Processive Recoding and Metazoan Evolution of Selenoprotein P: Up to 132 UGAs in Molluscs.

Selenoproteins typically contain a single selenocysteine, the 21st amino acid, encoded by a context-redefined UGA. However, human selenoprotein P (SelenoP) has a redox-functioning selenocysteine in its N-terminal domain and nine selenium transporter-functioning selenocysteines in its C-terminal domain. Here we show that diverse SelenoP genes are present across metazoa with highly variable numbers of Sec-UGAs, ranging from a single UGA in certain insects, to 9 in common spider, and up to 132 in bivalve molluscs. SelenoP genes were shaped by a dynamic evolutionary process linked to selenium usage. Gene evolution featured modular expansions of an ancestral multi-Sec domain, which led to particularly Sec-rich SelenoP proteins in many aquatic organisms. We focused on molluscs, and chose Pacific oyster Magallana gigas as experimental model. We show that oyster SelenoP mRNA with 46 UGAs is translated full-length in vivo. Ribosome profiling indicates that selenocysteine specification occurs with ∼5% efficiency at UGA1 and approaches 100% efficiency at distal 3' UGAs. We report genetic elements relevant to its expression, including a leader open reading frame and an RNA structure overlapping the initiation codon that modulates ribosome progression in a selenium-dependent manner. Unlike their mammalian counterparts, the two SECIS elements in oyster SelenoP (3'UTR recoding elements) do not show functional differentiation in vitro. Oysters can increase their tissue selenium level up to 50-fold upon supplementation, which also results in extensive changes in selenoprotein expression.

How patients with multiple sclerosis weigh treatment risks and benefits.

OBJECTIVE: Although the effectiveness and risks of multiple sclerosis (MS) therapies are established, relatively little is known about how these benefits and risks are perceived and weighed by patients. This risk-benefit trade-off is important for clinicians, industry, and regulators to consider when determining which therapies to develop, approve for clinical use, and recommend to individual patients. The primary objective of the present study was to describe individual differences in how MS patients weigh risks and benefits when making treatment decisions. METHOD: Two hundred ninety patients with MS completed tasks assessing their willingness to take a hypothetical disease-modifying therapy (DMT) at varying levels of efficacy, side effect probability, and side effect severity. Patients also completed questionnaires assessing MS knowledge, medication beliefs, health care climate, and disease severity. RESULTS: Patients with a primary progressive course reported increased DMT willingness compared to patients with relapsing-remitting and secondary progressive courses. Patients were less willing to initiate a DMT across a range of efficacies and side effects if they had never taken a DMT, reported more complementary and alternative health beliefs, or reported a history of discontinuing DMTs due to side effects. More MS knowledge was associated with more willingness to initiate a DMT. CONCLUSIONS: The results represent an initial step in understanding how patients with chronic disease balance the risks and benefits of medication initiation. Extension of this research may have implications for pharmaceutical development, physician-patient interaction, adherence intervention, and disease education. (PsycINFO Database Record

Assessment of the effects of sulfated polysaccharides extracted from the red seaweed Irish moss Chondrus crispus on the immune-stimulant activity in mussels Mytilus spp.

Seaweeds contain a number of health enhancing and antimicrobial bioactive compounds including sulfated polysaccharides (SP). In the present study, SP extracted from a European red seaweed Irish moss Chondrus crispus was chemically analyzed, SP content extracted and the immune-response effect on wild Irish mussels Mytilus spp. investigated for the first time. A high percent yield of SP was extracted from C. crispus and the immune-stimulant activity of SP was assessed in a laboratory trial with mussels exposed to three different treatments of low (10 µg mL-1), medium (20 µg mL-1) and high (50 µg mL-1) SP dose concentrations and a control mussel group with no exposure to SP. An initial mussel sample was processed prior to the trial commencing and mussels were subsequently sampled on Days 1, 2, 3, 4, 7, and 10 post SP exposure. Both cell, humoral and immune related gene responses including haemocyte cell viability, haemocyte counts, lysozyme activity and expression of immune related genes (defensin, mytimycin and lysozyme mRNA) were assessed. No mussel mortalities were observed in either the treated or non-treated groups. Mussels exposed with SP showed an increase in haemocyte cell viability and the total number of haemocytes compared to control mussels. Lysozyme activity was also higher in treated mussels. Additionally, up-regulated expression of defensin, mytimycin and lysozyme mRNA was observed in SP treated mussels shortly after exposure (on Days 1, 2, and 3) to SP. These results indicate that a high quality yield of SP can be readily extracted from C. crispus and more importantly based on the animal model used in this study, SP extracted from C. crispus can rapidly induce health enhancing activities in Mytilus spp. at a cellular, humoral and molecular level and with a prolonged effect up to ten days post treatment.

