Formation of Grown-In Nitrogen Vacancies and Interstitials in Highly Mg-Doped Ammonothermal GaN.

The formation of intrinsic point defects in the N-sublattice of semi-insulating Mg-doped GaN crystals grown by the ammonothermal method (SI AT GaN:Mg) was investigated for the first time. The grown-in defects produced by the displacement of nitrogen atoms were experimentally observed as deep traps revealed by the Laplace transform photoinduced transient spectroscopy in the compensated p-type crystals with the Mg concentrations of 6 × 1018 and 2 × 1019 cm-3 and resistivities of ~1011 Ωcm and ~106 Ωcm, respectively. In both kinds of materials, three closely located traps with activation energies of 430, 450, and 460 meV were revealed. The traps, whose concentrations in the stronger-doped material were found to be significantly higher, are assigned to the (3+/+) and (2+/+) transition levels of nitrogen vacancies as well as to the (2+/+) level of nitrogen split interstitials, respectively. In the material with the lower Mg concentration, a middle-gap trap with the activation energy of 1870 meV was found to be predominant. The results are confirmed and quantitatively described by temperature-dependent Hall effect measurements. The mechanism of nitrogen atom displacement due to the local strain field arising in SI AT GaN:Mg is proposed and the effect of the Mg concentration on the charge compensation is discussed.

The PWWP domain and the evolution of unique DNA methylation toolkits in Hymenoptera.

DNMT3 in Hymenoptera has a unique duplication of the essential PWWP domain. Using GST-tagged PWWP fusion proteins and histone arrays we show that these domains have gained new properties and represent the first case of PWWP domains binding to H3K27 chromatin modifications, including H3K27me3, a key modification that is important during development. Phylogenetic analyses of 107 genomes indicate that the duplicated PWWP domains separated into two sister clades, and their distinct binding capacities are supported by 3D modeling. Other features of this unique DNA methylation system include variable copies, losses, and duplications of DNMT1 and DNMT3, and combinatorial generations of DNMT3 isoforms including variants missing the catalytic domain. Some of these losses and duplications of are found only in parasitic wasps. We discuss our findings in the context of the crosstalk between DNA methylation and histone methylation, and the expanded potential of epigenomic modifications in Hymenoptera to drive evolutionary novelties.

Evolution of the Growth Mode and Its Consequences during Bulk Crystallization of GaN.

A detailed analysis of morphology of gallium nitride crystal growth obtained by ammonothermal and halide vapor phase epitaxy methods was carried out. The work was conducted to determine the source of triangular planar defects visible in X-ray topography as areas with locally different lattice parameters. It is shown that the occurrence of these defects is related to growth hillocks. Particular attention was paid to analyzing the manner and consequences of merging hillocks. In the course of the study, the nature of the mentioned defects and the cause of their formation were determined. It was established that the appearance of the defects depends on the angle formed between the steps located on the sides of two adjacent hillocks. A universal growth model is presented to explain the cause of heterogeneity during the merging of growth hillocks.

DNA Methylation in Honey Bees and the Unresolved Questions in Insect Methylomics.

DNA methylation has been found in most invertebrate lineages except for Diptera, Placozoa and the majority of Nematoda. In contrast to the mammalian methylation toolkit that consists of one DNMT1 and several DNMT3s, some of which are catalytically inactive accessory isoforms, invertebrates have different combinations of these proteins with some using just one DNMT1 and the others, like the honey bee, two DNMT1s one DNMT3. Although the insect DNMTs show sequence similarity to mammalian DNMTs, their in vitro and in vivo properties are not well investigated. In contrast to heavily methylated mammalian genomes, invertebrate genomes are only sparsely methylated in a 'mosaic' fashion with the majority of methylated CpG dinucleotides found across gene bodies that are frequently associated with active transcription. Additional work also highlights that obligatory methylated epialleles influence transcriptional changes in a context-specific manner. We argue that some of the lineage-specific properties of DNA methylation are the key to understanding the role of this genomic modification in insects. Future mechanistic work is needed to explain the relationship between insect DNMTs, genetic variation, differential DNA methylation, other epigenetic modifications, and the transcriptome in order to fully understand the role of DNA methylation in converting genomic sequences into phenotypes.

