Pseudoautosomal repeat displays higher variability in Blacks than in Caucasians

Summary DNA patterns from a pseudoautosomal variable number tandem repeat-like minisatellite (locus DXYS20) were compared in two samples: a Caucasian and a Black sample. We defined 3 types of DNA patterns named A, B and C, and found that these patterns have different frequencies in the Caucasian and Black groups. A set of alleles (the C group) in 48% of the Black sample is not found in the Caucasian sample. We also found a greater degree of fragment-size variability among Black individuals than among those of Caucasian origin. The large degree of ethnic variation indicates that this locus will be useful in population genetic studies.     

Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study

Introduction  

Cardiovascular disease (CVD) is the leading cause of death in patients with inflammatory polyarthritis (IP), especially in seropositive disease. In established rheumatoid arthritis (RA), insulin resistance (IR) is increased and associated with CVD. We investigated factors associated with IR in an inception cohort of patients with early IP.     

Insulin resistance in the liver: Deficiency or excess of insulin?

In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states.     

Sheep prions with molecular properties intermediate between classical scrapie,BSE and CH1641–scrapie

Efforts to differentiate bovine spongiform encephalopathy (BSE) from scrapie in prion infected sheep have resulted in effective methods to decide about the absence of BSE. In rare instances uncertainties remain due to assumptions that BSE, classical scrapie and CH1641–a rare scrapie variant–could occur as mixtures. In field samples including those from fallen stock, triplex Western blotting analyses of variations in the molecular properties of the proteinase K resistant part of the disease‑associated form of prion protein (PrP^res) represents a powerful tool for quick discrimination purposes. In this study we examined 7 deviant ovine field cases of scrapie for some typical molecular aspects of PrP^res found in CH1641‑scrapie, classical scrapie and BSE. One case was most close to scrapie with respect to molecular mass of its non-glycosylated fraction and N-terminally located 12B2‑epitope content. Two cases were unlike classical scrapie but too weak to differentiate between BSE or CH1641. The other 4 cases appeared intermediate between scrapie and CH1641 with a reduced molecular mass and 12B2‑epitope content, together with the characteristic presence of a second PrP^res population. The existence of these 2 PrP^res populations was further confirmed through deglycosylation by PNGaseF. The findings indicate that discriminatory diagnosis between classical scrapie, CH1641 and BSE can remain inconclusive with current biochemical methods. Whether such intermediate cases represent mixtures of TSE strains should be further investigated e.g. in bioassays with rodent lines that are varying in their susceptibility or other techniques suitable for strain typing.     

The cellular function of srGAP3 and its role in neuronal morphogenesis

The Slit-Robo GTPase activating protein 3 (srGAP3) dynamically regulates cytoskeletal reorganisation through inhibition of the Rho GTPase Rac1 and interaction with actin remodelling proteins. SrGAP3-mediated reorganisation of the actin cytoskeleton is crucial for the normal development of dendritic spines and loss of srGAP3 leads to abnormal synaptic activity and impaired cognitive behaviours in mice, which is reminiscent of an association between disrupted srGAP3 and intellectual disability in humans. Additionally, srGAP3 has been implicated to act downstream of Slit-Robo signalling in commissural axons of the spinal cord. Thus, srGAP3-mediated cytoskeletal reorganisation has an important influence on a variety of neurodevelopmental processes, which may be required for normal cognitive function.     

Modelling the effect of fishing on southern Buller's albatross using a 60-year dataset

Abstract

Many albatross populations are declining and a major cause is believed to be incidental mortality from fishing. We investigated the effect of fishing on southern Buller's albatross Thalassarche bulleri bulleri, using a new approach to seabird population modelling that allows estimation of demographic parameters from multiple data types. Three types of data were used: a 60-year set of mark–recapture observations, four censuses of the breeding population, and estimates of fishing effort and bycatch. The fisheries risk to the viability of this population over the last 60 years appears to have been small, since the adult population is estimated to have increased about five-fold over that time. There is some cause for concern in recent changes (population growth has slowed, and perhaps reversed, and adult survival rates are falling). The most common age at first breeding was 12 years, and about 80% of adults breed each year. Annual survival was estimated to be 0.91 for juveniles, and varied between this value and 1 for adults. Though this population is not in immediate danger from fishing, there is a need for continued monitoring to see whether the recent fall in survival rates persists and causes a decline in abundance. Our analysis showed that when, as is common, mark–recapture data do not provide good estimates of all demographic rates, the assessment of seabird population trends can be improved by the use of other types of data, particularly abundance.     

