Comparison of carbonate C and O stable isotope records across the Jurassic/Cretaceous boundary in the Tethyan and Boreal Realms

Carbon and oxygen stable isotope records were compared for Jurassic/Cretaceous (J/K) boundary sections located in the Tethyan Realm (Brodno, Western Slovakia, and Puerto Escaño, Southern Spain; bulk limestones), and the Boreal Realm (Nordvik Peninsula, Northern Siberia, belemnites). Since a detailed biostratigraphic correlation of these Tethyan and Boreal sections is impossible due to different faunal assemblages, correlation of the isotope records was based on paleomagnetic data. This novel approach can improve our understanding of the synchroneity of individual isotope excursions in sections where detailed biostratigraphic correlation is impossible. No significant excursions in either the carbon or oxygen isotope records to be used for future Boreal/Tethyan correlations were found around the J/K boundary (the upper Tithonian and lower Berriasian; magnetozones M20n to M18n) in the studied sections. At the Nordvik section, where a much longer section (middle Oxfordian–basal Boreal Berriasian) was documented, the transition from the middle Oxfordian to the Kimmeridgian and further to the Volgian is characterized by a decrease in belemnite δ¹⁸O values (from δ¹⁸O values up to + 1.6‰ vs. V-PDB in the Oxfordian to values between + 0.3 and ? 0.8‰ in the late Volgian and earliest Boreal Berriasian). This trend, which has previously been reported from the Russian Platform and Tethyan Realm sections, corresponds either to gradual warming or a decrease in seawater δ¹⁸O. Supposing that the oxygen isotope compositions of seawater in the Arctic/Boreal and Tethyan Realms were similar, then the differences between oxygen isotope datasets for these records indicate differences in temperature. The Boreal/Tethyan temperature difference of 7–9 °C in the middle and late Oxfordian decreases towards the J/K boundary, indicating a significant decrease in latitudinal climatic gradients during the Late Jurassic. Two positive carbon isotope excursions recorded for the middle Oxfordian and upper Kimmeridgian in the Nordvik section can be correlated with a similar excursion described earlier for the Russian Platform. Minor influence of biofractionation at the carbon isotopes, and the influence of migration of belemnites to deeper, slightly cooler water at the oxygen isotopes, cannot be excluded for the obtained belemnite data.     

Phenylpiperidine-type γ-secretase modulators target the transmembrane domain 1 of presenilin 1

Amyloid-β peptide ending at the 42nd residue (Aβ42) is implicated in the pathogenesis of Alzheimer's disease (AD). Small compounds that exhibit selective lowering effects on Aβ42 production are termed γ-secretase modulators (GSMs) and are deemed as promising therapeutic agents against AD, although the molecular target as well as the mechanism of action remains controversial. Here, we show that a phenylpiperidine-type compound GSM-1 directly targets the transmembrane domain (TMD) 1 of presenilin 1 (PS1) by photoaffinity labelling experiments combined with limited digestion. Binding of GSM-1 affected the structure of the initial substrate binding and the catalytic sites of the γ-secretase, thereby decreasing production of Aβ42, possibly by enhancing its conversion to Aβ38. These data indicate an allosteric action of GSM-1 by directly binding to the TMD1 of PS1, pinpointing the target structure of the phenylpiperidine-type GSMs.     

Vaginal irritation models: the current status of available alternative and in vitro tests

Mucosal surfaces, such as the vaginal epithelium, are natural barriers to infection that are constantly exposed to bacteria and viruses, and are therefore potential sites of entry for numerous pathogens. The vaginal epithelium can be damaged mechanically, e.g. by the incorrect use of objects such as tampons, and by chemicals that are irritating or corrosive. Consequently, this can lead to an increase in susceptibility to further damage or infection. Pharmaceutical, cosmetic and personal care products that are specifically formulated for application onto human external mucosae can occasionally induce undesirable local or systemic side-effects. Therefore, the compatibility of applied materials with this mucosal surface represents a key issue to be addressed by manufacturers. The most frequently used method for assessing vaginal mucosal irritation is the in vivo rabbit vaginal irritation test. However, the current emphasis in the field of toxicology is to use alternative in vitro methods that reduce, refine, and replace the use of animals, and which model and predict human, not animal, responses. Such an approach is of particular interest to the personal care and cosmetic industries in their effort to comply with European legislative measures, such as the 7th Amendment to the EU Cosmetics Directive that does not permit the marketing of cosmetic products if they, or their ingredients, have been tested for irritation responses in animals. The focus of this review is to provide an overview of the alternative and in vitro tests that are currently available for vaginal mucosal irritation assessment, and which are already used, or may become useful, to establish the safety of newly-designed products for human use.     

Role of Acetylcholinesterase on the Structure and Function of Cholinergic Synapses: Insights Gained from Studies on Knockout Mice