Large-Scale Defect Clusters with Hexagonal Honeycomb-like Arrangement in Ammonothermal GaN Crystals.

In this paper, we investigate, using X-ray Bragg diffraction imaging and defect selective etching, a new type of extended defect that occurs in ammonothermally grown gallium nitride (GaN) single crystals. This hexagonal "honeycomb" shaped defect is composed of bundles of parallel threading edge dislocations located in the corners of the hexagon. The observed size of the honeycomb ranges from 0.05 mm to 2 mm and is clearly correlated with the number of dislocations located in each of the hexagon's corners: typically ~5 to 200, respectively. These dislocations are either grouped in areas that exhibit "diameters" of 100-250 µm, or they show up as straight long chain alignments of the same size that behave like limited subgrain boundaries. The lattice distortions associated with these hexagonally arranged dislocation bundles are extensively measured on one of these honeycombs using rocking curve imaging, and the ensemble of the results is discussed with the aim of providing clues about the origin of these "honeycombs".

Fundamental Studies on Crystallization and Reaching the Equilibrium Shape in Basic Ammonothermal Method: Growth on a Native Lenticular Seed.

In this paper, a detailed investigation of the basic ammonothermal growth process of GaN is presented. By analyzing the crystallization on a native seed with a lenticular shape, thus with an intentionally varying off-cut, we wanted to answer some basic questions: (i) Which crystallographic planes play the most important role during growth (which planes are formed and which disappear)? (ii) What is the relationship between the growth rates in different crystallographic directions? (iii) What is the influence of the off-cut of the seed on the growth process? Two non-polar slices, namely, 12¯10 and 1¯100, as well as a 0001 basal plane slice of an ammonothermal crystal were analyzed. The examined planes were selectively etched in order to reveal the characteristic features of the growth process. The applied characterization methods included: optical microscopy with Nomarski contrast and ultraviolet illumination, X-ray topography and high-resolution X-ray diffraction, and secondary ion mass spectrometry. The obtained results allowed for creating a growth model of an ammonothermal GaN crystal on a lenticular seed. These findings are of great importance for the general understanding of the basic ammonothermal crystal growth process of GaN.

Without mechanisms, theories and models in insect epigenetics remain a black box.

Insect epigenetics must confront the remarkable diversity of epigenomic systems in various lineages and use mechanistic approaches to move beyond vague functional explanations based on predictions and inferences. To accelerate progress, what is required now is a convergence of genomic data with biochemical and single-cell-type analyses in selected species representing contrasting evolutionary solutions in epigenetics.

Structural Analysis of Low Defect Ammonothermally Grown GaN Wafers by Borrmann Effect X-ray Topography.

X-ray topography defect analysis of entire 1.8-inch GaN substrates, using the Borrmann effect, is presented in this paper. The GaN wafers were grown by the ammonothermal method. Borrmann effect topography of anomalous transmission could be applied due to the low defect density of the substrates. It was possible to trace the process and growth history of the GaN crystals in detail from their defect pattern imaged. Microscopic defects such as threading dislocations, but also macroscopic defects, for example dislocation clusters due to preparation insufficiency, traces of facet formation, growth bands, dislocation walls and dislocation bundles, were detected. Influences of seed crystal preparation and process parameters of crystal growth on the formation of the defects are discussed.

Transcriptome-based insights into gene networks controlling myopia prevention.

Myopia (short-sightedness), usually caused by excessive elongation of the eye during development, has reached epidemic proportions worldwide. In animal systems including the chicken model, several treatments have been shown to inhibit ocular elongation and experimental myopia. Although diverse in their apparent mechanism of action, each one leads to a reduction in the rate of ocular growth. We hypothesize that a defined set of retinal molecular changes may underlie growth inhibition, irrespective of the treatment agent used. Accordingly, across five well-established but diverse methods of inhibiting myopia, significant overlap is seen in the retinal transcriptome profile (transcript levels and alternative splicing events) in chicks when analyzed by RNA-seq. Within the two major pathway networks enriched during growth inhibition, that of cell signaling and circadian entrainment, transcription factors form the largest functional grouping. Importantly, a large percentage of those genes forming the defined retinal response are downstream targets of the transcription factor EGR1 which itself shows a universal response to all five growth-inhibitory treatments. This supports EGR1's previously implicated role in ocular growth regulation. Finally, by contrasting our data with human linkage and GWAS studies on refractive error, we confirm the applicability of our study to the human condition. Together, these findings suggest that a universal set of transcriptome changes, which sit within a well-defined retinal network that cannot be bypassed, is fundamental to growth regulation, thus paving a way for designing novel targets for myopia therapies.

