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In simple terms, consciousness is constituted by multiple goals for action and the continuous adjudication of such goals to implement action, which is referred to as the maps of meaning (MoM) consciousness theory. The MoM theory triangulates through three parallel corollaries: action (behavior), mechanism (morphology/pathophysiology), and goals (teleology). (1) An organism’s consciousness contains fluid, nested goals. These goals are not intentionality, but intersectionality, via the Darwinian byproduct of embodiment meeting the world, i.e., Darwinian inclusive fitness or randomization and then survival of the fittest. (2) These goals are formed via a gradual descent under inclusive fitness and are the abstraction of a "match" between the evolutionary environment and the organism. (3) Human consciousness implements the brain efficiency hypothesis, genetics, epigenetics, and experience-crystallized efficiencies, not necessitating best or objective but fitness, i.e., perceived efficiency based on one’s adaptive environment. These efficiencies are objectively arbitrary but determine the operation and level of one’s consciousness, termed as extreme thrownness. (4) Since inclusive fitness drives efficiencies in the physiologic mechanism, morphology, and behavior (action) and originates one’s goals, embodiment is necessarily entangled to human consciousness as it is at the intersection of mechanism or action (both necessitating embodiment) occurring in the world that determines fitness. (5) Perception is the operant process of consciousness and is the de facto goal adjudication process of consciousness. Goal operationalization is fundamentally efficiency-based via one’s unique neuronal mapping as a byproduct of genetics, epigenetics, and experience. (6) Perception involves information intake and information discrimination, equally underpinned by efficiencies of inclusive fitness via extreme thrownness. Perception is not a ‘frame rate’ but Bayesian priors of efficiency based on one’s extreme thrownness. (7) Consciousness and human consciousness are modular (i.e., a scalar level of richness, which builds up like building blocks) and dimensionalized (i.e., cognitive abilities become possibilities as the emergent phenomena at various modularities such as the stratified factors in factor analysis). (8) The meta dimensions of human consciousness seemingly include intelligence quotient, personality (five-factor model), richness of perception intake, and richness of perception discrimination, among other potentialities. (9) Future consciousness research should utilize factor analysis to parse modularities and dimensions of human consciousness and animal models. [ABSTRACT FROM AUTHOR]

In simple terms, consciousness is constituted by multiple goals for action and the continuous adjudication of such goals to implement action, which is referred to as the maps of meaning (MoM) consciousness theory. The MoM theory triangulates through three parallel corollaries: action (behavior), mechanism (morphology/pathophysiology), and goals (teleology). (1) An organism’s consciousness contains fluid, nested goals. These goals are not intentionality, but intersectionality, via the Darwinian byproduct of embodiment meeting the world, i.e., Darwinian inclusive fitness or randomization and then survival of the fittest. (2) These goals are formed via a gradual descent under inclusive fitness and are the abstraction of a “match” between the evolutionary environment and the organism. (3) Human consciousness implements the brain efficiency hypothesis, genetics, epigenetics, and experience-crystallized efficiencies, not necessitating best or objective but fitness, i.e., perceived efficiency based on one’s adaptive environment. These efficiencies are objectively arbitrary but determine the operation and level of one’s consciousness, termed as extreme thrownness. (4) Since inclusive fitness drives efficiencies in the physiologic mechanism, morphology, and behavior (action) and originates one’s goals, embodiment is necessarily entangled to human consciousness as it is at the intersection of mechanism or action (both necessitating embodiment) occurring in the world that determines fitness. (5) Perception is the operant process of consciousness and is the de facto goal adjudication process of consciousness. Goal operationalization is fundamentally efficiency-based via one’s unique neuronal mapping as a byproduct of genetics, epigenetics, and experience. (6) Perception involves information intake and information discrimination, equally underpinned by efficiencies of inclusive fitness via extreme thrownness. Perception is not a ‘frame rate’ but Bayesian priors of efficiency based on one’s extreme thrownness. (7) Consciousness and human consciousness are modular (i.e., a scalar level of richness, which builds up like building blocks) and dimensionalized (i.e., cognitive abilities become possibilities as the emergent phenomena at various modularities such as the stratified factors in factor analysis). (8) The meta dimensions of human consciousness seemingly include intelligence quotient, personality (five-factor model), richness of perception intake, and richness of perception discrimination, among other potentialities. (9) Future consciousness research should utilize factor analysis to parse modularities and dimensions of human consciousness and animal models.

