174 research outputs found
ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
Background
Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a
cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been
assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in
pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism
and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was
identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic
mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient
material and in ACBD5-deficient HeLa cells to uncover this role.
Methods
We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and
retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material
and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing.
Results
We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5
protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very longchain
fatty acids (VLCFAs) due to impaired peroxisomal beta-oxidation. No effect on pexophagy was
found.
Conclusions
Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in
the cytosol and thereby facilitates transport into the peroxisome and subsequent beta-oxidation.
Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired
VLCFA metabolism and leading to retinal dystrophy and white matter disease.Supported in part by funding through the Marie Curie Initial Training Networks (ITN) action to
KDF, MS and HRW (FP7-2012-PERFUME-316723). MS is supported by the Biotechnology and
Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1)
Protracted shearing at mid‐crustal conditions during large‐scale thrusting in the Scandinavian Caledonides
During continental collision, large tracts of crust are mobilised along major shear zones. The metamorphic conditions at which these zones operate, the duration of thrusting, and the deformation processes that facilitated hundreds of km of tectonic transport are still unclear. In the Scandinavian Caledonides, the Lower Seve Nappe displays a main mylonitic foliation with thickness of ~1 km. This foliation is overprinted by a brittle‐to‐ductile deformation pattern localized in C and C’‐type shear bands proximal to the tectonic contact with the underlying Särv Nappe. Thermobarometry of amphibolites and micaschists suggest a first high‐pressure stage at 400‐500°C and 1‐1.3 GPa recorded in mineral relics. The main mylonitic foliation developed under epidote amphibolite facies conditions along the retrograde path from 600°C and 1 GPa to 500°C and 0.5 GPa. Age dating of synkinematic titanite grains in the amphibolites indicates that this mylonitic fabric formed at around 417 ± 9 Ma, but older ages spanning 460‐430 Ma could represent earlier stages of mylonitization. The shear bands developed at lower metamorphic conditions of 300‐400°C and ~0.3 GPa. In the micaschists, the recrystallized grain size of quartz decreases towards the shear bands. Monomineralic quartz layers are eventually dismembered to form polyphase aggregates deforming by dominant grain size sensitive creep accompanied by slip in muscovite and chlorite. Plagioclase zoning truncations suggest that the shear bands originated by fracturing followed by ductile deformation. The results suggest protracted and long‐lasting shearing under amphibolite to greenschist facies conditions during the juxtaposition, stacking and exhumation of the Lower Seve Nappe
Body mass index is not a predictor of biochemical recurrence after radical prostatectomy in Dutch men diagnosed with prostate cancer
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95677.pdf (publisher's version ) (Closed access)PURPOSE: To determine the effect of body mass index (BMI) on clinical and pathological characteristics at time of diagnosis and on risk of biochemical recurrence after radical prostatectomy among Dutch men diagnosed with prostate cancer. METHODS: In total, 1,116 prostate cancer patients with known BMI, diagnosed between 2003 and 2006, were identified from the population-based cancer registry held by the Comprehensive Cancer Centre East, The Netherlands. Of these, 504 patients underwent a radical prostatectomy. Patients were categorized as normal weight (BMI /= 30 kg/m(2)). Multivariable proportional hazards regression models, adjusted for age, prediagnostic PSA levels, and pathological characteristics were used to evaluate BMI as a prognostic factor for biochemical recurrence after radical prostatectomy. RESULTS: Overall, clinical and biopsy characteristics did not significantly differ among BMI groups. Pathological characteristics after radical prostatectomy did not significantly differ among BMI groups, except for tumor stage, which was highest in obese patients (P = 0.017). For patients treated with radical prostatectomy, 5-year risk (95% Confidence Intervals) of biochemical recurrence was 30% (23-37%) for normal weight, 32% (25-39%) for overweight, and 25% (9-41%) for obese patients (log rank P = 0.810). BMI was not an independent prognostic factor for biochemical recurrence in multivariable proportional hazards regression analyses (HR 0.99 per kg/m(2), 95% CI: 0.93-1.06). CONCLUSIONS: Compared with non-obese men, pathological tumor stage tended to be higher in obese men. Clinical relevance of this finding is unclear, because BMI was not an independent predictor of biochemical recurrence after radical prostatectomy
