Figure Figure1 Research Articles

Chemical biology of protein arginine modifications in epigenetic regulation.

Post-translational modifications (PTMs) of histone proteins are a hallmark of epigenetic regulation. They provide a mechanism to modulate chromatin structure and constitute the main features of the so-called “histone code”.1 The proposed function of this code is to integrate exogenous and endogenous signals into a diverse set of histone PTM patterns to enable the epigenetic control of gene expression. The key regulators of this process are the so-called “writers” and “erasers”, which act by dynamically modifying histones, and other chromatin-associated proteins, as well as the “readers”, which interpret these PTMs, thereby facilitating the downstream activation or repression of gene expression.2 The writers are histone-modifying enzymes that can be grouped according to their amino acid substrate preference, affecting mainly lysine, arginine, and serine residues.3 These enzymes can be further classified according to the type of covalent modification that they catalyze. Histone modifications include acetylation, methylation, phosphorylation, and the more recently described modifications of citrullination, ubiquitination, SUMOylation, proline isomerization, O-GlcNAcylation, and ADP-ribosylation.1b,3 On the basis of detailed mass spectrometric analyses, there are at least 15 different types of covalent histone modifications,4 and since histone proteins are modified at multiple sites, and different stoichiometries, the total number of histone marks is >160.5 Although our understanding of how histone modifications contribute to the epigenetic control of gene transcription has grown immensely over the past ∼15 years, the precise impact of this vast number of modifications, not to mention the crosstalk between them, has yet to be fully realized. Histone proteins are small, highly basic proteins consisting of a globular domain and flexible N-terminal and C-terminal tails that protrude from the nucleosome. The core histone proteins (histones H2A, H2B, H3, and H4) form an octameric particle consisting of two H2A–H2B dimers and an H3–H4 tetramer, around which wrap two helical turns of DNA (∼150 bp).6 This structure, which is generally termed a nucleosome, comprises the basic building block of higher order chromatin structures that are further organized through the function of linker histones such as histone H1. On the basis of nucleosome positioning studies, around 80% of the yeast genome and even 99% of the mappable genome of human granulocytes is occupied by nucleosomes, thereby highlighting the importance of nucleosome-packaged DNA for eukaryotic cells.7 Importantly, while histone PTMs are found throughout the entire protein, they are most often clustered within the N-terminal tail. Although research on histone lysine modifications has drawn considerable attention and even resulted in the approval of novel anticancer drugs,8 the modification of histone arginine residues is a recently emerging nucleosomal mark of similar importance (Figure ​(Figure11). Figure 1 N-terminal tails of histone proteins are the preferred targets of histone-modifying enzymes. The major modifications of histone arginine residues are citrullination and methylation. Abbreviations: Cit, citrulline; MMA, monomethylarginine; ADMA, asymmetric ...

Corrigendum: Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus.

By mistake, Figure ​Figure22 of the article by Haddad-Tovolli et al. (2015) showed in panels (A) and (B) the same image of Gli1 expression in E8.5 wildtype mouse embryos. It should have shown Gli1 expression in (A) and Gli2 expression in (B). Therefore, we provide a corrected Figure ​Figure2,2, now with panel (B) showing Gli2 expression, as we originally intended and as the Figure legend indicates. This is a minor change not affecting the scientific content of the article. Figure 2 Expression of Gli genes in the presumptive hypothalamus at E8.5. In situ detection of marker gene expression in Gli2zfd/+ and Gli2zfd/zfd mutant E8.5 embryos as indicated. “lat” and “med” in (A) indicate progenitor domains. ...

Alpha-bisabolol, not a matter for cancer therapy. Commentary: "Research on the immunosuppressive activity of ingredients contained in sunscreens".

Alpha-bisabolol, not a matter for cancer therapy. Commentary: "Research on the immunosuppressive activity of ingredients contained in sunscreens".

The nucleoid as a smart polymer.

The nucleoid as a smart polymer.

Fostering Healthy Aging through Evidence-Based Prevention Programs: Perspectives from the Administration for Community Living/Administration on Aging.