In developed countries, the aging of the population and the associated increase in age-related diseases are causing major unresolved medical, social, and environmental matters. Therefore, research on aging has become one of the most important and urgent issues in life sciences. If the molecular mechanisms of the onset and progression of neurodegenerative diseases are elucidated, we can expect to develop disease-modifying methods to prevent neurodegeneration itself. Since the discovery of induced pluripotent stem cells (iPSCs), there has been an explosion of disease models using disease-specific iPSCs derived from patient-derived somatic cells. By inducing the differentiation of iPSCs into neurons, disease models that reflect the patient-derived pathology can be reproduced in culture dishes, and are playing an active role in elucidating new pathological mechanisms and as a platform for new drug discovery. At the same time, however, we are faced with a new problem: how to recapitulate aging in culture dishes. It has been pointed out that cells differentiated from pluripotent stem cells are juvenile, retain embryonic traits, and may not be fully mature. Therefore, attempts are being made to induce cell maturation, senescence, and stress signals through culture conditions. It has also been reported that direct conversion of fibroblasts into neurons can reproduce human neurons with an aged phenotype. Here, we outline some state-of-the-art insights into models of neuronal aging in vitro. New frontiers in which stem cells and methods for inducing differentiation of tissue regeneration can be applied to aging research are just now approaching, and we need to keep a close eye on them. These models are forefront and intended to advance our knowledge of the molecular mechanisms of aging and contribute to the development of novel therapies for human neurodegenerative diseases associated with aging. [ABSTRACT FROM AUTHOR]

In developed countries, the aging of the population and the associated increase in age-related diseases are causing major unresolved medical, social, and environmental matters. Therefore, research on aging has become one of the most important and urgent issues in life sciences. If the molecular mechanisms of the onset and progression of neurodegenerative diseases are elucidated, we can expect to develop disease-modifying methods to prevent neurodegeneration itself. Since the discovery of induced pluripotent stem cells (iPSCs), there has been an explosion of disease models using disease-specific iPSCs derived from patient-derived somatic cells. By inducing the differentiation of iPSCs into neurons, disease models that reflect the patient-derived pathology can be reproduced in culture dishes, and are playing an active role in elucidating new pathological mechanisms and as a platform for new drug discovery. At the same time, however, we are faced with a new problem: how to recapitulate aging in culture dishes. It has been pointed out that cells differentiated from pluripotent stem cells are juvenile, retain embryonic traits, and may not be fully mature. Therefore, attempts are being made to induce cell maturation, senescence, and stress signals through culture conditions. It has also been reported that direct conversion of fibroblasts into neurons can reproduce human neurons with an aged phenotype. Here, we outline some state-of-the-art insights into models of neuronal aging in vitro. New frontiers in which stem cells and methods for inducing differentiation of tissue regeneration can be applied to aging research are just now approaching, and we need to keep a close eye on them. These models are forefront and intended to advance our knowledge of the molecular mechanisms of aging and contribute to the development of novel therapies for human neurodegenerative diseases associated with aging.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF. [ABSTRACT FROM AUTHOR]

The CD4+ and CD8+ T cell immune response against T. cruzi, the parasite causing Chagas disease, are relevant for both parasite control and disease pathogenesis. Several studies have been focused on their phenotype and functionally, but only a few have drilled down to identify the parasite proteins that are processed and presented to these cells, especially to CD4+ T lymphocytes. Although approximately 10,000 proteins are encoded per haploid T. cruzi genome, fewer than 200 T cell epitopes from 49 T. cruzi proteins have been identified so far. In this context, a detailed knowledge of the specific targets of T cell memory response emerges as a prime tool for the conceptualization and development of prophylactic or therapeutic vaccines, an approach with great potential to prevent and treat this chronic disease. Here, we review the available information about this topic in a comprehensive manner and discuss the future challenges in the field.