For Psyche
In the present study we investigated peroxisomal functions in cultured human muscle cells from control subjects and from a patient with the Zellweger syndrome, a genetic disease characterized by the absence of morphologically distinguishable peroxisomes in liver and kidney. In homogenates of cultured muscle cells from control subjects, catalase is contained within subcellular particles, acyl-CoA:dihydroxyacetonephosphate acyltransferase activity is present and palmitoyl-CoA can be oxidized by a peroxisomal beta-oxidative pathway; these findings are indicative of the presence of peroxisomes in the cells. In homogenates of cultured muscle cells from the patient with the Zellweger syndrome, acyl-CoA:dihydroxyacetonephosphate acyltransferase activity was deficient, peroxisomal beta-oxidation of palmitoyl-CoA was impaired and catalase was not particle-bound. These findings indicate that functional peroxisomes are absent in muscle from patients with the Zellweger syndrome. We conclude that cultured human muscle cells can be used as a model system to study peroxisomal functions in muscle and the consequences for this tissue of a generalized dysfunction of peroxisome
Teachers' ideas versus experts' descriptions of 'the good teacher' in postgraduate medical education: implications for implementation. A qualitative study
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96394.pdf (publisher's version ) (Open Access)BACKGROUND: When innovations are introduced in medical education, teachers often have to adapt to a new concept of what being a good teacher includes. These new concepts do not necessarily match medical teachers' own, often strong beliefs about what it means to be a good teacher.Recently, a new competency-based description of the good teacher was developed and introduced in all the Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. We compared the views reflected in the new description with the views of teachers who were required to adopt the new framework. METHODS: Qualitative study. We interviewed teachers in two Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. The transcripts of the interviews were analysed independently by two researchers, who coded and categorised relevant fragments until consensus was reached on six themes. We investigated to what extent these themes matched the new description. RESULTS: Comparing the teachers' views with the concepts described in the new competency-based framework is like looking into two mirrors that reflect clearly dissimilar images. At least two of the themes we found are important in relation to the implementation of new educational methods: the teachers' identification and organisational culture. The latter plays an important role in the development of teachers' ideas about good teaching. CONCLUSIONS: The main finding of this study is the key role played by the teachers' feelings regarding their professional identity and by the local teaching culture in shaping teachers' views and expectations regarding their work. This suggests that in implementing a new teaching framework and in faculty development programmes, careful attention should be paid to teachers' existing identification model and the culture that fostered it
Channel-Forming Activities in the Glycosomal Fraction from the Bloodstream Form of Trypanosoma brucei
Background: Glycosomes are a specialized form of peroxisomes (microbodies) present in unicellular eukaryotes that belong to the Kinetoplastea order, such as Trypanosoma and Leishmania species, parasitic protists causing severe diseases of livestock and humans in subtropical and tropical countries. The organelles harbour most enzymes of the glycolytic pathway that is responsible for substrate-level ATP production in the cell. Glycolysis is essential for bloodstream-form Trypanosoma brucei and enzymes comprising this pathway have been validated as drug targets. Glycosomes are surrounded by a single membrane. How glycolytic metabolites are transported across the glycosomal membrane is unclear. Methods/Principal Findings: We hypothesized that glycosomal membrane, similarly to membranes of yeast and mammalian peroxisomes, contains channel-forming proteins involved in the selective transfer of metabolites. To verify this prediction, we isolated a glycosomal fraction from bloodstream-form T.brucei and reconstituted solubilized membrane proteins into planar lipid bilayers. The electrophysiological characteristics of the channels were studied using multiple channel recording and single channel analysis. Three main channel-forming activities were detected with current amplitudes 70–80 pA, 20–25 pA, and 8–11 pA, respectively (holding potential +10 mV and 3.0 M KCl as an electrolyte). All channels were in fully open state in a range of voltages 6150 mV and showed no sub-conductance transitions. The channel with current amplitude 20–25 pA is anion-selective (P K+/P Cl2,0.31), while the other two types of channels are slightl
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