Here we first review published computer-aided structural predicti

Here we first review published computer-aided structural predictions of HIV-1 integrase in complex with its interactors. These include DNA and the human HAT protein. Next, we present a prediction of the complex between HIV-1 integrase with the human prolyl-isomerase-1 (hPin1) enzyme. Interaction with hPin1 is crucial for efficient HIV-1 infection and it increases integrase stability (Manganaro et. al 2010, Nat. Med. 16, 329). The modeling presented here, which is validated against experimental data, provides a rationale for a variety of viral protein’s mutations which impair protein function and

HIV-1 virus replication in vivo without significantly affecting enzymatic activity.”
“Pink-footed geese Anser brachyrhynchus nest in two contrasting but commonly found habitats: steep cliffs and open tundra slopes. In Svalbard, we compared nest densities Cyclosporin A chemical structure and nesting success in these two environments over ten breeding seasons to assess the impact of spring snow cover, food availability to nesting adults and arctic fox Vulpes lagopus (main terrestrial predator) abundance. In years with extensive spring snow cover, fewer geese at both colonies attempted to breed, possibly because snow cover limited pre-nesting feeding

opportunities, leaving adults in poor breeding condition. Nesting success at the steep cliff colony was lower with extensive spring snow cover; such conditions force birds to commit to repeated and prolonged recess periods at far distant feeding areas, leaving nests open to predation. By contrast, nesting success at the open tundra slope was 5-Fluoracil molecular weight not affected by spring snow cover; even if birds were apparently in poor condition they could feed immediately adjacent to their nests and defend them from predators. Foxes were the main nest predator in the open tundra slopes but avian predators https://www.selleckchem.com/products/ca3.html likely had a larger impact at the steep cliffs colony. Thus, the relative inaccessibility

of the cliffs habitat may bring protection from foxes but also deprives geese from readily accessing feeding areas, with the best prospects for successful nesting in low spring snow cover years. Our findings indicate that spring snow cover, predator abundance and food proximity did not uniformly influence nesting success of this herbivore, and their effects were dependent on nesting habitat choice.”
“As an important enzyme in the conjugation phase of drug clearance, UGT2B4 helps metabolize various endogenous and exogenous substances, and polymorphisms in the corresponding gene can influence enzyme activity. This study investigated the association between polymorphisms in UGT2B4 and the risk of developing pancreatic cancer in Han Chinese individuals. A hospital-based case-control study was conducted with 1579 healthy controls and 406 pancreatic cancer patients from China. Genomic DNA was obtained from peripheral blood lymphocytes.

Aldosterone-receptor antagonists (ARAs) are increasingly used in

Aldosterone-receptor antagonists (ARAs) are increasingly used in patients with resistant hypertension, often with impressive results. However, definitive evidence for the benefit of ARAs in these patients from randomized, controlled trials is lacking. This review gives an overview of the current data on this topic. Future studies should focus on the identification of factors that are able to predict the response to treatment, as to select patients who will benefit most from treatment with ARAs. On the basis of the current knowledge, we recommend prescription of ARAs to patients with primary aldosteronism, resistant hypertension and patients with hypertension and hypokalemia. J Hypertens

27:680-691 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.”
“Heat shock proteins (HSPs) are molecular chaperones critical for cell survival under adverse environmental conditions and for normal cellular Tariquidar chemical structure homeostasis. Bicyclol, a novel Dibutyryl-cAMP manufacturer antihepatitis drug, has been shown to protect against liver injury in animals. However, it is unclear how bicyclol protects against liver injury. We recently found that bicyclol is an

inducer of HSPs. We wondered whether bicyclol regulated the expression of HSPs to produce a liver protection in vivo. Thus, this study was designed to address these questions using a mouse model with concanavalin A (ConA)-induced liver injury. Oral administration of bicyclol markedly alleviated ConA-caused liver injury in mice as indicated by the reduction of serum aminotransferases, liver necrosis, and the