Quantitative assessment of retinal thickness and vessel density using optical coherence tomography angiography in patients with Alzheimer's disease and glaucoma.

PURPOSE: Assessment and a direct comparison of retinal vessel density with the thickness of inner retinal layer (IRL) and outer retinal layer (ORL) in the same regions of the macula in subjects with Alzheimer's disease (AD) and primary open-angle glaucoma (POAG). METHODS: We analyzed data from 48 eyes of healthy control (HC) participants, 71 eyes with POAG, and 49 eyes of AD patients. Ophthalmic examination included optical coherence tomography (OCT) imaging to measure IRL and ORL thickness and OCT angiography (OCTA) in the same region for the imaging of vessel density in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) of the retina. A direct comparison of vessel density and retinal layers thickness, which different dynamic ranges, was obtained by normalizing values as percentage losses. RESULTS: Patients with AD presented significantly greater losses of vascular density in the DVP and ORL thickness compared to POAG (p <0.001), but percentage losses of vessel density in SVP and IRL thickness were considerable in POAG compared to AD eyes (p<0.001). Positive associations among presence of AD were observed primarily in outer retina where a 1% decrease of ORL thickness was associated with about 24-29% increase in odds of the presence of AD. According to OCTA measurements, a 1% decrease of vessel density in DVP was positively associated with a 4-9% increase in odds of the presence of AD. In POAG positive associations among presence of disease were observed only in inner retina where 1% loss of IRL thickness and a 1% loss of vessel density in the SVP were positively associated with a 13-23% increase in risk of presence of the disease. CONCLUSIONS: Analysis of ORL thickness and vessel density in DVP could potentially improve diagnostic capabilities and may provide a valuable approach for predicting of AD.

Exploring DNA Methylation Diversity in the Honey Bee Brain by Ultra-Deep Amplicon Sequencing.

Understanding methylation dynamics in organs or tissues containing many different cell types is a challenging task that cannot be efficiently addressed by the low-depth bisulphite sequencing of DNA extracted from such sources. Here we explored the feasibility of ultra-deep bisulphite sequencing of long amplicons to reveal the brain methylation patterns in three selected honey bee genes analysed across five distinct conditions on the Illumina MiSeq platform. By combing 15 libraries in one run we achieved a very high sequencing depth of 240,000-340,000 reads per amplicon, suggesting that most of the cell types in the honey bee brain, containing approximately 1 million neurons, are represented in this dataset. We found a small number of gene-specific patterns for each condition in individuals of different ages and performing distinct tasks with 80-90% of those were represented by no more than a dozen patterns. One possibility is that such a small number of frequent patterns is the result of differentially methylated epialleles, whereas the rare and less frequent patterns reflect activity-dependent modifications. The condition-specific methylation differences within each gene appear to be position-dependent with some CpGs showing significant changes and others remaining stable in a methylated or non-methylated state. Interestingly, no significant loss of methylation was detected in very old individuals. Our findings imply that these diverse patterns represent a special challenge in the analyses of DNA methylation in complex tissues and organs that cannot be investigated by low-depth genome-wide bisulphite sequencing. We conclude that ultra-deep sequencing of gene-specific amplicons combined with genotyping of differentially methylated epialleles is an effective way to facilitate more advanced neuro-epigenomic studies in honey bees and other insects.

Characterization of a Dopamine Transporter and Its Splice Variant Reveals Novel Features of Dopaminergic Regulation in the Honey Bee.

