A dynamic model of proliferation and differentiation in the intestinal crypt based on a hypothetical intraepithelial growth factor

A widely accepted model of the temporal and spatial organization of proliferation and differentiation in intestinal epithelia is based on a cellular pedigree with all cells descending from a few active stem cells and undergoing a sequence of transitory divisions until the non-proliferating maturing cell stages develop. Model simulations have shown that such a pedigree concept can explain a large variety of data. However, so far there is neither a direct experimental proof for the existence of an intrinsic age structure in the transitory proliferative cell stages nor for the distinction between stem and transitory cells. It is our objective to suggest an alternative model which is based on evidence for intercellular communications such as might be mediated through gap junctions. We consider the diffusion of a hypothetical intraepithelial growth factor in a chain of cells which are connected via gap junctions. Individual cells can divide if a critical growth factor concentration is exceeded. Simulation studies show that the model is consistent with many observed features of the small intestinal crypt in steady state and after perturbation.     

Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype

Background and Purpose  

The impact of traumatic brain injury (TBI) on the pathogenesis of Alzheimer disease (AD) is still controversial. The aim of our retrospective autopsy study was to assess the impact of TBE and ApoE allele frequency on the development of AD.     

Diversity of saprobic microfungi

The data needed to derive an accurate estimate of saprobic microfungi are insufficient, incomplete and contradictory. We therefore address issues that will ultimately reveal whether there are 1.5 million global fungal species, which is the generally accepted working estimate. Our data indicates that large numbers of fungi occur on host families, such as Musaceae, host genera such as Nothofagus and individual host species such as Eucalyptus globulus, and that fungi may be specific or recurrent on different plant groups. Recent studies have shown that fungal numbers on hosts may be larger than originally thought as saprobes are organ-specific/-recurrent and changes in fungal communities occur as substrata decays. Other issues, such as the impact of geography, of methodology and of taxonomy are also addressed. There is evidence that fungi on the same host at different locations also differs; site-specific factors and geographic distance may be more important than host/substrate in shaping fungal assemblages. Methodology impacts on estimates of species diversity with many more taxa observed using indirect isolation protocols as compared to direct isolations from leaves. Our understanding of fungal species numbers in speciose genera is important. In some fungal groups accepted species have been reduced to a few species, while in other groups many cryptic species are being uncovered. While we make a number of generalisations from the studies reported here, this review also highlights some of the limitations mycologists currently have to contend with. A large body of knowledge exists for certain groups of microfungi or for microfungi occurring on certain substrata/hosts. However, it is likely that we are drawing conclusions from data that are somewhat biased toward fungi and host/substrata that are of interest to human endeavours. The discrepancy between the numbers of fungi described from only one economically important genus, Eucalyptus, and all the other members of the Myrtaceae is but one example of this bias. By incorporating the large body of work that is already available and adding appropriate complementary studies, we can accelerate our understanding of microfungal diversity and this will eventually lead us to a realistic estimate of global fungal species numbers.     

Histone h3 lysine 4 methylation marks postreplicative human cytomegalovirus chromatin

In the nuclei of permissive cells, human cytomegalovirus genomes form nucleosomal structures initially resembling heterochromatin but gradually switching to a euchromatin-like state. This switch is characterized by a decrease in histone H3 K9 methylation and a marked increase in H3 tail acetylation and H3 K4 methylation across the viral genome. We used ganciclovir and a mutant virus encoding a reversibly destabilized DNA polymerase to examine the impact of DNA replication on histone modification dynamics at the viral chromatin. The changes in H3 tail acetylation and H3 K9 methylation proceeded in a DNA replication-independent fashion. In contrast, the increase in H3 K4 methylation proved to depend widely on viral DNA synthesis. Consistently, labeling of nascent DNA using "click chemistry" revealed preferential incorporation of methylated H3 K4 into viral (but not cellular) chromatin during or following DNA replication. This study demonstrates largely selective epigenetic tagging of postreplicative human cytomegalovirus chromatin.     

Oxoferryl-porphyrin radical catalytic intermediate in cytochrome bd oxidases protects cells from formation of reactive oxygen species

The quinol-linked cytochrome bd oxidases are terminal oxidases in respiration. These oxidases harbor a low spin heme b(558) that donates electrons to a binuclear heme b(595)/heme d center. The reaction with O(2) and subsequent catalytic steps of the Escherichia coli cytochrome bd-I oxidase were investigated by means of ultra-fast freeze-quench trapping followed by EPR and UV-visible spectroscopy. After the initial binding of O(2), the O-O bond is heterolytically cleaved to yield a kinetically competent heme d oxoferryl porphyrin π-cation radical intermediate (compound I) magnetically interacting with heme b(595). Compound I accumulates to 0.75-0.85 per enzyme in agreement with its much higher rate of formation (~20,000 s(-1)) compared with its rate of decay (~1,900 s(-1)). Compound I is next converted to a short lived heme d oxoferryl intermediate (compound II) in a phase kinetically matched to the oxidation of heme b(558) before completion of the reaction. The results indicate that cytochrome bd oxidases like the heme-copper oxidases break the O-O bond in a single four-electron transfer without a peroxide intermediate. However, in cytochrome bd oxidases, the fourth electron is donated by the porphyrin moiety rather than by a nearby amino acid. The production of reactive oxygen species by the cytochrome bd oxidase was below the detection level of 1 per 1000 turnovers. We propose that the two classes of terminal oxidases have mechanistically converged to enzymes in which the O-O bond is broken in a single four-electron transfer reaction to safeguard the cell from the formation of reactive oxygen species.     

The importance of timing in segregated theta phase-coupling for cognitive performance

Functional cortical circuits for central executive functions have been shown to emerge by theta (~6 Hz) phase-coupling of distant cortical areas. It has been repeatedly shown that frontoparietal theta coupling at ~0° relative phase is associated with recognition, encoding, short-term retention, and planning; however, a causal link has not been demonstrated so far. Here we used transcranial alternating current stimulation simultaneously applied at 6 Hz over left prefrontal and parietal cortices with a relative 0° ("synchronized" condition) or 180° ("desynchronized" condition) phase difference or a placebo stimulation condition, whereas healthy subjects performed a delayed letter discrimination task. We show that exogenously induced frontoparietal theta synchronization significantly improves visual memory-matching reaction times as compared to placebo stimulation. In contrast, exogenously induced frontoparietal theta desynchronization deteriorates performance. The present findings provide for the first time evidence of causality of theta phase-coupling of distant cortical areas for cognitive performance in healthy humans. Moreover, the results demonstrate the suitability of transcranial alternating current stimulation to artificially induce coupling or decoupling of behaviorally relevant brain rhythms between segregated cortical regions.