release of cytochrome c and apoptosis-inducing factor from mitochondria and hepatic DNA fragmentation. Correlated with this, bicyclol induced the increase of mRNA and protein levels of hepatic 27- and 70-kDa HSPs (HSP27 and HSP70) in the mice. Correspondingly, the elevated HSP27 and HSP70 suppressed inhibitor kappa B degradation and nuclear factor kappa B (NF-kappa B) activation that were caused by ConA. The protective effects of bicyclol on ConA-induced mouse liver injury were markedly attenuated by quercetin, an inhibitor of HSPs synthesis. Our results suggest that the antihepatitis drug bicyclol may protect against liver injury by inducing the expression of hepatic HSP27 and HSP70 and consequently inhibit the transcription factor NF-kappa B-mediated apoptosis and necrosis in liver tissue.”
“Oxytocin buy GSK1904529A facilitates stress regulation but little is known about individual differences in this effect. The present study investigates whether the effect of intranasal oxytocin on stress-contingent cortisol release differs between individuals with high vs. low emotional regulation abilities (ERA). In a double-blind study thirty-six healthy male students with either high or low ERA were randomly assigned to receive intranasally 24 IU oxytocin or placebo. Cortisol was measured at several times before and after a social stressor (public speaking).

We show here that the all-or-none characteristic of form preparat

We show here that the all-or-none characteristic of form preparation is specific to task format. Preparation for sets that included an exception item occurred in ecologically valid production tasks, picture naming (Experiment 1), and word naming (Experiment 2). Preparation failed only in the commonly used, but indirect and resource-intensive, associative cuing task (Experiment 3). We outline an account of form preparation in which anticipation of word-initial phonological fragments uses a limited-capacity,

sustained attentional capability MK5108 that points to rather than enacts possibilities for imminent speech.”
“Chagas disease is caused by the parasite Trypanosoma cruzi. Because of its distribution throughout Latin America, sometimes it can overlap with other parasitic diseases, such as leishmaniasis, caused by Leishmania spp. This might represent a problem when performing serological diagnosis, because both parasites share antigens, resulting in cross-reactions. In the present work we

evaluated Mexican sera samples: 83.8% of chagasic patients recognized at least one antigen of high molecular weight ( bigger than 95 kDa) when evaluated by Western blot. Proteins of 130 kDa and 160 kDa are predominantly being recognized by asymptomatic chagasic patients. When the proteins were extracted using Triton X-100 detergent, a larger number of specific T. cruzi proteins were obtained. This protein fraction can be used to increase specificity to 100% in Western blot assays without losing sensitivity of Selleck AZD1208 the test. High molecular weight proteins of T. cruzi include glycoproteins with a great amount of alpha Man

(alpha-mannose), alpha Glc (alpha-glucose), GlcNAc (N-acetylglucosamine), and alpha Gal (alpha-galactose) content and these structures play an essential role in antigens recognition by antibodies present in patients’ sera.”
“BACKGROUND: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. OBJECTIVES: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. METHODS: Cyclopamine solubility dmso This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. DISCUSSION: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb.

Characteristics of the multi-resistant Pseudomonas sp demonstrat

Characteristics of the multi-resistant Pseudomonas sp. demonstrated its origin from a hospital environment LDN-193189 due to its previous exposure to a variety of antibiotics.\n\nConclusions. Corneal extraction site must guarantee an antiseptic preparation and aseptic tissue donor recuperation; although in this study it was not feasible to accurately establish the infection source, all of the findings led to suspect a possible contamination at the morgue.”
“The rheological properties of alpha-cellulose 1-allyl-3-methylimidazolium formate solutions were investigated using shear viscosity and dynamic rheological measurements

in a large range of concentrations (0.1-10 wt%) at 25 degrees C. In steady shear measurement, the overlap concentration (c*) and the entanglement concentration Z-VAD-FMK purchase (c(e)) were determined to be 0.5 and 2.0 wt% respectively, and the exponents of