Dopamine is an important neuromodulator involved in reward-processing, movement control, motivational responses, and other aspects of behavior in most animals. In honey bees (Apis mellifera), the dopaminergic system has been implicated in an elaborate pheromonal communication network between individuals and in the differentiation of females into reproductive (queen) and sterile (worker) castes. Here we have identified and characterized a honey bee dopamine transporter (AmDAT) and a splice variant lacking exon 3 (AmDATΔex3). Both transcripts are present in the adult brain and antennae as well as at lower levels within larvae and ovaries. When expressed separately in the Xenopus oocyte system, AmDAT localizes to the oocyte surface whereas the splice variant is retained at an internal membrane. Oocytes expressing AmDAT exhibit a 12-fold increase in the uptake of [3H]dopamine relative to non-injected oocytes, whereas the AmDATΔex3-expressing oocytes show no change in [3H]dopamine transport. Electrophysiological measurements of AmDAT activity revealed it to be a high-affinity, low-capacity transporter of dopamine. The transporter also recognizes noradrenaline as a major substrate and tyramine as a minor substrate, but does not transport octopamine, L-Dopa, or serotonin. Dopamine transport via AmDAT is inhibited by cocaine in a reversible manner, but is unaffected by octopamine. Co-expression of AmDAT and AmDATΔex3 in oocytes results in a substantial reduction in AmDAT-mediated transport, which was also detected as a significant decrease in the level of AmDAT protein. This down-regulatory effect is not attributable to competition with AmDATΔex3 for ER ribosomes, nor to a general inhibition of the oocyte's translational machinery. In vivo, the expression of both transcripts shows a high level of inter-individual variability. Gene-focused, ultra-deep amplicon sequencing detected methylation of the amdat locus at ten 5'-C-phosphate-G-3' dinucleotides (CpGs), but only in 5-10% of all reads in whole brains or antennae. These observations, together with the localization of the amdat transcript to a few clusters of dopaminergic neurons, imply that amdat methylation is positively linked to its transcription. Our findings suggest that multiple cellular mechanisms, including gene splicing and epigenomic communication systems, may be adopted to increase the potential of a conserved gene to contribute to lineage-specific behavioral outcomes.

Comparison of Retinal Microvasculature in Patients With Alzheimer's Disease and Primary Open-Angle Glaucoma by Optical Coherence Tomography Angiography.

Purpose: Comparison of retinal microvasculature within the macula and the optic nerve head in the eyes of patients with Alzheimer's disease (AD), primary open-angle glaucoma (POAG), and in a healthy control (HC) group, using optical coherence tomography angiography (OCTA). Methods: In this cross-sectional study, 27 patients with AD, 27 with POAG, and 27 healthy controls were enrolled. The Mini-Mental State Examination test was used to assess cognitive function. Ophthalmic examination included OCTA, which was used for the imaging of vascular flow within the layer of radial peripapillary capillaries (RPCs), and also in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) of the retina. Results: In the AD group, the density of vessels in DVP was significantly reduced and the foveal avascular zone was increased when compared to POAG and HC groups (P < 0.001). Patients with POAG had a significantly reduced vessel density in RPCs and SVP as compared to AD and HC groups (P < 0.001). The average thickness of peripapillary retinal nerve fiber layer was correlated with the vessel density in SVP in patients with POAG (Pearson's r = 0.66; P = 0.0002) and was significantly lower in POAG and AD groups than in the HC group (P < 0.001). Conclusions: AD and POAG are neurodegenerative diseases associated with apoptosis of nerve cells and impairment of microvasculature. Despite the fact that in both diseases there are abnormalities of the entire retinal vascular system, significant microcirculatory impairment in POAG patients affects superficial vessels, whereas in AD patients it affects vessels located in the deeper retinal layers.

Peripapillary Retinal Nerve Fiber Layer Thickness in Patients with Alzheimer's Disease: A Comparison of Eyes of Patients with Alzheimer's Disease, Primary Open-Angle Glaucoma, and Preperimetric Glaucoma and Healthy Controls.