MEGAP impedes cell migration via regulating actin and microtubule dynamics and focal complex formation

Over the past several years, it has become clear that the Rho family of GTPases plays an important role in various aspects of neuronal development including cytoskeleton dynamics and cell adhesion processes. We have analysed the role of MEGAP, a GTPase-activating protein that acts towards Rac1 and Cdc42 in vitro and in vivo, with respect to its putative regulation of cytoskeleton dynamics and cell migration. To investigate the effects of MEGAP on these cellular processes, we have established an inducible cell culture model consisting of a stably transfected neuroblastoma SHSY-5Y cell line that endogenously expresses MEGAP albeit at low levels. We can show that the induced expression of MEGAP leads to the loss of filopodia and lamellipodia protrusions, whereas constitutively activated Rac1 and Cdc42 can rescue the formation of these structures. We have also established quantitative assays for evaluating actin dynamics and cellular migration. By time-lapse microscopy, we show that induced MEGAP expression reduces cell migration by 3.8-fold and protrusion formation by 9-fold. MEGAP expressing cells also showed impeded microtubule dynamics as demonstrated in the TC-7 3x-GFP epithelial kidney cells. In contrast to the wild type, overexpression of MEGAP harbouring an artificially introduced missense mutation R542I within the functionally important GAP domain did not exert a visible effect on actin and microtubule cytoskeleton remodelling. These data suggest that MEGAP negatively regulates cell migration by perturbing the actin and microtubule cytoskeleton and by hindering the formation of focal complexes.     

Biomechanical factors and physical examination findings in osteoarthritis of the knee: associations with tissue abnormalities assessed by conventional radiography and high-resolution 3.0 Tesla magnetic resonance imaging

Introduction

We aimed to explore the associations between knee osteoarthritis (OA)-related tissue abnormalities assessed by conventional radiography (CR) and by high-resolution 3.0 Tesla magnetic resonance imaging (MRI), as well as biomechanical factors and findings from physical examination in patients with knee OA.

Methods

This was an explorative cross-sectional study of 105 patients with knee OA. Index knees were imaged using CR and MRI. Multiple features from CR and MRI (cartilage, osteophytes, bone marrow lesions, effusion and synovitis) were related to biomechanical factors (quadriceps and hamstrings muscle strength, proprioceptive accuracy and varus-valgus laxity) and physical examination findings (bony tenderness, crepitus, bony enlargement and palpable warmth), using multivariable regression analyses.

Results

Quadriceps weakness was associated with cartilage integrity, effusion, synovitis (all detected by MRI) and CR-detected joint space narrowing. Knee joint laxity was associated with MRI-detected cartilage integrity, CR-detected joint space narrowing and osteophyte formation. Multiple tissue abnormalities including cartilage integrity, osteophytes and effusion, but only those detected by MRI, were found to be associated with physical examination findings such as crepitus.

Conclusion

We observed clinically relevant findings, including a significant association between quadriceps weakness and both effusion and synovitis, detected by MRI. Inflammation was detected in over one-third of the participants, emphasizing the inflammatory component of OA and a possible important role for anti-inflammatory therapies in knee OA. In general, OA-related tissue abnormalities of the knee, even those detected by MRI, were found to be discordant with biomechanical and physical examination features.     

Comparative platelet proteome analysis reveals an increase of monoamine oxidase-B protein expression in Alzheimer's disease but not in non-demented Parkinson's disease patients

Monoamine oxidase-B (Mao-B) catalysing the breakdown of the neurotransmitter dopamine, is known to be involved in the pathophysiology of Parkinson's (PD) and Alzheimer's disease (AD). Increased brain Mao-B activity is associated with AD. This alteration can also be seen in platelets, albeit the cause has hitherto remained elusive. To gain a deeper understanding of the etiology of AD, the platelet proteome was characterised, (2D DIGE pH6-9, including Mao-B) from 150 individuals: 34 AD, 13 vascular dementia, 15 non-demented PD patients, 49 matched controls, 18 oldest old and 21 young individuals. One significant change was noted after applying false discovery rate with the upregulation of the Mao-B expression (30% adjusted P value<0.001; effect size 1.31) in AD compared to age- and sex-matched controls. In contrast, Mao-B levels were unchanged in PD to matched controls. Western blot and mRNA analyses verified these findings. Moreover, Mao-B concentration correlated with age in the cognitive healthy individuals (r=0.53; P<0.001) and PD patients but not in those suffering from AD (r=-0.03; P=0.874). Mao-B activity correlated with the increased Mao-B protein expression in AD (r=0.81; P=0.016). We suggest that Mao-B platelet protein level may serve as a biomarker for age-related dementia, especially AD.