the specific viscosity (eta(sp)) versus the concentration (c) were determined as 1.0, 2.0 and 4.7 for dilute, semidilute unentangled and entangled regimes respectively, which were in accordance with the scaling prediction for neutral polymer in theta solvent. The slopes of the relaxation time (tau) against the concentration for semidilute unentangled and entangled regimes were observed as 1.0 and 2.5 respectively. In dilute and semidilute unentangled regimes, failure of the Cox-Merz rule with steady shear viscosity larger than complex viscosity was observed; while the deviation from the Cox-Merz rule disappeared in semidilute entangled regime. (C) 2013 Elsevier Ltd. All rights reserved.”
“Aromatic acetates can be selectively deprotected in the presence of aliphatic acetates under ammonium acetate mediated condition. B3LYP/6-31++G** level of theory was demonstrated to be successfully used to model the relative reaction rates for deacylation reactions for aliphatic and aromatic ester systems. On the basis of the mechanistic studies, acetate anion is most likely to be the active catalyst for the ester deacylation

reactions under ammonium acetate mediated condition.”
“Dr adhesins are expressed on the surface of uropathogenic www.selleckchem.com/products/cftrinh-172.html and diffusely adherent strains of Escherichia coli. The major adhesin subunit (DraE/AfaE) of these organelles mediates attachment of the bacterium to the surface of the host cell and possibly intracellular invasion through its recognition of the complement regulator decay-accelerating factor (DAF) and/or members of the carcinoembryonic antigen (CEA) family. The adhesin subunit of the Dr haemagglutinin, a Dr-family member, additionally binds type IV collagen and is inhibited in all its receptor interactions by the antibiotic chloramphenicol (CLM). In this study, previous structural work is built upon by reporting the X-ray structures of DraE bound to two chloramphenicol derivatives: chloramphenicol succinate (CLS) and bromamphenicol (BRM).


“High relative humidity (RH) can cause lower concentration


“High relative humidity (RH) can cause lower concentrations of boron (B) accumulating in plants. The common greenhouse practice of controlling excess temperatures by applying mist irrigation to young plants (plugs) can result in elevated RH levels, especially with plugs grown in high heat and humidity conditions of summer. ‘Dynamite

Yellow’ pansy (Viola Xwittrockiana Gams.), ‘White Storm’ petunia (Petunia Xhybrida Vilm.), and ‘Festival Apricot’ gerbera (Gerbera jamesonii Bolus) plugs were grown in high or ambient RH conditions to determine the effect RH had AZD6094 cost on B uptake. Results indicate that an increase in RH decreased the amount of water the plant lost as a result of transpiration resulting in lower concentrations of B in shoot tissue. Boron concentrations in leaf tissue were 9.43, 10.56, and 17.81 mg.L-1 in pansy, petunia, and gerbera

plants, respectively, grown in high RH conditions. These values were significantly lower than pansy, petunia, and gerbera plants grown in ambient RH conditions (19.94, 25.49, and 42.71 mg.L-1, respectively). Leaf distortion, consistent with B deficiency symptoms, was present in petunia and gerbera plants. Similar trends were observed when the experiment was repeated and leaf distortion was present in all species. This provides convincing evidence that the distorted growth observed in pansy, petunia, and gerbera plug production is the result of limited B caused by excessive humidity.”
“In this study, throughfall and stemflow samples were collected

from selleck chemicals six forest stands (EU1 = 1 year-old Eucalyptus; EU3 = 3 year-old Eucalyptus; EU7 = 7 year-old Eucalyptus; AM = 7 year-old Acacia mangium; PL = 13 year-old Pinus massoniana Lamb and BL = mixed broadleaved softwood) during www.selleckchem.com/products/Belinostat.html storm events in 2009. Water quality indicators including turbidity, color, pH chemical oxygen demand (COD), total phosphorus (TP) and total nitrogen (TN) were measured on the water samples collected from different durations of the throughfall and stemflow. The experiment results clearly demonstrated that the water quality of throughfall and stemflow was substantially modified by tree canopy and the effects differed significantly among forest stands. Overall, the canopy water quality effect was significantly stronger in 3 year and 7 year old Eucalyptus stands than in other forest stands. Significant acidification, nutrients enrichment and organic matter accumulation in the throughfall and stemflow were observed in the Eucalyptus forest stands. The throughfall concentrations of COD ranged from 86 +/- 10 to 894 +/- 106 mg L-1 and TN ranged from 0.29 +/- 0.03 to 3.1 +/- 1.0 mg L-1 for different rainfall events on 3 year-old Eucalyptus, which showed the strongest overall effect. Similar patterns were also observed on stemflow water quality but the effects were more pronounced.

