Aims
Although changes in extracellular matrix (ECM) scaffold have been reported previously in Alzheimer's disease (AD) compared to normal ageing, it is not known how alterations in the numerous ...components of the perivascular ECM might occur at different stages of AD. This study therefore investigates potential changes in basement membrane‐associated ECM molecules in relation to increasing Braak stages.
Methods
Thirty patients were divided into three groups (control subject, subclinical AD and AD patients). ECM levels of collagen IV, perlecan and fibronectin as well as human platelet endothelial cell adhesion molecule (hPECAM) were quantified by immunohistochemistry. Von Willebrand factor staining was measured to assess vessel density. Expression levels were correlated with the presence of amyloid plaques.
Results
Collagen IV, perlecan and fibronectin expression was increased in subclinical AD and AD patients when compared to controls, in frontal and temporal cortex, whilst no further increase was detected between subclinical AD and AD. These changes were not associated with an increase in vessel density, which was instead decreased in the temporal cortex of AD patients. In contrast, hPECAM levels remained unchanged. Finally, we found similar pattern in levels of amyloid deposition between the different Braak stages and showed that changes in ECM components correlated with amyloid deposition.
Conclusion
Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.
Changes in component of the extracellular matrix occur early in Alzheimer's disease (AD) and correlate with amyloid β deposition. The study indicates that brain microvascular dysfunction may be important in early disease and contributes to the drive to find early disease biomarkers and therapeutic targets for AD.
•Tides and waves alter land-derived nutrient discharge pathways and transformations.•Nutrient fate is strongly controlled by inputs of marine-derived constituents.•Fate of land-derived nutrients ...depends on redox conditions in mixing zones.•Simulated nutrient regeneration from DOM degradation not controlled by mixing.
A numerical investigation is presented that demonstrates the influence of tides and waves on the transport and transformation of nutrients (NO3-,NH4+,PO43-) in a homogeneous unconfined nearshore aquifer and subsequent fluxes to the sea. Simulations of an aquifer subject to semi-diurnal tides and constant waves acting on a sloping beach face were conducted using SEAWAT-2005 combined with PHT3D v2.10. Tidal amplitude (A) and wave height (Hrms) varying from 0.25 to 0.75m and 1 to 2m, respectively, were examined. Results show that tides and waves modify the subsurface discharge pathway of land-derived nutrients by changing the nearshore groundwater flow dynamics. More importantly, the oceanic forcing impacts nutrient cycling as it causes significant seawater exchange (along with dissolved O2 and organic matter) across the aquifer-ocean interface. Although steady wave forcing caused higher seawater influx, tides led to greater seawater-freshwater mixing in the nearshore aquifer and subsequently greater transformation of land-derived nutrients. Nutrient processing was strongly controlled by the availability and reactivity of marine dissolved organic matter (DOM) as its degradation consumed O2, released inorganic N and P, and altered redox conditions in the salt-freshwater mixing zones. For the conditions and reaction network simulated, nutrient regeneration by marine DOM degradation was independent of the seawater-freshwater mixing intensity, and therefore was greatest for the wave case due to the high seawater influx. For simulations without marine DOM considered, NO3- discharge to the sea increased by 32% for the tidal case (A=0.5m) compared to only 13% and 8% for the wave (Hrms=1m) and no oceanic forcing cases. With labile marine DOM considered, the NO3- discharge decreased by 90% relative to the land-derived flux for the tidal case (A=0.5m). For all simulations PO43-removal was high due to its adsorption to Fe oxide minerals. The model enables evaluation of the complex coupled physical-biogeochemical processes controlling nutrient loading to the sea via submarine groundwater discharge in dynamic coastal environments.
Crystal Structure of Arp2/3 Complex Robinson, Robert C.; Turbedsky, Kirsi; Kaiser, Donald A. ...