Fostering Healthy Aging through Evidence-Based Prevention Programs: Perspectives from the Administration for Community Living/Administration on Aging.

The CDC Healthy Aging Research Network: Advancing Science toward Action and Policy for the Evidence-Based Health Promotion Movement.

Despite recent progress in the uptake of evidence-based health promotion (EBHP) programs within communities, many factors contribute to the need to focus on dissemination. These include the growth in the aging population, health care resource limitations, and interests in preserving community-based opportunities for maintaining independence and maximizing quality of life. For these reasons, The Prevention Research Centers’ Healthy Aging Research Network (HAN), funded by the Centers for Disease Control and Prevention’s (CDC’s) Healthy Aging Program, has as its core mission, to translate effective healthy aging interventions into sustainable community-based programs. Researchers and community-based stakeholders collaborate across HAN’s seven member center and two affiliate universities (Figure ​(Figure1)1) to develop and implement health promotion programs for older adults at individual, organizational, environmental, and policy levels (1–3). This commentary highlights selected HAN contributions to the EBHP movement from 2001 to 2014. These contributions serve as examples of potential models for future partnership efforts to enhance implementation, dissemination, and sustainability of EBHP programs. Figure 1 CDC Healthy Aging Research Network (HAN) member centers and affiliates (FY 2009-2014).

Locally advanced breast cancer - strategies for developing nations.

Worldwide, cancer incidence and cancer-related deaths are steadily rising. According to the International Agency for Research on Cancer, new cancer cases rose from 12.7 million in 2008 to 14.1 million in 2012 (1). Similarly, 7.6 million cancer-related deaths occurred in 2008 compared to 8.2 million in 2012. A significant proportion of these cases are attributed to breast cancer, the predominant malignancy affecting women worldwide. Since 2008, breast cancer incidence has increased by over 20% and breast cancer deaths have risen by 14% (1). Although the incidence of breast cancer is still highest in developed countries, women in developing nations are disproportionately dying as a result of this disease. Six of the 10 countries with the highest breast cancer mortality rate are low- to middle-income countries (LMICs) (Figure ​(Figure1).1). Moreover, breast cancer in LMICs often presents when locally advanced breast cancer (LABC) (2–4) that can be easily appreciated at physical exam but is still limited to the breast and draining lymph nodes, without clinical evidence of metastatic spread. LABC is defined as tumors: (1) more than 5 cm in diameter, (2) involve the skin or the underlying pectoral muscles, (3) involve axillary, supraclavicular, and/or infraclavicular lymph nodes, or (4) inflammatory breast cancer. Despite being confined to the breast and regional nodes, locally advanced stage often heralds the rapid onset of metastatic disease, explaining high mortality rates. Solutions are needed to address this health issue. We propose practical strategies to improve the early detection of breast cancer and the treatment of LABC within developing nations. Figure 1 Age-standardized mortality rates, number of deaths per 100,000 women (1).

Adipose tissue dysfunction and impaired metabolic health in human obesity: a matter of oxygen?