01) Additionally, Ashvagandharishta administration revealed up-r

01). Additionally, Ashvagandharishta administration revealed up-regulation in antioxidant genes

such as CAT and GPx in liver with concomitant down-regulation in proinflammatory IL-6gene (p<0.01). Histopathological parameters revealed restoration of normal tissue architecture by both doses of Ashvagandharishta.\n\nConclusions: Consortium of yeasts from Woodfordia fruticosa flowers showed better fermentation pattern for Ashvagandharishta produced with acceptable organoleptic properties. Hepatoprotection shown by Ashvagandharishta was mainly through prevention of oxidative damage. Up-regulation of CAT and GPx genes and corresponding down regulation of proinflammatory IL6 gene was revealed as possible mechanism of its action. (C) 2013 Elsevier Ireland Ltd. All rights reserved.”
“Site-directed mutants of the gene encoding selleck kinase inhibitor wild-type Vitreoscilla hemoglobin were made that changed Tyr29 (B10) of the wild-type Vitreoscilla hemoglobin (VHb) to either Phe or Ala. The wild-type and the two mutant hemoglobins were expressed in Escherichia coli and purified to homogeneity. The binding of the two mutants to CO was essentially identical to that of wild-type VHb as determined by CO-difference spectra. Circular-dichroism spectra also showed the two mutants to be essentially the same as wild-type VHb regarding overall helicity. All three VHbs were

crystallized and their structures were determined at resolutions of 1.71.9 Hydroxylase inhibitor angstrom, which are similar to that of the original wild-type structure determination. The Tyr29Phe mutant has a structure that is essentially indistinguishable from that of the wild type. However, the structure of the Tyr29Ala mutant has significant differences from that of the wild type. In addition, for the Tyr29Ala mutant it was possible to determine the positions of most of the residues in the D region, which was disordered in the originally reported structure of wild-type VHb as well as in the wild-type VHb structure reported here. In the Tyr29Ala mutant, the five-membered ring of proline E8 (Pro54) occupies

the space occupied by the aromatic Luminespib order ring of Tyr29 in the wild-type structure. These results are discussed in the context of the proposed role of Tyr29 in the structure of the oxygen-binding pocket.”
“Moderate alcohol consumption (one to two drinks per day) has been associated with better cognitive function and lower risk of developing dementia in the elderly. In light of alcohol’s well-known neurotoxic properties, more evidence from well-controlled population-based studies is required. The objective of this study was to examine whether self-reported alcohol intake at age 70 is linked to cognitive function (assessed by trail making tests (TMTs) A and B, which are measures of attention, mental speed, and flexibility) in a population-based cohort consisting of 652 cognitively healthy elderly men. Linear regression models were used to assess both cross-sectional (i.e., age 70) and prospective (i.e.

The Selleckchem CD

The see more first-aid unit should make full preparations after organization, and its service process should be flexible to adapt to the needs of medical assistant mission.”
“The genus Rhodomantis Giglio-Tos is revised. A total of nine species are recognised. Seven new species, R. helenae, R. kimberley, R. macula, R. microptera, R. mitchell, R. napier, and R. rentzi are described. Rhodomantis carinicollis Werner and R. gracilis Tindale are new synonyms of R. queenslandica Sjostedt.”
“The Sable Gully is the largest submarine canyon along the shelf break off the east coast of North America. The circulation and hydrography in the Gully have significant temporal

and spatial variability. This paper presents a numerical study of the three-dimensional circulation and hydrography in the Gully using a multi-nested ocean circulation model. The model is

forced by tides, wind stress and surface heat/freshwater fluxes. Model results are in fair agreement with the current and hydrographic observations made in the Gully in 2006 and 2007. A process study is conducted to examine the main physical processes affecting the circulation and hydrography, including tide-topography interaction, wind forcing, and the shelf-scale circulation over the eastern Canadian Shelf. The model results demonstrate that the circulation and hydrography above the canyon rim are influenced significantly by