The CD4+ and CD8+ T cell immune response against T. cruzi , the parasite causing Chagas disease, are relevant for both parasite control and disease pathogenesis. Several studies have been focused on their phenotype and functionally, but only a few have drilled down to identify the parasite proteins that are processed and presented to these cells, especially to CD4+ T lymphocytes. Although approximately 10,000 proteins are encoded per haploid T. cruzi genome, fewer than 200 T cell epitopes from 49 T. cruzi proteins have been identified so far. In this context, a detailed knowledge of the specific targets of T cell memory response emerges as a prime tool for the conceptualization and development of prophylactic or therapeutic vaccines, an approach with great potential to prevent and treat this chronic disease. Here, we review the available information about this topic in a comprehensive manner and discuss the future challenges in the field. [ABSTRACT FROM AUTHOR]

The healthy state of an organism is constantly threatened by external cues. Due to the daily inhalation of hundreds of particles and pathogens, the immune system needs to constantly accomplish the task of pathogen clearance in order to maintain this healthy state. However, infection dynamics are highly influenced by the peculiar anatomy of the human lung. Lung alveoli that are packed in alveolar sacs are interconnected by so called Pores of Kohn. Mainly due to the lack of in vivo methods, the role of Pores of Kohn in the mammalian lung is still under debate and partly contradicting hypotheses remain to be investigated. Although it was shown by electron microscopy that Pores of Kohn may serve as passageways for immune cells, their impact on the infection dynamics in the lung is still unknown under in vivo conditions. In the present study, we apply a hybrid agent-based infection model to quantitatively compare three different scenarios and discuss the importance of Pores of Kohn during infections of Aspergillus fumigatus. A. fumigatus is an airborne opportunistic fungus with rising incidences causing severe infections in immunocompromised patients that are associated with high mortality rates. Our hybrid agent-based model incorporates immune cell dynamics of alveolar macrophages – the resident phagocytes in the lung – as well as molecular dynamics of diffusing chemokines that attract alveolar macrophages to the site of infection. Consequently, this model allows a quantitative comparison of three different scenarios and to study the importance of Pores of Kohn. This enables us to demonstrate how passaging of alveolar macrophages and chemokine diffusion affect A. fumigatus infection dynamics. We show that Pores of Kohn alter important infection clearance mechanisms, such as the spatial distribution of macrophages and the effect of chemokine signaling. However, despite these differences, a lack of passageways for alveolar macrophages does impede infection clearance only to a minor extend. Furthermore, we quantify the importance of recruited macrophages in comparison to resident macrophages.

Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause severe infections in immunocompromised patients. Conidia that reach the lower respiratory tract are confronted with alveolar macrophages, which are the resident phagocytic cells, constituting the first line of defense. If not efficiently removed in time, A. fumigatus conidia can germinate causing severe infections associated with high mortality rates. Mice are the most extensively used model organism in research on A. fumigatus infections. However, in addition to structural differences in the lung physiology of mice and the human host, applied infection doses in animal experiments are typically orders of magnitude larger compared to the daily inhalation doses of humans. The influence of these factors, which must be taken into account in a quantitative comparison and knowledge transfer from mice to humans, is difficult to measure since in vivo live cell imaging of the infection dynamics under physiological conditions is currently not possible. In the present study, we compare A. fumigatus infection in mice and humans by virtual infection modeling using a hybrid agent-based model that accounts for the respective lung physiology and the impact of a wide range of infection doses on the spatial infection dynamics. Our computer simulations enable comparative quantification of A. fumigatus infection clearance in the two hosts to elucidate (i) the complex interplay between alveolar morphometry and the fungal burden and (ii) the dynamics of infection clearance, which for realistic fungal burdens is found to be more efficiently realized in mice compared to humans.

Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause severe infections in immunocompromised patients. Conidia that reach the lower respiratory tract are confronted with alveolar macrophages, which are the resident phagocytic cells, constituting the first line of defense. If not efficiently removed in time, A. fumigatus conidia can germinate causing severe infections associated with high mortality rates. Mice are the most extensively used model organism in research on A. fumigatus infections. However, in addition to structural differences in the lung physiology of mice and the human host, applied infection doses in animal experiments are typically orders of magnitude larger compared to the daily inhalation doses of humans. The influence of these factors, which must be taken into account in a quantitative comparison and knowledge transfer from mice to humans, is difficult to measure since in vivo live cell imaging of the infection dynamics under physiological conditions is currently not possible. In the present study, we compare A. fumigatus infection in mice and humans by virtual infection modeling using a hybrid agent-based model that accounts for the respective lung physiology and the impact of a wide range of infection doses on the spatial infection dynamics. Our computer simulations enable comparative quantification of A. fumigatus infection clearance in the two hosts to elucidate (i) the complex interplay between alveolar morphometry and the fungal burden and (ii) the dynamics of infection clearance, which for realistic fungal burdens is found to be more efficiently realized in mice compared to humans. [ABSTRACT FROM AUTHOR]

Context: Low bone mineral density (BMD) is the most important risk factor for fragility fracture. Body weight is a simple screening predictor of difference in BMD between individuals. However, it is not clear which component of body weight, lean (LM), or fat mass (FM), is associated with BMD. People with the genetic disorder of Prader-Willi syndrome (PWS) uniquely have a reduced LM despite increased FM.Objective: We sought to define the individual impact of LM and FM on BMD by investigating subjects with and without PWS.Design, Setting and Participants: This cross-sectional study was conducted at the Clinical Research Facility of the Garvan Institute of Medical Research, with PWS and control participants recruited from a specialized PWS clinic and from the general public by advertisement, respectively. The study involved 11 adults with PWS, who were age- and sex-matched with 12 obese individuals (Obese group) and 10 lean individuals (Lean group).Main Outcome Measures: Whole body BMD was measured by dual-energy X-ray absorptiometry. Total body FM and LM were derived from the whole body scan. Differences in BMD between groups were assessed by the analysis of covariance model, taking into account the effects of LM and FM.Results: The PWS group had significantly shorter height than the lean and obese groups. As expected, there was no significant difference in FM between the Obese and PWS group, and no significant difference in LM between the Lean and PWS group. However, obese individuals had greater LM than lean individuals. BMD in lean individuals was significantly lower than in PWS individuals (1.13 g/cm2 vs. 1.21 g/cm2, p < 0.05) and obese individuals (1.13 g/cm2 vs. 1.25 g/cm2, p < 0.05). After adjusting for both LM and FM, there was no significant difference in BMD between groups, and the only significant predictor of BMD was LM.Conclusions: These data from the human genetic model Prader-Willi syndrome suggest that LM is a stronger determinant of BMD than fat mass.

Context: Low bone mineral density (BMD) is the most important risk factor for fragility fracture. Body weight is a simple screening predictor of difference in BMD between individuals. However, it is not clear which component of body weight, lean (LM), or fat mass (FM), is associated with BMD. People with the genetic disorder of Prader-Willi syndrome (PWS) uniquely have a reduced LM despite increased FM. Objective: We sought to define the individual impact of LM and FM on BMD by investigating subjects with and without PWS. Design, Setting and Participants: This cross-sectional study was conducted at the Clinical Research Facility of the Garvan Institute of Medical Research, with PWS and control participants recruited from a specialized PWS clinic and from the general public by advertisement, respectively. The study involved 11 adults with PWS, who were age- and sex-matched with 12 obese individuals (Obese group) and 10 lean individuals (Lean group). Main Outcome Measures: Whole body BMD was measured by dual-energy X-ray absorptiometry. Total body FM and LM were derived from the whole body scan. Differences in BMD between groups were assessed by the analysis of covariance model, taking into account the effects of LM and FM. Results: The PWS group had significantly shorter height than the lean and obese groups. As expected, there was no significant difference in FM between the Obese and PWS group, and no significant difference in LM between the Lean and PWS group. However, obese individuals had greater LM than lean individuals. BMD in lean individuals was significantly lower than in PWS individuals (1.13 g/cm2 vs. 1.21 g/cm2, p < 0.05) and obese individuals (1.13 g/cm2 vs. 1.25 g/cm2, p < 0.05). After adjusting for both LM and FM, there was no significant difference in BMD between groups, and the only significant predictor of BMD was LM. Conclusions: These data from the human genetic model Prader-Willi syndrome suggest that LM is a stronger determinant of BMD than fat mass. [ABSTRACT FROM AUTHOR]