BACKGROUND The aim of this study was to assess and compare peripapillary retinal nerve fiber layer (RNFL) thickness in patients with Alzheimer's disease (AD), primary open-angle glaucoma (POAG), preperimetric glaucoma (PPG), and healthy controls with the use of Spectral Domain Optical Coherence Tomography (SD-OCT). MATERIAL AND METHODS Thirty patients with AD, 30 patients with POAG, 30 patients with PPG, and 30 healthy controls were enrolled in this cross-sectional study. Only 1 randomly selected eye of each patient was analyzed. Every subject underwent a thorough ophthalmological examination and OCT of the optic disc. The peripapillary RNFL thickness in each of the 6 sectors and globally was analyzed. RESULTS The RNFL was thinnest in patients with POAG. The mean RNFL thickness value was 60.97±12.97 µm and it was significantly lower than in healthy controls (106.30±8.95 µm), patients with PPG (93.20±12.04 µm), and AD patients (95.73±13.52 µm). Mean RNFL thickness in patients with AD was significantly lower when compared to healthy controls, and was higher compared to eyes with POAG, while there were no significant differences compared to patients with PPG. CONCLUSIONS Neuronal damage in the central nervous system (CNS) also affects to retinal axons. A major problem is to distinguish the cause for a moderate decrease in the RNFL thickness. This is particularly true for patients with glaucoma who have not been diagnosed with changes in the visual field. It is not possible to distinguish the cause of a mild decrease in the RNFL thickness based on the SD-OCT. This may result in misdiagnosis of glaucoma, unnecessary use of anti-glaucoma eye drops, and a delayed diagnosis of AD.

AlGaN/GaN High Electron Mobility Transistors on Semi-Insulating Ammono-GaN Substrates with Regrown Ohmic Contacts.

AlGaN/GaN high electron mobility transistors on semi-insulating bulk ammonothermal GaN have been investigated. By application of regrown ohmic contacts, the problem with obtaining low resistance ohmic contacts to low-dislocation high electron mobility transistor (HEMT) structures was solved. The maximum output current was about 1 A/mm and contact resistances was in the range of 0.3⁻0.6 Ω ·mm. Good microwave performance was obtained due to the absence of parasitic elements such as high access resistance.

Visceral fat reference values derived from healthy European men and women aged 20-30 years using GE Healthcare dual-energy x-ray absorptiometry.

Dual energy X-ray absorptiometry (DXA) is an established technique used in clinical and research settings to evaluate total and regional fat. Additionally, recently developed software allow to quantify visceral adipose tissue (VAT). Currently, there are no reference values available for GE Healthcare DXA systems for VAT. The aim of this study was to develop reference values for VAT in healthy European adults aged 20-30 years using a GE Healthcare Prodigy densitometer along with the dedicated CoreScan application. We also assessed the associations of VAT with traditional cardiometabolic risk factors. In 421 participants (207 men; 214 women), we performed DXA whole-body scans and calculated total body fat (BF) and VAT (in gender-specific percentiles). We also measured blood pressure and fasting glucose, insulin, and blood lipids. Males, in comparison with females, had 2-fold greater VAT both in units of mass (542 ± 451 g; 95% CI: 479.6‒605.1 g vs. 258 ± 226 g; 95% CI: 226.9‒288.6 g) and volume (570 ± 468 cm3; 95% CI: 505.1‒635.2 cm3 vs. 273 ± 237 cm3; 95% CI: 240.6‒305.3 cm3). They also had significantly higher the VAT/BF ratio. VAT showed a stronger positive correlation than BF with blood pressure, triglycerides, LDL-cholesterol, glucose, insulin, and homeostasis model assessment-insulin resistance index and a stronger negative correlation with HDL-cholesterol. Among these variables, VAT had the highest area under the curve for triglycerides ≥150 mg/dL (0.727 in males and 0.712 in females). In conclusion, we provide reference values for VAT obtained from healthy adults using the GE Healthcare DXA. These values may be useful in the diagnosis of visceral obesity, for identifying subjects with high obesity-related risks, in epidemiological studies, as a target for therapies, and in physically trained individuals. In both genders, VAT was associated with traditional cardiometabolic risk factors, particularly hypertriglyceridemia.

Age-dependent transcriptional and epigenomic responses to light exposure in the honey bee brain.