CDK inhibitor wind, particularly during storm events, while the subsurface flow over the shelf slope is affected by the shelf-scale circulation. There is also significant tide-topography interaction inside the Gully. (C) 2013 Elsevier Ltd. E1 Activating inhibitor All rights reserved.”
“Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are generally considered to be distinct and easily differentiated neurologic conditions. However, there are case reports of the co-occurrence of ALS with HD. We present a 57-year-old male with a clinical diagnosis of sporadic ALS in the context of a family history of HD. This case adds to the limited literature regarding individuals with a family history of HD who present with features of ALS. There were several genetic counseling challenges in counseling this patient including the diagnostic consideration of two fatal conditions, complex risk information, the personal and familial implications, and the patient’s inability to communicate verbally or through writing due to disease progression. DNA banking effectively preserved the right of our patient and his wife not to learn his HD genetic status during a stressful time of disease progression while providing the option for family members to learn this information in the future if desired. We present lessons learned and considerations for other clinical genetics professionals who are presented with similar challenging issues.

We conclude that non-type A fusions associate with distinctclinic

We conclude that non-type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile. (Blood. 2013;121(2):385-391)”
“The aim of this study was to examine how adults processed common fractions with common numerators under two distinct conditions. Whereas participants were presented with only common fractions in a “simple” condition, a “complex” condition involved the random presentation of common fractions

as well as decimal fractions. In both find more conditions, participants were required to assess whether various “target” fractions were larger than or smaller than a “standard” common fraction (1/5). Behavioral results indicated that under both conditions, participants mentally processed the fractions componentially in terms of their constituent parts rather than holistically in terms of the numerical value of the fraction as a whole. The data provided by the event-related potentials (ERPs) demonstrated electrophysiological correlates of the componential processing of common

fractions in the simple condition, as reflected in the latency and amplitude of P3. However, in contrast to what the behavioral data showed, there was no strong electrophysiological evidence to indicate that common fractions were accessed componentially in the complex condition. In addition, the complex condition was linked to longer latency and more negative amplitude of N2 over the frontal PP2 Angiogenesis inhibitor scalp than the simple condition, which could be attributed to the fact that the comparison of fractions in the complex condition involved task switching and thus was WH-4-023 research buy more taxing on cognitive control than the simple condition.”
“Glycerol dialkyl glycerol tetraethers (GDGTs) found in hot springs reflect the abundance and community structure of Archaea in these extreme environments. The relationships between GDGTs, archaeal communities, and physical or geochemical variables are underexamined

to date and when reported often result in conflicting interpretations. Here, we examined profiles of GDGTs from pure cultures of Crenarchaeota and from terrestrial geothermal springs representing a wide distribution of locations, including Yellowstone National Park (United States), the Great Basin of Nevada and California (United States), Kamchatka (Russia), Tengchong thermal field (China), and Thailand. These samples had temperatures of 36.5 to 87 degrees C and pH values of 3.0 to 9.2. GDGT abundances also were determined for three soil samples adjacent to some of the hot springs. Principal component analysis identified four factors that accounted for most of the variance among nine individual GDGTs, temperature, and pH. Significant correlations were observed between pH and the GDGTs crenarchaeol and GDGT-4 (four cyclopentane rings, m/z 1,294); pH correlated positively with crenarchaeol and inversely with GDGT-4.

Lowest observed effect concentrations (LOEC) and 100% lethal conc

Lowest observed effect concentrations (LOEC) and 100% lethal concentrations (LC100) data were collected from the scientific literature. Comparisons were made amon Data on low dissolved oxygen (DO2) tolerance of freshwater fish species of north-western Eurg life stages as well as between native and exotic species. In addition, lethal DO2 concentrations were compared to oxygen concentrations corresponding to maximum tolerable water temperatures of the same species. Fish eggs and embryos were the least tolerant. Juveniles had a significantly Ulixertinib datasheet lower mean LOEC than adults,

but there was no difference in mean LC100 between the two groups. The difference in lethal oxygen concentrations between adults and juveniles was largest for three salmonids,