Iron chelation and multiple sclerosis.

Histochemical and MRI studies have demonstrated that MS (multiple sclerosis) patients have abnormal deposition of iron in both gray and white matter structures. Data is emerging indicating that this iron could partake in pathogenesis by various mechanisms, e.g., promoting the production of reactive oxygen species and enhancing the production of proinflammatory cytokines. Iron chelation therapy could be a viable strategy to block iron-related pathological events or it can confer cellular protection by stabilizing hypoxia inducible factor 1α, a transcription factor that normally responds to hypoxic conditions. Iron chelation has been shown to protect against disease progression and/or limit iron accumulation in some neurological disorders or their experimental models. Data from studies that administered a chelator to animals with experimental autoimmune encephalomyelitis, a model of MS, support the rationale for examining this treatment approach in MS. Preliminary clinical studies have been performed in MS patients using deferoxamine. Although some side effects were observed, the large majority of patients were able to tolerate the arduous administration regimen, i.e., 6-8 h of subcutaneous infusion, and all side effects resolved upon discontinuation of treatment. Importantly, these preliminary studies did not identify a disqualifying event for this experimental approach. More recently developed chelators, deferasirox and deferiprone, are more desirable for possible use in MS given their oral administration, and importantly, deferiprone can cross the blood-brain barrier. However, experiences from other conditions indicate that the potential for adverse events during chelation therapy necessitates close patient monitoring and a carefully considered administration regimen.

Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects.

T cells are important mediators of autoimmune inflammation in relapsing-remitting multiple sclerosis (RRMS). Previous studies found that deferiprone, an iron chelator, suppressed disease activity in a mouse model of multiple sclerosis, and inhibition of T cell proliferation was implicated as a putative mechanism. The objective of the present study was to examine the effects of deferiprone on suppressing in vitro responses of T cells from control and RRMS subjects. Peripheral blood T cells were co-stimulated with anti-CD3+anti-CD28 and cultured with or without interleukin 2 (IL-2). Proliferating CD4+ T cells from control and RRMS subjects, cultured with or without IL-2, decreased in response to 75 µM deferiprone, although the extent of decreased proliferation of CD4+ T cells from RRMS subjects was less than for control subjects. Proliferating CD8+ T cells from control subjects, cultured with or without IL-2, also decreased in response to 75 µM deferiprone, and this decrease was seen in proliferating CD8+ T cells from RRMS cultured with IL-2. CD4+CD25+ and CD8+CD25+ cells from control subjects, cultured with or without IL-2, declined in 75 µM deferiprone, but the decrease was smaller than for the CD4+ and CD8+ proliferative responses. CD4+CD25+ and CD8+CD25+ cells from RRMS subjects showed more variability than for control subjects, but CD4+CD25+ cultured with IL-2 and CD8+CD25+ cells cultured without IL-2 significantly declined in 75 µM deferiprone. CD4+FoxP3+ and CD4+CD25+FoxP3+ cells tended to remain constant or increase. In summary, deferiprone induced declines in proliferative responses at a dosage that is within peak serum pharmacological concentrations.

Evaluating processing speed in multiple sclerosis: a comparison of two rapid serial processing measures.

Processing speed deficits in patients with multiple sclerosis (MS) are usually assessed with tests requiring rapid serial processing. Two such tests were compared here, the Paced Auditory Serial Addition Test (PASAT) and a computerized version of the Stroop test. The purpose of this study was to examine the concurrent validity of processing speed measures derived from the Stroop test and to relate these measures to disability ratings in a sample of 75 patients with relapsing-remitting MS. Patients evidenced slower processing speed than controls on both tests. Processing speed scores on the Stroop test were more closely related to patients' disability status. These results demonstrate the usefulness of rapid serial processing tests in assessing what is increasingly recognized as the primary cognitive deficit in MS. A less-distressing approach than the item-paced performance required by the PASAT appears to be fully adequate for evaluating this deficit.

Omega-3 fatty acids and multiple sclerosis: relationship to depression.

Depression is a common problem among patients with multiple sclerosis (MS). Previous research has shown differences between MS patients and controls in the levels of certain fatty acids, and differences in many of these same fatty acids have also been reported in psychiatric patients with major depression. The current study sought to determine whether fatty acid levels in MS patients might be associated with depression. Fatty acids were measured in red blood cells (RBCs) for 38 patients with relapsing-remitting MS and 33 healthy controls who also completed 3-day dietary records and depression questionnaires. Levels of certain omega-3 and omega-6 fatty acids were lower and levels of certain monounsaturated and saturated fatty acids were higher in the MS patients. These differences were generally of medium effect size and occurred despite the fact that no differences were found between the two groups in dietary intake of any fatty acids. However, neither RBC nor dietary fatty acid levels were related to depression in the MS sample.