbate myocarditis in both animals and patients [11] and [12]. Moreover,

clozapine-induced myocarditis has been associated with an increased release of inflammatory HSP90 cytokines [13]. Numerous reports have shown an increase in the level of reactive oxygen species (ROS) in the myocardium during the development of myocarditis and heart failure in experimental animals and in patients [14]. Myocardial ischemia can lead to cell injury with the release of ROS [15]. Cell injury in the ischemic area also causes infiltration of neutrophils, which produce ROS and cytokines. Certain cytokines, such as tumour necrosis factor-α (TNF-α), trigger mitochondrial release of ROS [16]. In addition, an increase in ROS has been detected in various animal models of heart failure [17] and [18]. An increase in oxidative stress, which may result from increased production of ROS, a relative deficit in the endogenous antioxidant defences, or both, can cause myocarditis, contractile dysfunction and cardiomyopathy [17]. Therefore, this study aimed to investigate the possible mechanisms of clozapine-induced cardiotoxicity and the role of oxidative stress and proinflammatory cytokines in that process.

All methods for assessment of IJV valve competence have in common

All methods for assessment of IJV valve competence have in common that valve function is examined using a short Valsalva maneuver. This has to be strong enough to induce a complete closure of the investigated valve. Sander et al. described a method which is based on the observation of retrograde flow in color-mode during a Valsalva maneuver [7]. A second method is based on the detection

of air bubbles in the jugular vein that had been administered intravenously just prior to the maneuver by injecting agitated saline into an antecubital vein [8]. The most wide spread method utilizes Akt inhibitor the detection of a retrograde flow in the Doppler spectrum (Fig. 2) [9]. Even in competent valves, a Valsalva maneuver leads to a short reflux during valve closure (Fig. 2A). This physiological reflux, with a duration corresponding to the valve closing time, AZD2281 datasheet has to be differentiated from an ongoing retrograde flow component in insufficient valves. Nedelmann et al. evaluated a cut-off time of 0.88 ms which differentiates normal valve closure from valve incompetence with reflux

with a sensitivity and specificity of 100% [9]. Using this method, care has also to be taken to increase the sample volume size to the size of the IJV because retrograde jet streams along the venous wall might otherwise be missed. The vertebral veins are part of the outer vertebral venous plexus. The veins themselves largely follow the course of the vertebral artery and descent through the first to the sixths vertebral transverse processes, then run free down the neck to enter the brachiocephalic vein. The opening of the veins into the brachiocephalic vein has bicuspid valves [10]. In principal, valve function

can be assessed similar to the IJV. However, no evaluated criteria exist so far. Other than in the extracranial venous system, intracranial veins and dural sinuses lack any valves. As a consequence, Fossariinae their flow direction is governed solely by the current pressure gradient and flow resistance. The location within the cranial cavity leads to a Starling resistor behavior, i.e. intracranial veins and sinuses show a constant outwards flow as long as the ICP is lower than the arterial inflow pressure. Only those venous structures located in proximity of the cranial base and in the posterior fossa can be examined by ultrasound techniques. The most important limitation of venous ultrasound is the inability to visualize cortical veins and the superior sagittal sinus (SSS) in its frontal, mid, and posterior part, except for the portion adjacent the confluens sinuum [11]. For venous transcranial color coded duplex sonography (TCCS) examinations adjustments in the machine settings are necessary: a low-flow sensitive color program with a low wall filter setting has to be used, the PRF needs to be reduced, and the color gain has to be increased to the artifact threshold.

, 1997) However, these lectins commonly exhibit distinct affinit

, 1997). However, these lectins commonly exhibit distinct affinity for the same ligand (Ramos et al., 2002). As a result, they frequently differ in terms of dose–response activity (Barbosa et al., 2001). Despite the numerous uses of lectins as tools, there are few studies that refer to their antitumor activity or report the underlying mechanisms involved in lectin cytotoxicity. One aspect of this study shows lectins ConA and ConBr to be cytotoxic against both MOLT-4 and HL-60 cells, with IC50 values being approximately 3 μg/ml (ConA) and 20 μg/mL (ConBr) after 72 h of incubation (Table 1). For PBMC, ConA and ConBr

lectins were not cytotoxic at high concentrations (200 μg/ml), demonstrating selectivity for tumor cells (Fig. 2). Several studies have revealed data that corroborates our findings, demonstrating the cytotoxicity of this website ConA lectin in tumor cells. ConA was shown to be more toxic because it becomes completely tetrameric at physiological pH, exposing its catalytic site better than ConBr. Hence, it is able to exert more pronounced activity than ConBr, which presents as a mixture of dimers and tetramers at physiological pH (Sanz-Aparicio

et al., 1997 and Calvete et al., 1999). In order to identify the mechanism of action Androgen Receptor Antagonist related to the antiproliferative effect of lectins, genetic toxicity, morphological changes, and experiments of cell death using flow cytometry were conducted.