although it remains uncertain if this was a result of smoltification. There were no significant differences between native and exotic species; however, data on exotics are limited. DO2 concentrations converted from maximum tolerable water temperatures were 39 times higher than the measured lethal DO2 concentrations, which may reflect changes in respiration rates (Q(10)) and may also relate to the Ruboxistaurin nmr simplicity of the model used. (C) 2013 The Authors Journal of Fish Biology (C) 2013 The Fisheries Society of the British Isles”
“Introduction: PrestoBlue is a new resazurin based reagent to assess cell viability and cytotoxicity. It is claimed to be a fast and highly sensitive assay. Here, we compared PrestoBlue, alamarBlue, and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoniumbromide (MTT) in assessing cell viability of human corneal epithelial cells (HCEC), and investigated the NSC23766 mw effect of plate color, reading mode, and plate storage on the performance of PrestoBlue assay. Methods: The viability of different numbers of healthy HCEC and the toxicity of various chemicals on HCEC were evaluated

using PrestoBlue (fluorescence), alamarBlue (fluorescence), and MTT (absorbance). The sensitivities of the three assays were compared. In the PrestoBlue assay, three plate colors and two reading modes were used and compared in assessing the toxic effect of sodium dodecyl sulfate (SDS). The PrestoBlue solutions after reaction were stored and measured on day 1, 2, 3, 5, and 7. The fluorescence readings obtained on different days were then compared. Results: Both PrestoBlue and alamarBlue were able to detect 5000 healthy cells after 30 min incubation and 1000 cells after 1 h, 2 h, and 4 h incubation; while MTT was able to detect 5000 cells after 3 h incubation. In the assessment of the toxicity of various chemicals, PrestoBlue and alamarBlue performed similarly. There was no significant difference between the results obtained by these two reagents. All the three plate colors and two reading modes showed similar results in the PrestoBlue assay in assessing the toxicity of SDS. Plate storage up to 7 days did not affect the result of the PrestoBlue assay.

Muscle stretching (sinusoidal half-waves of different amplitudes

Muscle stretching (sinusoidal half-waves of different amplitudes and combinations of such waves) allowed us to obtain well-reproducible

successions of impulses with no significant changes in the resting MP of the studied motoneurons. In 14 of such cells, we found NCT-501 cost significant correlation between normalized variations of the instantaneous frequency (in a sequence of preceding and subsequent action potentials, APs), indicative of a considerable probability of alternation of high and low values of this parameter. The same trend (toward alternation of high and low values) was observed in successive magnitudes of afterhyperpolarization (AH) that followed APs. Between the values of the extrema of AH trajectories and values of the instantaneous frequency of impulsation, we observed significant negative correlation. The mechanisms underlying the formation of

AH in spinal motoneurons and also the effects of this hyperpolarization on the characteristics of impulse activity generated by these cells are discussed.”
“Pyomyositis, a subacute bacterial infection of muscles, is uncommon in children. Three children with pyomyositis and multiple abscesses caused by Staphylococcus aureus are reported. The intercostal muscles were involved in one case, the paraspinal muscles in another and in the third there was associated septic arthritis.”
“An emotional version of Sapir-Whorf hypothesis suggests that differences in language emotionalities influence differences among find more cultures no less than conceptual differences. Conceptual contents of languages and Cultures to significant extent are determined by words and their semantic differences; these could be borrowed among languages and exchanged among cultures. Emotional

differences, as suggested in the paper, are related to grammar and mostly cannot be borrowed. The paper considers conceptual selleck chemicals and emotional mechanisms of language along with their role in the mind and Cultural evolution. Language evolution from primordial undifferentiated animal cries is discussed: while conceptual contents increase, emotional reduced. Neural mechanisms of these processes are suggested as well as their mathematical models: the knowledge instinct, the dual model connecting language and cognition, neural modeling fields, Mathematical results are related to cognitive science, linguistics, and psychology. Experimental evidence and theoretical arguments are discussed. Dynamics of the hierarchy-heterarchy Of human minds and cultures is formulated using mean-field approach and approximate equations are obtained. The knowledge instinct operating in the mind heterarchy leads to mechanisms of differentiation and synthesis determining ontological development and cultural evolution.