The number of studies in the field of adipose tissue biology has increased exponentially over the last decade. This shift in research focus is primarily driven by the tremendous increase in the prevalence of obesity and related chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. Adipose tissue is a fascinating and complex organ, with marked effects on whole-body physiology. Intriguingly, expansion of adipose tissue does not necessarily translate into increased metabolic and cardiovascular disease risk. A proportion of obese individuals seems to be relatively protected against worsening of metabolic health (1), suggesting that adipose tissue dysfunction, rather than the amount of fat mass, may be a key factor in the pathophysiology of obesity-related metabolic and cardiovascular diseases (2–4). It is widely accepted that impairments in adipose tissue lipid metabolism, a decreased adipose tissue blood flow (ATBF) and an increased production of pro-inflammatory cytokines by hypertrophic adipocytes and infiltrating adaptive and innate immune cells are characteristics of dysfunctional adipose tissue in obesity (2, 5). These impairments not only induce insulin resistance locally in the adipose tissue but also have detrimental effects at the whole-body level, thereby affecting metabolic health. The reason for this is that adipose tissue dysfunction in obesity is accompanied by lipid spillover in the circulation and subsequent lipid accumulation in non-adipose tissues (ectopic fat storage), and may contribute to systemic low-grade inflammation, thereby accelerating the development and progression of obesity-related insulin resistance and chronic metabolic diseases (Figure ​(Figure1)1) (2). Figure 1 Adipose tissue dysfunction in obesity is related to impaired metabolic health. A long-term positive energy balance, leading to body weight gain, will increase adipocyte size. Adipocyte hypertrophy in obesity is accompanied by disturbances in lipid metabolism ... Adipose Tissue Oxygen Tension in Human Obesity Since adipose tissue dysfunction has been recognized as a key process in the pathophysiology of obesity-related disorders (2, 5), the number of studies aimed at identifying the trigger of adipose tissue dysfunction in obesity has increased substantially. A prevailing concept is that an insufficient amount of oxygen within adipose tissue, commonly referred to as “adipose tissue hypoxia,” may underlie adipose tissue dysfunction in obesity (6, 7). Adipose tissue hypoxia in obesity: The concept It has been postulated that adipose tissue angiogenesis is insufficient to maintain normoxia in the entire fat depot during the progressive development of obesity (8). In other words, a reduced supply of oxygen to the tissue has been proposed to instigate adipose tissue dysfunction. Indeed, a lower expression of angiogenic genes (e.g., VEGF) and lower capillary density have been found in abdominal subcutaneous adipose tissue of obese as compared to lean individuals (9, 10). The net result of structural and functional properties of the adipose tissue vasculature determines tissue blood flow. A consistent observation made by our lab and others is that fasting and postprandial ATBF is decreased in obese insulin resistant versus lean insulin sensitive subjects (9, 11–13), indicating that oxygen delivery to adipose tissue is indeed impaired in obesity. We have recently demonstrated, for the first time, that both pharmacological (local administration of vasoactive agents into adipose tissue) and physiological (oral glucose drink) manipulation of ATBF induce concomitant alterations in adipose tissue oxygen partial pressure (AT PO2) in humans (9), indicating that adipose tissue oxygen supply indeed affects AT PO2. A second argument that has been put forward to develop the concept of adipose tissue hypoxia in obesity is that the diameter of hypertrophic adipocytes in obesity exceeds the normal diffusion distance of oxygen across tissues (100–200 μm) (14). However, in human adipose tissue, there seems to be only a very small proportion of adipocytes with a diameter >100 μm (9, 15, 16). Therefore, the significance of reduced oxygen diffusion from the capillaries to hypertrophic fat cells in obese humans can be questioned.

Case of newly onset type 1 diabetes after highly active antiretroviral therapy against HIV infection.