Comet assay has shown that lectins ConA and ConBr promoted a significant increase in DNA strand breaks in MOLT-4 and HL-60 cells. Since the DNA lesions may disturb the maintenance of genomic integrity, the use of molecules that cause extensive damage to the DNA of these cells can induce programmed cell death and block tumor development (Hanahan and Weinberg, 2000, Hoang et al., 2007 and Leonetti and Zupi, 2007). The morphological analysis by differential staining with EB/AO demonstrated that cells treated with the lectins (ConA and ConBr) predominantly showed specific apoptosis features, as opposed to necrosis. Once again, our findings (Fig. 3) are supported by previous studies on the apoptotic effects of lectins (Barbosa et Nintedanib (BIBF 1120) al., 2001, Gastman et al., 2004, Kulkarni et al., 1998, Liu et al., 2009a, Liu et al., 2009b and Liu et al., 2009c). An important marker of cell death by apoptosis is the internucleosomal cleavage of chromatin and the fragmentation of DNA by DNases, such as the Apoptosis Induction Factor (AIF), endonuclease G, and caspase-activated DNase (CAD). These DNases are released from the mitochondria during apoptosis and are then translocated to the nucleus to promote DNA fragmentation (Elmore, 2007). The apoptotic nuclei can be distinguished by their hypodiploid DNA content, compared with the diploid DNA content of normal cells (Cury-Boaventura et al., 2003).

44 ppm; Ribeiro et al , 2011) Under this condition, HQ exposure

44 ppm; Ribeiro et al., 2011). Under this condition, HQ exposure did not alter the number of circulating mononuclear cells but it did reduce the migration of mononuclear cells into the BALF after LPS inhalation, with a consequent reduction in the

number of macrophages. Leukocyte migration to the inflammatory site depends on the highly controlled, sequential expression of adhesion molecules and inflammatory mediators (Borregaard, http://www.selleckchem.com/products/PD-0325901.html 2010 and Ley et al., 2007). It was reported that in vivo HQ exposure increased the physiological expression of β2 and β3-integrins and PECAM-1 and reactive oxygen species (ROS) production by circulating neutrophils. These effects appeared to be connected to impairments to leukocyte migration to the LPS-inflamed lung due to the lack of a neutrophilic response under a challenge ( Ribeiro et al., 2011). However, CH5424802 cost in the current study, adhesion molecules expression on the mononuclear cell membranes was not altered, suggesting that other mechanisms may be involved. It has been clearly demonstrated that mononuclear cell traffics is effectively influenced by MCP-1/CCR2 interactions, mainly under inflammatory conditions (Huffnagle et al., 1995, Melgarejo et al., 2009, Yadav et al., 2010 and Young and Arndt, 2009). Interestingly, reduced levels of

MCP-1 were found in the BALF of HQ-exposed animals after LPS inflammation. The effect depended on functional alterations in AMs and tracheal tissue as reduced MCP-1 levels were found in the supernatant of these cultures. Since a limited number of AMs is found

in the BALF of mice, rendering total RNA extraction unfeasible, an RT-PCR assay was only performed on the tracheal tissue, which showed that the reduction in MCP-1 was defined by impaired mRNA synthesis. Inappropriate MCP-1 secretion was also detected Wilson disease protein when naive mononuclear cells and tracheal tissue were incubated in vitro with HQ, indicating a direct action of the phenolic compound in these cells/tissues. In support of our data, it was recently shown that in vitro HQ exposure impairs MCP-1 secretion by human epithelial cells via the inhibition of mRNA synthesis and by human neutrophils via unknown mechanisms ( Pons and Marin-Castaño, 2011 and Yang et al., 2011). Monocyte chemoattractant protein-1 is a fundamental chemotactic molecule that is mainly released following cell stimulation. It is transcriptionally induced after NF-κB, AP-1 and/or STAT activation in a highly controlled process, which is tissue and stimulus specific (Ding et al., 2010, Tanimoto et al., 2008 and Yadav et al., 2010). Unlike other cytokines synthesized via NF-κB activation ( Ribeiro et al., 2011), only MCP-1 levels were reduced in the respiratory system by HQ exposure. We believe that this effect could be related to the following: (1) the partial activation of transcription factors; (2) reduced interaction between transcription factors and their specific gene promoter region or (3) diminished mRNA stability ( Ding et al.