Science (American Association for the Advancement of Science),
11/2001, Volume:
294, Issue:
5547
Journal Article
Peer reviewed
We determined a crystal structure of bovine Arp2/3 complex, an assembly of seven proteins that initiates actin polymerization in eukaryotic cells, at 2.0 angstrom resolution. Actin-related protein 2 ...(Arp2) and Arp3 are folded like actin, with distinctive surface features. Subunits ARPC2 p34 and ARPC4 p20 in the core of the complex associate through long carboxyl-terminal α helices and have similarly folded amino-terminal α/β domains. ARPC1 p40 is a seven-blade β propeller with an insertion that may associate with the side of an actin filament. ARPC3 p21 and ARPC5 p16 are globular α-helical subunits. We predict that WASp/Scar proteins activate Arp2/3 complex by bringing Arp2 into proximity with Arp3 for nucleation of a branch on the side of a preexisting actin filament.
Abstract Background Radiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the child’s developing nervous system at a ...crucial time – with a resultant reduction in IQ leading to cognitive impairment, associated endocrinopathy and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with malignant brain tumours other than ependymoma, the results of which have already been published. Methods Ninety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma ( n = 31), astrocytoma (26), choroid plexus carcinoma CPC (15), CNS PNET (11), atypical teratoid/rhabdoid tumours AT/RT (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression. Findings Over all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6–73.0) and for classic medulloblastoma 33.3% (CI: 4.6–67.6); the 5-year EFS were 35.3% (CI: 14.5–57.0) and 33.3% (CI: 4.6–67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas HGGs was 13.0% (CI: 2.2–33.4) and the OS was 30.9% (CI: 11.5–52.8). For CPC the 5-year OS was 26.67% (CI: 8.3–49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8–51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5–33.3). Interpretation The outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.
Aims/hypothesis
To compare the effectiveness of low-fat high-protein and low-fat high-carbohydrate dietary advice on weight loss, using group-based interventions, among overweight people with type 2 ...diabetes.
Study design
Multicentre parallel (1:1) design, blinded randomised controlled trial.
Methods
Individuals with type 2 diabetes aged 30–75 years and a BMI >27 kg/m
2
were randomised, by an independent statistician using sequentially numbered sealed envelopes, to be prescribed either a low-fat high-protein (30% of energy as protein, 40% as carbohydrate, 30% as fat) or a low-fat high-carbohydrate (15% of energy as protein, 55% as carbohydrate, 30% as fat) diet. Participants attended 18 group sessions over 12 months. Primary outcomes were change in weight and waist circumference assessed at baseline, 6 and 12 months. Secondary outcomes were body fatness, glycaemic control, lipid profile, blood pressure and renal function. A further assessment was undertaken 12 months after the intervention. Research assessors remained blinded to group allocation throughout. Intention-to-treat analysis was performed.
Results
A total of 419 participants were enrolled (mean ± SD age 58 ± 9.5 years, BMI 36.6 ± 6.5 kg/m
2
and HbA
1c
8.1 ± 1.2% (65 mmol/mol)). The study was completed by 70% (294/419). No differences between groups were found in change in weight or waist circumference during the intervention phase or the 12-month follow-up. Both groups had lost weight (2–3 kg,
p
< 0.001) and reduced their waist circumference (2–3 cm,
p
< 0.001) by 12 months and largely maintained this weight loss for the following 12 months. By 6 months, the difference in self-reported dietary protein between groups was small (1.1% total energy;
p
< 0.001). No significant differences between groups were found in secondary outcomes: body fatness, HbA
1c
, lipids, blood pressure and renal function. There were no important adverse effects.
Conclusions/interpretation
In a ‘real-world’ setting, prescription of an energy-reduced low-fat diet, with either increased protein or carbohydrate, results in similar modest losses in weight and waist circumference over 2 years.
Trial registration:
Australia New Zealand Clinical Trials Register ACTRN12606000490572
Funding:
The Health Research Council of New Zealand (06/337).
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