The survival of patients infected with human immunodeficiency virus (HIV) has been dramatically improved after the introduction of highly active antiretroviral therapy (HAART), the combination of multi-antiretroviral agents to decrease the replication of HIV type 1 (HIV-1). Although HIV-infected patients commonly show a low CD4-positive lymphocyte (CD4) count and a high CD8 count, HAART can effectively reduce the plasma HIV load, thus the CD4 count drastically increases, which is denoted as ‘immune reconstitution’. It was reported that several autoimmune diseases could occur after immune reconstitution during HAART1. Here, we report a case of newly-onset type 1 diabetes after HAART against HIV infection. A previously healthy 40-year-old Japanese man presented to Kawasaki Medical School (Kurashiki, Japan) in June 2009 for further examination of HIV-1 infection. HAART was started because of the low CD4 count and high titer of HIV ribonucleic acid. Then, the laboratory findings showed a total disappearance of HIV ribonucleic acid and increase of CD4 count with good clinical course (Figure​(Figure1).1). Around October 2011, however, the patient had nocturia and intense thirst with 6-kg weight loss. On admission, laboratory findings showed the elevation of glycated hemoglobin (12.5%) and glycoalbumin (30.8%) with mild ketosis. Endogenous insulin secretion was disturbed; serum C-peptide level was 0.6 ng/mL with plasma glucose level 242 mg/dL. Furthermore, anti-GAD antibody was positive (34.8 U/mL), but IA-2 antibody and anti-insulin antibody were negative. In addition, the patient had no obesity and/or diabetic family history, and human leukocyte antigen deoxyribonucleic acid typing of DRB1 and DQB1 was DRB1 *09:01-DQB1* 03:03, which is typical haplotype in Japanese type 1 diabetes. Thereby, we diagnosed the patient with newly-onset type 1 diabetes and introduced multiple daily injection, using insulin aspart and detemir. After that, his glycemic control was gradually improved, and he was discharged at day 19. It is likely that when the CD4 count is markedly increased, autoimmunity is stimulated by the CD4 dominant state. In the present case, the onset of type 1 diabetes and the marked increase of CD4 count around October 2011 were completely synchronized (Figure​(Figure1).1). To the best of our knowledge, there was only one report about the onset of type 1 diabetes after HAART2. According to the allele frequency net database (http://www.allelefrequencies.net)3, human leukocyte antigen DRB1*09:03 is very rare or absent in Caucasians, but this is common in Japan. In fact, the difference in haplotypes associated with type 1 diabetes between Japanese and Caucasian populations has been reported, and it can be explained by the frequency of haplotypes in each ethnicity4. Although the mechanism of the onset of type 1 diabetes is not clear, we assume that after HAART, type 1 diabetes can be induced in Japanese rather than in Caucasians. Therefore, we believe that the present case report would call for attention from the clinical point of view, and that we should consider the possibility of newly-onset type 1 diabetes when HAART is introduced against HIV infection, especially in Japanese patients. Figure 1 Time-course of CD4 cell count and human immunodeficiency virus (HIV)-ribonucleic acid (RNA) copies after highly active antiretroviral therapy in an HIV-infected patient.

Branched-chain amino acids and the association with type2 diabetes.

Branched-chain amino acids and the association with type2 diabetes.

Phosphoproteomics-based peptide ligand-receptor kinase pairing. Commentary on: "A peptide hormone and its receptor protein kinase regulate plant cell expansion".

Phosphoproteomics-based peptide ligand-receptor kinase pairing. Commentary on: "A peptide hormone and its receptor protein kinase regulate plant cell expansion".

Wiretapping into microbial interactions by single cell genomics.

Wiretapping into microbial interactions by single cell genomics.

P-values as percentiles. Commentary on: "Null hypothesis significance tests. A mix-up of two different theories: the basis for widespread confusion and numerous misinterpretations".

Schneider's (2015) article is contemporary work addressing the shortcomings of null hypothesis significance testing (NHST). It summarizes previous work on the topic and provides original examples illustrating NHST-induced confusions in scientometrics. Among the confusions cited are those associated with the interpretation of p-values, old misinterpretations already investigated by Oakes (1986), Falk and Greenbaum (1995); Haller and Krauss (2000), and Perezgonzalez (2014a), and discussed in, for example, Carver (1978); Nickerson (2000), Hubbard and Bayarri (2003); Kline (2004), and Goodman (2008). That they are still relevant in recent times testifies to the fact that the lessons of the past have not been learnt. As the title anticipates, there is a twist to this saga, a pedagogical one: p-values are typically taught and presented as probabilities, and this may be the cause behind the confusions. A change in the heuristic we use for teaching and interpreting the meaning of p-values may be all we need to start working the path toward clarification and understanding. In this article I will illustrate the differences in interpretation that a percentile heuristic and a probability one make. As guiding example, I will use a one-tailed p-value in a normal distribution—z = −1.75, p = 0.04; Figure ​Figure1).1). The default testing approach will be Fisher's tests of significance, but Neyman–Pearson's tests of acceptance approach will be assumed when discussing Type I errors and alternative hypotheses (for more information about those approaches see Perezgonzalez, 2014b, 2015). The scenario is the scoring of a sample of suspected schizophrenics on a validated psychological normality scale. The hypothesis tested (Fisher's H0, Neyman–Pearson's HM) is that the mean score of the sample on the normality scale does not differ from that of the normal population (no H0 = the sample does not score as normal; HA = the sample scores as schizophrenic, assuming previous knowledge that schizophrenics score low on the scale, by a given effect size). Neither a level of significance nor a rejection region is needed for the discussion. Figure 1 Location of an observed z-score and its corresponding p-value in the frequency distribution of the hypothesis under test. The accompanying scales are for the theoretical z-scores and percentiles, respectively.

