The importance of premotor cortex for supporting speech production after left capsular-putaminal damage.

The left putamen is known to be important for speech production, but some patients with left putamen damage can produce speech remarkably well. We investigated the neural mechanisms that support this recovery by using a combination of techniques to identify the neural regions and pathways that compensate for loss of the left putamen during speech production. First, we used fMRI to identify the brain regions that were activated during reading aloud and picture naming in a patient with left putamen damage. This revealed that the patient had abnormally high activity in the left premotor cortex. Second, we used dynamic causal modeling of the patient's fMRI data to understand how this premotor activity influenced other speech production regions and whether the same neural pathway was used by our 24 neurologically normal control subjects. Third, we validated the compensatory relationship between putamen and premotor cortex by showing, in the control subjects, that lower connectivity through the putamen increased connectivity through premotor cortex. Finally, in a lesion-deficit analysis, we demonstrate the explanatory power of our fMRI results in new patients who had damage to the left putamen, left premotor cortex, or both. Those with damage to both had worse reading and naming scores. The results of our four-pronged approach therefore have clinical implications for predicting which patients are more or less likely to recover their speech after left putaminal damage

Regulation of the dystrophin-associated glycoprotein complex composition by the metabolic properties of muscle fibres

The dystrophin-glycoprotein complex (DGC) links the muscle cytoskeleton to the extracellular matrix and is responsible for force transduction and protects the muscle fibres from contraction induced damage. Mutations in components of the DGC are responsible for muscular dystrophies and congenital myopathies. Expression of DGC components have been shown to be altered in many myopathies. In contrast we have very little evidence of whether adaptive changes in muscle impact on DGC expression. In this study we investigated connection between muscle fibre phenotype and the DGC. Our study reveals that the levels of DGC proteins at the sarcolemma differ in highly glycolytic muscle compared to wild-type and that these changes can be normalised by the super-imposition of an oxidative metabolic programme. Importantly we show that the metabolic properties of the muscle do not impact on the total amount of DGC components at the protein level. Our work shows that the metabolic property of a muscle fibre is a key factor in regulating the expression of DGC proteins at the sarcolemma

Selection at a single locus leads to widespread expansion of toxoplasma gondii lineages that are virulent in mice

The determinants of virulence are rarely defined for eukaryotic parasites such as T. gondii, a widespread parasite of mammals that also infects humans, sometimes with serious consequences. Recent laboratory studies have established that variation in a single secreted protein, a serine/threonine kinase known as ROPO18, controls whether or not mice survive infection. Here, we establish the extent and nature of variation in ROP18among a collection of parasite strains from geographically diverse regions. Compared to other genes, ROP18 showed extremely high levels of diversification and changes in expression level, which correlated with severity of infection in mice. Comparison with an out-group demonstrated that changes in the upstream region that regulates expression of ROP18 led to an historical increase in the expression and exposed the protein to diversifying selective pressure. Surprisingly, only three atypically distinct protein variants exist despite marked genetic divergence elsewhere in the genome. These three forms of ROP18 are likely adaptations for different niches in nature, and they confer markedly different virulence to mice. The widespread distribution of a single mouse-virulent allele among geographically and genetically disparate parasites may have consequences for transmission and disease in other hosts, including humans

Export of functional Streptomyces coelicolor alditol oxidase to the periplasm or cell surface of Escherichia coli and its application in whole-cell biocatalysis

Streptomyces coelicolor A3(2) alditol oxidase (AldO) is a soluble monomeric flavoprotein in which the flavin cofactor is covalently linked to the polypeptide chain. AldO displays high reactivity towards different polyols such as xylitol and sorbitol. These characteristics make AldO industrially relevant, but full biotechnological exploitation of this enzyme is at present restricted by laborious and costly purification steps. To eliminate the need for enzyme purification, this study describes a whole-cell AldO biocatalyst system. To this end, we have directed AldO to the periplasm or cell surface of Escherichia coli. For periplasmic export, AldO was fused to endogenous E. coli signal sequences known to direct their passenger proteins into the SecB, signal recognition particle (SRP), or Twin-arginine translocation (Tat) pathway. In addition, AldO was fused to an ice nucleation protein (INP)-based anchoring motif for surface display. The results show that Tat-exported AldO and INP-surface-displayed AldO are active. The Tat-based system was successfully employed in converting xylitol by whole cells, whereas the use of the INP-based system was most likely restricted by lipopolysaccharide LPS in wild-type cells. It is anticipated that these whole-cell systems will be a valuable tool for further biological and industrial exploitation of AldO and other cofactor-containing enzymes.

Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

Peer reviewedPublisher PD

Impacts of climate change on plant diseases – opinions and trends

There has been a remarkable scientific output on the topic of how climate change is likely to affect plant diseases in the coming decades. This review addresses the need for review of this burgeoning literature by summarizing opinions of previous reviews and trends in recent studies on the impacts of climate change on plant health. Sudden Oak Death is used as an introductory case study: Californian forests could become even more susceptible to this emerging plant disease, if spring precipitations will be accompanied by warmer temperatures, although climate shifts may also affect the current synchronicity between host cambium activity and pathogen colonization rate. A summary of observed and predicted climate changes, as well as of direct effects of climate change on pathosystems, is provided. Prediction and management of climate change effects on plant health are complicated by indirect effects and the interactions with global change drivers. Uncertainty in models of plant disease development under climate change calls for a diversity of management strategies, from more participatory approaches to interdisciplinary science. Involvement of stakeholders and scientists from outside plant pathology shows the importance of trade-offs, for example in the land-sharing vs. sparing debate. Further research is needed on climate change and plant health in mountain, boreal, Mediterranean and tropical regions, with multiple climate change factors and scenarios (including our responses to it, e.g. the assisted migration of plants), in relation to endophytes, viruses and mycorrhiza, using long-term and large-scale datasets and considering various plant disease control methods

High versus standard doses interferon-alpha in the treatment of naïve chronic hepatitis C patients in Taiwan: a 10-year cohort study

BACKGROUND: Interferon-alpha monotherapy is effective in less than one-third patients with chronic hepatitis C. The dose-effect, tolerability and durability of interferon-alpha treatment and its long-term effect on the prevention of cirrhosis and hepatocellular carcinoma in naïve Taiwanese patients with chronic hepatitis C have not been well investigated. We conducted the present cohort study treated with high and standard interferon-alpha to illustrate the issues. METHODS: We performed a long-term virologic and histological follow-up of 214 chronic hepatitis C patients treated with interferon-alpha, 3 million units (3-MU, n = 80) or 6-MU (n = 134) thrice weekly for 24 weeks, in Taiwan between 1992 and 2001. RESULTS: There was no difference in the incidence of discontinuation between 3-MU and 6-MU groups (4/80, 5.0% versus 10/134. 7.5%). The 6-MU group had similar incidence of adverse events with the 3-MU group, except that 6-MU group had significantly higher incidence of psychological manifestations, mainly presented as irritability. The rates of sustained virological response (SVR) were significantly higher in 6-MU regimen (37.1%) than in 3-MU regimen (23.7%, p < 0.05) in per protocol analysis. Based on multivariate analysis, baseline viral load was strongly associated with SVR, followed by hepatitis C virus genotype, interferon-alpha regimen, and liver fibrosis. A histological improvement in necroinflammatory activity, but not in fibrosis was observed in the follow-up biopsy performed 0.5–5.5 years (mean: 1.9 years, n = 51) after end-of-treatment. Among patients without SVR, there was more activity improvement in 6-MU group. The durability of SVR was 100% (18/18) and 97.8% (45/46) for 3-MU and 6-MU group, respectively, in a mean follow-up period of 6.81 years (5.25–9.18 years). For 163 baseline non-cirrhotic patients, 9 of 84 (10.7%) non-responders and 3 of 79 (3.8%) sustained responders progressed to cirrhosis during a mean follow-up period of 5.52 and 5.74 years, respectively (p = 0.067, Kaplan-Meier survival analysis, log-rank test). For all 200 patients, hepatocellular carcinoma was detected in 12 of 113 (10.6%) non-responders and one of 87 (1.1%) sustained responders during a mean follow-up period of 5.67 and 5.73 years, respectively (p < 0.01, Kaplan-Meier survival analysis, log-rank test). CONCLUSION: We confirm the dose effect of interferon-alpha in chronic hepatitis C. Six-MU regimen had better efficacy than 3-MU regimen in virologic and histological responses. Both regimens had good tolerability and durability in Taiwan. Sustained response could reduce the incidence of cirrhotic change and hepatocarcinogenesis

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

BACKGROUND: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. CASE PRESENTATION: We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m(2 )of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. CONCLUSION: To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects