Control of Phytoplankton Growth by Iron and Silicic Acid Availability in the Subantarctic Ocean: Experimental Results From the SAZ Project

Subantarctic Southern Ocean surface waters in the austral summer and autumn are characterized by high concentrations of nitrate and phosphate but low concentrations of dissolved iron (Fe, similar to0.05 nM) and silicic acid (Si, \u3c1 muM). During the Subantarctic Zone AU9706 cruise in March 1998 we investigated the relative importance of Fe and Si in controlling phytoplankton growth and species composition at a station within the subantarctic water mass (46.8degreesS, 142degreesE) using shipboard bottle incubation experiments. Treatments included unamended controls; 1.9 nM added iron (+Fe); 9 muM added silicic acid (+Si); and 1.9 nM addediron plus 9 muM added silicic acid (+Fe+Si). We followed a detailed set of biological and biogeochemical parameters over 8 days. Fe added alone clearly increased community growth rates and nitrate drawdown and altered algal community composition relative to control treatments. Surprisingly, small, lightly silicified pennate diatoms grew when Fe was added either with or without Si, despite the extremely low ambient silicic acid concentrations. Pigment analyses suggest that lightly silicified chrysophytes (type 4 haptophytes) may have preferentially responded to Si added either with or without Fe. However, for many of the parameters measured the +Fe+Si treatments showed large increases relative to both the +Fe and +Si treatments. Our results suggest that iron is the proximate limiting nutrient for chlorophyll production, photosynthetic efficiency, nitrate drawdown, and diatom growth, but that Si also exerts considerable control over algal growth and species composition. Both nutrients together are needed to elicit a maximum growth response, suggesting that both Fe and Si play important roles in structuring the subantarctic phytoplankton community

Control of Phytoplankton Growth by Iron Supply and Irradiance in the Subantarctic Southern Ocean: Experimental Results From the SAZ Project

The influence of irradiance and Fe supply on phytoplankton processes was studied, north (47°S, 142°E) and south (54°S, 142°E) of the Subantarctic Front in austral autumn (March 1998). At both sites, resident cells exhibited nutrient stress (Fv/Fm 0 at 47°S and 9% I0 at 54°S because of MLDs of 40 (47°S) and 90 m (54°S), when these stations were occupied. The greater MLD at 54°S is reflected by tenfold higher cellular chlorophyll a levels in the resident phytoplankton. In the 47°S experiment, chlorophyll a levels increased to \u3e1 μg/L-1 only in the high-Fe treatments, regardless of irradiance levels, suggesting Fe limitation. This trend was also noted for cell abundances, silica production, and carbon fixation rates. In contrast, in the 54°S experiment there were increases in chlorophyll a (to \u3e2 μg/L-1), cell abundances, silica production, and carbon fixation only in the high-light treatments to which Fe had been added, suggesting that Fe and irradiance limit algal growth rates. Irradiance by altering algal Fe quotas is a key determinant of algal growth rate at 54°S (when silicic acid levels are nonlimiting); however, because of the integral nature of Fe/light colimitation and the restricted nature of the current data set, it was not possible to ascertain the relative contributions of Fe and irradiance to the control of phytoplankton growth. On the basis of a climatology of summer mean MLD for subantarctic (SA) waters south of Australia the 47° and 54°S sites appear to represent minimum and maximum MLDs, where Fe and Fe/irradiance, respectively, may limit/colimit algal growth. The implications for changes in the factors limiting algal growth with season in SA waters are discussed

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy

Impact of a referral management “gateway” on the quality of referral letters; a retrospective time series cross sectional review

Background Referral management centres (RMC) for elective referrals are designed to facilitate the primary to secondary care referral path, by improving quality of referrals and easing pressures on finite secondary care services, without inadvertently compromising patient care. This study aimed to evaluate whether the introduction of a RMC which includes triage and feedback improved the quality of elective outpatient referral letters. Methods Retrospective, time-series, cross-sectional review involving 47 general practices in one primary care trust (PCT) in South-East England. Comparison of a random sample of referral letters at baseline (n = 301) and after seven months of referral management (n = 280). Letters were assessed for inclusion of four core pieces of information which are used locally to monitor referral quality (blood pressure, body mass index, past medical history, medication history) and against research-based quality criteria for referral letters (provision of clinical information and clarity of reason for referral). Results Following introduction of the RMC, the proportion of letters containing each of the core items increased compared to baseline. Statistically significant increases in the recording of ‘past medical history’ (from 71% to 84%, p < 0.001) and ‘medication history’ (78% to 87%, p = 0.006) were observed. Forty four percent of letters met the research-based quality criteria at baseline but there was no significant change in quality of referral letters judged on these criteria across the two time periods. Conclusion Introduction of RMC has improved the inclusion of past medical history and medication history in referral letters, but not other measures of quality. In approximately half of letters there remains room for further improvement

Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice

Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan’s Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage

Aspirin as an adjuvant treatment for cancer:feasibility results from the Add-Aspirin randomised trial

BACKGROUND: Preclinical, epidemiological, and randomised data indicate that aspirin might prevent tumour development and metastasis, leading to reduced cancer mortality, particularly for gastro-oesophageal and colorectal cancer. Randomised trials evaluating aspirin use after primary radical therapy are ongoing. We present the pre-planned feasibility analysis of the run-in phase of the Add-Aspirin trial to address concerns about toxicity, particularly bleeding after radical treatment for gastro-oesophageal cancer.METHODS: The Add-Aspirin protocol includes four phase 3 randomised controlled trials evaluating the effect of daily aspirin on recurrence and survival after radical cancer therapy in four tumour cohorts: gastro-oesophageal, colorectal, breast, and prostate cancer. An open-label run-in phase (aspirin 100 mg daily for 8 weeks) precedes double-blind randomisation (for participants aged under 75 years, aspirin 300 mg, aspirin 100 mg, or matched placebo in a 1:1:1 ratio; for patients aged 75 years or older, aspirin 100 mg or matched placebo in a 2:1 ratio). A preplanned analysis of feasibility, including recruitment rate, adherence, and toxicity was performed. The trial is registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN74358648) and remains open to recruitment.FINDINGS: After 2 years of recruitment (October, 2015, to October, 2017), 3494 participants were registered (115 in the gastro-oesophageal cancer cohort, 950 in the colorectal cancer cohort, 1675 in the breast cancer cohort, and 754 in the prostate cancer cohort); 2719 (85%) of 3194 participants who had finished the run-in period proceeded to randomisation, with rates consistent across tumour cohorts. End of run-in data were available for 2253 patients; 2148 (95%) of the participants took six or seven tablets per week. 11 (0·5%) of the 2253 participants reported grade 3 toxicity during the run-in period, with no upper gastrointestinal bleeding (any grade) in the gastro-oesophageal cancer cohort. The most frequent grade 1-2 toxicity overall was dyspepsia (246 [11%] of 2253 participants).INTERPRETATION: Aspirin is well-tolerated after radical cancer therapy. Toxicity has been low and there is no evidence of a difference in adherence, acceptance of randomisation, or toxicity between the different cancer cohorts. Trial recruitment continues to determine whether aspirin could offer a potential low cost and well tolerated therapy to improve cancer outcomes.FUNDING: Cancer Research UK, The National Institute for Health Research Health Technology Assessment Programme, The MRC Clinical Trials Unit at UCL.</p

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity

Characterization of lamin Mutation Phenotypes in Drosophila and Comparison to Human Laminopathies

Lamins are intermediate filament proteins that make up the nuclear lamina, a matrix underlying the nuclear membrane in all metazoan cells that is important for nuclear form and function. Vertebrate A-type lamins are expressed in differentiating cells, while B-type lamins are expressed ubiquitously. Drosophila has two lamin genes that are expressed in A- and B-type patterns, and it is assumed that similarly expressed lamins perform similar functions. However, Drosophila and vertebrate lamins are not orthologous, and their expression patterns evolved independently. It is therefore of interest to examine the effects of mutations in lamin genes. Mutations in the mammalian lamin A/C gene cause a range of diseases, collectively called laminopathies, that include muscular dystrophies and premature aging disorders. We compared the sequences of lamin genes from different species, and we have characterized larval and adult phenotypes in Drosophila bearing mutations in the lam gene that is expressed in the B-type pattern. Larvae move less and show subtle muscle defects, and surviving lam adults are flightless and walk like aged wild-type flies, suggesting that lam phenotypes might result from neuromuscular defects, premature aging, or both. The resemblance of Drosophila lam phenotypes to human laminopathies suggests that some lamin functions may be performed by differently expressed genes in flies and mammals. Such still-unknown functions thus would not be dependent on lamin gene expression pattern, suggesting the presence of other lamin functions that are expression dependent. Our results illustrate a complex interplay between lamin gene expression and function through evolution