Combination Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Whom, When, and Where?

To the editor—We appreciate the thoughtful comments raised by Wolbers and Day [1] in response to our article [2]. We agree with their primary point—that our meta-analysis summarized data across studies, and it is therefore best suited to evaluate study-level and not individual-level predictors of outcomes. We should have specified more clearly that our analysis is best suited for drawing inferences about relationships among patient populations, but not about individual patients. Indeed, this point is true for almost all meta-analysis, and it also applies to most individual randomized trials [3]. It is important to note that we did not intend to imply that combination amphotericin B and flucytosine conferred a benefit in patients with cryptococcal meningitis with altered mental status. Rather, in our meta-analysis, we were unable to identify a statistically significant treatment benefit across all published literature, for combination amphotericin B with flucytosine over amphotericin B alone. Although there was some implication of a benefit from adjunctive flucytosine in a subanalysis limited to studies that included patients with altered levels of consciousness, this estimate was not statistically significant (odds ratio = 0.56; 95% confidence interval [CI], .23–1.43) (Figure ​(Figure1).1). As such, we hypothesized in the discussion that populations with altered consciousness might be more likely to benefit from adjunctive flucytosine therapy. If this hypothesis were correct, it would require patient-level data for confirmation. Figure 1. Forrest plot from network meta-analysis comparing odds of early (2-week) and late (10-week) mortality between combination amphotericin B and flucytosine with amphotericin B alone for human immunodeficiency virus-associated cryptococcal meningitis. Abbreviations: ... In their recent large, randomized trial, Day et al [4] demonstrated superiority of combination amphotericin B and flucytosine over amphotericin B alone at 10 weeks. They now present a subanalysis with patient-level data that suggests that those with a normal Glasgow Coma Score (GCS) appeared to derive as much benefit (if not more) from the addition of flucytosine as those with a GCS < 15. Although their study was not powered to detect differences in these subgroups, their data do lend support to the use of flucytosine in individual patients with normal mental status within their study population. It should be noted that the overall mortality in their study was 36% at 10 weeks (and 30% among those who received amphotericin B and flucytosine combination therapy). In contrast, the only other large randomized trial to compare amphotericin B alone with amphotericin B and adjunctive flucytosine found no difference in mortality between groups at 10 weeks (6.7% versus 6.9%; relative risk = 0.97; 95% CI, .46–2.04) [5]. It is noteworthy that this other study was conducted in the United States, excluded comatose patients from enrollment, and had a lower prevalence of participants with altered mental status than the Day et al [4] study (11% vs 28%). We believe that the contrasting data from these 2 studies are in line with our overall conclusion: that current available evidence suggests that the adjunctive use of flucytosine might be beneficial in populations with advanced disease who are at high overall risk for mortality. As Wolbers and Day [4] point out, this does not necessarily mean that patients with normal mental status will not benefit from adjunctive flucytosine, only that populations with low overall risk of mortality are less likely to benefit. Unfortunately, for the time being, it appears that flucytosine is largely only available and in use in the areas of the world where the current data suggest it has the least benefit, whereas populations with the highest mortality often cannot access it [6, 7]. Indeed, the most important conclusion we draw from our study is that more data is required, across a range of patient populations and disease stages, to elucidate which drugs are needed for which patients, and to ensure that the optimal therapies are available to those who need them.

