Frobenius Splittings

We give a gentle introduction to Frobenius splittings. Then we recall a few results that have been obtained with the method.Comment: 21 pages, typos correcte

Associations between DSM-IV diagnosis, psychiatric symptoms and morning cortisol levels in a community sample of adolescents

Purpose. Dysfunction of the hypothalamic-pituitary-adrenocortical axis (HPA-axis) is implicated in a variety of psychiatric and emotional disorders. In this study, we explore the association between HPA-axis functioning, as measured by morning cortisol, and common psychiatric disorders and symptoms among a community sample of adolescents. Method. Data from a cross-sectional school-based survey of 501 school pupils, aged 15, were used to establish the strength of association between salivary morning cortisol and both diagnosis of psychiatric disorders and a number of psychiatric symptoms, as measured via a computerised psychiatric interview. Analysis, conducted separately by gender, used multiple regressions, adjusting for relevant confounders. Results-á-áWith one exception (a positive association between conduct disorder symptoms and cortisol among females) there was no association between morning cortisol and psychiatric diagnosis or symptoms. However, there was a significant two-way interaction between gender and conduct symptoms, with females showing a positive and males a negative association between cortisol and conduct symptoms. A further three-way interaction showed that while the association between cortisol and conduct symptoms was negative among males with a few mood disorder symptoms, among females with many mood symptoms it was positive. Conclusions. Except in relation to conduct symptoms, dysregulation of morning cortisol levels seems unrelated to any psychiatric disorder or symptoms. However, the relationship between cortisol and conduct symptoms is moderated by both gender and mood symptoms. Findings are compatible with the recent work suggesting research should concentrate on the moderated associations between gender, internalising and externalising symptoms and cortisol, rather than any simple relationship

Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca2+-activated K+ channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures

Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed

Pore residues critical for μ-CTX binding to rat skeletal muscle Na+ channels revealed by cysteine mutagenesis

We have studied μ-conotoxin (μ-CTX) block of rat skeletal muscle sodium channel (rSkM1) currents in which single amine acids within the pore (P-loop) were substituted with cysteine. Among 17 cysteine mutants expressed in Xenopus oocytes, 7 showed significant alterations in sensitivity to μ- CTX compared to wild-type rSkM 1 channel (IC50- = 17.5 ± 2.8 nM). E758C and D1241C were less sensitive to μ-CTX block (IC50 = 220 ± 39 nM and 112 ± 24 nM, respectively), whereas the tryptophan mutants W402C, W1239C, and W1531C showed enhanced μ-CTX sensitivity (IC50 = 1.9 ± 0.1, 4.9 ± 0.9, and 5.5 ± 0.4 nM, respectively). D400C and Y401C also showed statistically significant yet modest (approximately twofold) changes in sensitivity to μ- CTX block compared to WT (p 1 μM) and increased the IC50 of D1241C by about threefold. Applications of MTSEA, MTSES, and the neutral MTSBN (benzyl methanethiosulfonate) to the tryptophan- to-cysteine mutants partially or fully restored the wild-type μ-CTX sensitivity, suggesting that the bulkiness of the tryptophan's indole group is a determinant of toxin binding. In support of this suggestion, the blocking IC50 of W1531A (7.5 ± 1.3 nM) was similar to W1531C, whereas W1531Y showed reduced toxin sensitivity (14.6 ± 3.5 nM) similar to that of the wild-type channel. Our results demonstrate that charge at positions 758 and 1241 are important for μ-CTX toxin binding and further suggest that the tryptophan residues within the pore in domains I, III, and IV negatively influence toxin-channel interaction.link_to_subscribed_fulltex