Electrophysiological and ultrastructural studies were performed on phrenic nerve-hemidiaphragm preparations isolated from wild-type and acetylcholinesterase (AChE) knockout (KO) mice to determine the compensatory mechanisms manifested by the neuromuscular junction to excess acetylcholine (ACh). The diaphragm was selected since it is the primary muscle of respiration, and it must adapt to allow for survival of the organism in the absence of AChE. Nerve-elicited muscle contractions, miniature endplate potentials (MEPPs) and evoked endplate potentials (EPPs) were recorded by conventional electrophysiological techniques from phrenic nerve-hemidiaphragm preparations isolated from 1.5- to 2-month-old wild-type (AChE^+/+) or AChE KO (AChE^−/−) mice. These recordings were chosen to provide a comprehensive assessment of functional alterations of the diaphragm muscle resulting from the absence of AChE. Tension measurements from AChE^−/− mice revealed that the amplitude of twitch tensions was potentiated, but tetanic tensions underwent a use-dependent decline at frequencies below 70 Hz and above 100 Hz. MEPPs recorded from hemidiaphragms of AChE^−/− mice showed a reduction in frequency and a prolongation in decay (37%) but no change in amplitude compared to values observed in age-matched wild-type littermates. In contrast, MEPPs recorded from hemidiaphragms of wild-type mice that were exposed for 30 min to the selective AChE inhibitor 5-bis(4-allyldimethyl-ammoniumphenyl)pentane-3-one (BW284C51) exhibited a pronounced increase in amplitude (42%) and a more marked prolongation in decay (76%). The difference between MEPP amplitudes and decays in AChE^−/− hemidiaphragms and in wild-type hemidiaphragms treated with BW284C51 represents effective adaptation by the former to a high ACh environment. Electron microscopic examination revealed that diaphragm muscles of AChE^−/− mice had smaller nerve terminals and diminished pre- and post-synaptic surface contacts relative to neuromuscular junctions of AChE^+/+ mice. The morphological changes are suggested to account, in part, for the ability of muscle from AChE^−/− mice to function in the complete absence of AChE.     

Worldwide host plants of the highly polyphagous, invasive Epiphyas postvittana (Lepidoptera: Tortricidae)

The light brown apple moth, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae), is a highly successful biological invader. It was accidentally introduced to several countries including New Zealand, Hawaii, England, and California. Light brown apple moth attacks a wide range of crop plants and other woody and herbaceous plants, but a more comprehensive analysis of its host range is needed for risk assessments, to evaluate the likely economic and environmental impacts, and to enable targeting of particular plant species for detection surveys and treatments. We reviewed and synthesized the host range and host selection behavior of light brown apple moth by using information from Australia and invaded countries. The host range of light brown apple moth is determined by the behavior of both adult females and larvae. Females use visual, chemical and physical cues to choose host plants. Larvae are capable of limited active dispersal by walking and longer range dispersal by ballooning on silken strands; therefore, larvae also may need to select host plants. We review larval performance indicators across a range of plants. Based on our review, there are at least 545 plant species in 363 genera from 121 families that have been reported as hosts of light brown apple moth. Some plants were reported only once and need verification. Nevertheless, many host plant species and their wide phylogenetic range (from ferns to higher dicotyledons) indicates that light brown apple moth is one of the most polyphagous insects known. This information and our categorization of frequency of host use are valuable for incursion response and pest management activities.     

N-cadherin enhances APP dimerization at the extracellular domain and modulates Aβ production

Sequential processing of amyloid precursor protein (APP) by β- and γ-secretase leads to the generation of amyloid-β (Aβ) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Aβ production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Aβ production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of Aβ as well as soluble APPβ, indicating that β-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Aβ production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Aβ production.     

Effects of ethylene oxide and ethylene inhalation on DNA adducts, apurinic/apyrimidinic sites and expression of base excision DNA repair genes in rat brain, spleen, and liver

Ethylene oxide (EO) is an important industrial chemical that is classified as a known human carcinogen (IARC, Group 1). It is also a metabolite of ethylene (ET), a compound that is ubiquitous in the environment and is the most used petrochemical. ET has not produced evidence of cancer in laboratory animals and is "not classifiable as to its carcinogenicity to humans" (IARC, Group 3). The mechanism of carcinogenicity of EO is not well characterized, but is thought to involve the formation of DNA adducts. EO is mutagenic in a variety of in vitro and in vivo systems, whereas ET is not. Apurinic/apyrimidinic sites (AP) that result from chemical or glycosylase-mediated depurination of EO-induced DNA adducts could be an additional mechanism leading to mutations and chromosomal aberrations. This study tested the hypothesis that EO exposure results in the accumulation of AP sites and induces changes in expression of genes for base excision DNA repair (BER). Male Fisher 344 rats were exposed to EO (100 ppm) or ET (40 or 3000 ppm) by inhalation for 1, 3 or 20 days (6h/day, 5 days a week). Animals were sacrificed 2h after exposure for 1, 3 or 20 days as well as 6, 24 and 72 h after a single-day exposure. Experiments were performed with tissues from brain and spleen, target sites for EO-induced carcinogenesis, and liver, a non-target organ. Exposure to EO resulted in time-dependent increases in N7-(2-hydroxyethyl)guanine (7-HEG) in brain, spleen, and liver and N7-(2-hydroxyethyl)valine (7-HEVal) in globin. Ethylene exposure also induced 7-HEG and 7-HEVal, but the numbers of adducts were much lower. No increase in the number of aldehydic DNA lesions, an indicator of AP sites, was detected in any of the tissues between controls and EO-, or ET-exposed animals, regardless of the duration or strength of exposure. EO exposure led to a 3-7-fold decrease in expression of 3-methyladenine-DNA glycosylase (Mpg) in brain and spleen in rats exposed to EO for 1 day. Expression of 8-oxoguanine DNA glycosylase, Mpg, AP endonuclease (Ape), polymerase beta (Pol beta) and alkylguanine methyltransferase were increased by 20-100% in livers of rats exposed to EO for 20 days. The only effects of ET on BER gene expression were observed in brain, where Ape and Pol beta expression were increased by less than 20% after 20 days of exposure to 3000 ppm. These data suggest that DNA damage induced by exposure to EO is repaired without accumulation of AP sites and is associated with biologically insignificant changes in BER gene expression in target organs. We conclude that accumulation of AP sites is not a likely primary mechanism for mutagenicity and carcinogenicity of EO.