Microarrayed Jug r 1 shows the best diagnostic performance in walnut allergy

Several walnut (WN) allergens have been identified to date: Jug r 1 (2S albumin), Jug r 2 (7S globulin), Jug r 3 (LTP), Jug r 4 (11S globulin) and Jug r 5 (profilin), but their clinical significance is still to be determined in some cases. Allergen microarray (ISAC) provides information for three of these allergens. The aim of the study was to determine the importance of component resolved diagnosis in WN allergic patients. Ninety children suspected to have allergy to fruit, nuts and/or legumes were selected. Patients were classified as allergic if they presented at least 2 reactions unequivocally related to WN ingestion in the last 2 years. Patients were defined as tolerant if they consumed WN on a regular basis. Clinical questionnaire, skin prick test (SPT), total and specific IgE and ImmunoCAP ISAC (Thermo Fisher) were performed. Thirty-one patients (18 males) were defined as allergic and 59 (36 males) tolerant. WN-SPT wheal size (median diameter 5.25 mm; IQR: 4-7 vs. 0 mm; IQR: 0-2, p=0.000) and WN-sIgE (median 5.35 kU/L; IQR: 3.52-12.84 vs. 0.65 kU/L; IQR: 0.08-1.86, p=0.000) were significantly greater in allergic than in tolerant children. Positive Jug r 1-sIgE was significantly more frequent in allergic patients (80.65% vs. 5.08%, p=0.000). Jug r 1-sIgE values were also significantly higher in allergic children (median 2.5 ISU; IQR: 0-7.6 vs. 0 ISU; IQR: 0-0, p=0.000). This was not found for Jug r 2 or Jug r 3. ROC curves were constructed for the three allergens showing Jug r 1 the best diagnostic performance (AUC: 0.876, 95%CI: 0.788-0.965, p=0.000) (Figure ​(Figure11 and Table ​Table11). Figure 1 ROC curves for Walnut allergens Table 1 Diagnostic performance of walnut allergens (MAISAC) In conclusion, Jug r 1-sIgE is the best discriminating allergen in WN allergic patients.

Commentary on: “Number-space mapping in the newborn chick resembles humans' mental number line”

Commentary on: “Number-space mapping in the newborn chick resembles humans' mental number line”

ChemInform Abstract: Advances in Catalytic Enantioselective Fluorination, Mono‐, Di‐, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

AbstractReview: 211 refs.

Drugs of Abuse in HIV infection and neurotoxicity.

HIV is a neurotropic virus that enters the brain right after infection. In the brain, HIV replicates in macrophages, microglia and small number of astrocytes (4.7 ± 2.8% in vitro and 8.2 ± 3.9 in vivo) (Eugenin et al., 2011) causing inflammatory and neurotoxic host responses. Severe neurological disorders caused by HIV are collectively known as HIV-associated neurocognitive disorders (HAND). HAND is characterized by development of abnormal reduction of motor speed, concentration, and memory. HAND consists of several clinical forms ranging from asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND) to the most severe HIV-associated dementia (HAD) (McArthur and Brew, 2010). HIV-encephalitis (HIVE) is the main cause of HAND and the most common neurologic disorder of the brain in HIV-1 infection. HIV-1 exhibits extensive genetic variation worldwide and is categorized into three groups (M, O, and N) and genetically into nine different subtypes (A–K). Of these, clades B and C represent the majority (>86%) of circulating HIV-1 variants (Osmanov et al., 2002). While HIV-1 clade B is predominant in North America, Western Europe, and Australia; clade C is common in Southern and East Africa, India and Nepal (responsible for around half of all HIV infections). HIV-1 clade B has been reported to be more neuropathogenic than clade C (Atluri et al., 2013; Samikkannu et al., 2014). Before the worldwide use of highly antiretroviral therapy (HAART), approximately, 20–30% of individuals with advanced HIV-1 clade B infection showed symptoms of HAD (Gonzalez-Scarano and Martin-Garcia, 2005; Kaul et al., 2005). Although the prevalence of HAD has decreased intensely after the introduction of HAART, 40–50% of HIV positive patients still suffer from HAND (Sacktor et al., 2001; Sacktor, 2002; McArthur, 2004; Antinori et al., 2007; Ellis et al., 2007). In developed countries, about 30% of HIV-positive individuals are intravenous drug abusers, which place them in a higher risk for HAND (Miro et al., 2003; Beyrer et al., 2010). Cocaine and marijuana are the most common drugs of abuse among HIV patients, whereas opioids are abused only by a small number of patients (Kuo et al., 2004; Cook et al., 2007; Korthuis et al., 2008). Overall, several drugs of abuse such as tobacco, stimulants, cannabinoids, opioids and alcohol are found to be consumed among HIV infected individuals, having an effect on synaptic plasticity and development found in the brain (Hauser and Knapp, 2014). Figure ​Figure11 is showing different neurotoxic mechanisms of drugs of abuse in HIV infection which may lead to the impaired neurocognitive functions. Figure 1 Schematic representation of neurotoxic mechanisms of different illicit drugs of abuse in HIV infection. Nicotine and HIV Recently, in nicotine and HIV infected SK-N-MC cells, an up-regulation of HDAC2 was observed (Atluri et al., 2014). HDAC2 overexpression has been reported in depleted memory formation, synaptic plasticity and dendritic spine density (Guan et al., 2009). Nevertheless, use of nicotine in infected patients can have beneficial outcomes on neurological deficits that were HIV-1 induced (Cao et al., 2013). In nicotine injected HIV-1 transgenic rats brain regions, such as in the prefrontal cortex, Wnt/β-catenin signaling has shown improvement by restoring the down-regulation of Axin1, Wnt5a, Wnt7a and the up-regulation of Gnao1 (Cao et al., 2013). This signaling pathway plays an important role in the early development of the nervous system, in which a neuroprotective outcome in adults is established after the activation of this pathway (Nave and Trapp, 2008). These results are important since central demyelination and neurodegeneration have been observed in HIV-1 infected individuals. In the dorsal hippocampus, CREB signaling has also been restored, in which the decreased expression of calcium sensor proteins, Calm3 and Cabp1, was regulated to normal levels. This signaling pathway is significant in neuronal survival and long-term synaptic plasticity. In the dorsal striatum, nicotine has also shown to restore the function of the tricarboxylic acid (TCA) cycle and its related pathways, such as the down-regulation of Idh3B and up-regulation of Ndufs4 that came back to normal levels (Cao et al., 2013).

Semantic memory as the root of imagination.

“Imagination is what makes our sensory experience meaningful, enabling us to interpret and make sense of it, whether from a conventional perspective or from a fresh, original, individual one. It is what makes perception more than the mere physical stimulation of sense organs. It also produces mental imagery, visual and otherwise, which is what makes it possible for us to think outside the confines of our present perceptual reality, to consider memories of the past and possibilities for the future, and to weigh alternatives against one another. Thus, imagination makes possible all our thinking about what is, what has been, and, perhaps most important, what might be.”—Nigel J. T. Thomas (2004, as cited in Manu, 2006, p. 47)1. Investigations of the information processing mechanisms that underlie imaginative thought typically focus on a single branch of imagination, such as prospection, mental imagery or creativity, and are often generalized as being insightful to understanding the workings of imagination in general. In reality, however, there is very little in the way of theoretical or empirical exchange between the scientific communities that conduct research within the different domains of imagination. As a result, the research impetus in each of the sub-domains may be skewed to the pursuit of hypotheses that are not particularly viable in terms of understanding imagination as a whole. An example of this is pegging the roots of imagination to the processes of episodic memory—a reasonable assumption to make based on studies of episodic prospection. However, the associated findings and theoretical conclusions that follow are not entirely consistent with the literature on the mechanisms underlying creativity (Bubic and Abraham, 2014), which is another core realm of imagination. In an effort to promote interchange across the frontiers of imagination, in this Opinion Article we put forward the idea that all aspects of imagination emerge from semantic memory with increasingly higher-order levels of imaginative information processing emanating from and interacting with existing systems, eventually expanding beyond these to form new systems (Figure ​(Figure1).1). We compare the associated neurocognitive findings and assumptions in terms of their fit with current knowledge in other fields of imagination and discuss their implications for reformulating hypotheses regarding imagination as a whole. Figure 1 An informal illustration of how imaginative processes emerge from and expand beyond semantic memory operations.

The calcium-ROS-pH triangle and mitochondrial permeability transition: challenges to mimic cardiac ischemia-reperfusion.

The calcium-ROS-pH triangle and mitochondrial permeability transition: challenges to mimic cardiac ischemia-reperfusion.