Light is a powerful environmental stimulus of special importance in social honey bees that undergo a behavioral transition from in-hive to outdoor foraging duties. Our previous work has shown that light exposure induces structural neuronal plasticity in the mushroom bodies (MBs), a brain center implicated in processing inputs from sensory modalities. Here, we extended these analyses to the molecular level to unravel light-induced transcriptomic and epigenomic changes in the honey bee brain. We have compared gene expression in brain compartments of 1- and 7-day-old light-exposed honey bees with age-matched dark-kept individuals. We have found a number of differentially expressed genes (DEGs), both novel and conserved, including several genes with reported roles in neuronal plasticity. Most of the DEGs show age-related changes in the amplitude of light-induced expression and are likely to be both developmentally and environmentally regulated. Some of the DEGs are either known to be methylated or are implicated in epigenetic processes suggesting that responses to light exposure are at least partly regulated at the epigenome level. Consistent with this idea light alters the DNA methylation pattern of bgm, one of the DEGs affected by light exposure, and the expression of microRNA miR-932. This confirms the usefulness of our approach to identify candidate genes for neuronal plasticity and provides evidence for the role of epigenetic processes in driving the molecular responses to visual stimulation.

Decreased expression of heme oxygenase is associated with depressive symptoms and may contribute to depressive and hypertensive comorbidity.

BACKGROUND: There is strong evidence that hypertension and depression are comorbid and oxidative stress is implicated in both pathologies. We aimed to elucidate the relationship between biochemical markers of the antioxidant-pro-oxidant equilibrium and depression in hypertension. METHODS: Blood was collected from patients diagnosed with depression, hypertension, or comorbid depression and hypertension and healthy age- and sex-matched controls. Whole blood reduced glutathione, erythrocyte superoxide dismutase (SOD-1), glutathione peroxidase (GPx-1), glutathione reductase (GR), malondialdehyde (MDA), and plasma hydrogen peroxide (H2O2) were assayed using spectrophotometry, and heme oxygenase (HO-1) levels were determined immunoenzymatically. RESULTS: Both hypertension and depression were associated with altered antioxidant-pro-oxidant profiles. Decreased GPx-1 and SOD-1 activities, increased GR activity, increased levels of GSH, and increased concentrations of MDA and H2O2 were observed in patients compared to controls. Inducible HO-1 was specifically decreased in patients with depression and was significantly associated with both the prevalence and severity of depressive symptoms. CONCLUSIONS: Heme oxygenase is a biological factor that might explain the relationship between inflammation, oxidative stress, and the biological and functional changes in brain activity in depression. HO-1 is a candidate depression biomarker and provides an avenue for novel preventative and diagnostic strategies against this disease.

Differentially methylated obligatory epialleles modulate context-dependent LAM gene expression in the honeybee Apis mellifera.

Differential intragenic methylation in social insects has been hailed as a prime mover of environmentally driven organismal plasticity and even as evidence for genomic imprinting. However, very little experimental work has been done to test these ideas and to prove the validity of such claims. Here we analyze in detail differentially methylated obligatory epialleles of a conserved gene encoding lysosomal α-mannosidase (AmLAM) in the honeybee. We combined genotyping of progenies derived from colonies founded by single drone inseminated queens, ultra-deep allele-specific bisulfite DNA sequencing, and gene expression to reveal how sequence variants, DNA methylation, and transcription interrelate. We show that both methylated and non-methylated states of AmLAM follow Mendelian inheritance patterns and are strongly influenced by polymorphic changes in DNA. Increased methylation of a given allele correlates with higher levels of context-dependent AmLAM expression and appears to affect the transcription of an antisense long noncoding RNA. No evidence of allelic imbalance or imprinting involved in this process has been found. Our data suggest that by generating alternate methylation states that affect gene expression, sequence variants provide organisms with a high level of epigenetic flexibility that can be used to select appropriate responses in various contexts. This study represents the first effort to integrate DNA sequence variants, gene expression, and methylation in a social insect to advance our understanding of their relationships in the context of causality.

The impact of fragility fractures on health-related quality of life in patients with primary sclerosing cholangitis.

BACKGROUND: Osteoporosis occurs frequently in patients with chronic cholestatic liver diseases, yet data are scarce regarding the prevalence of osteoporosis and fragility fractures and their impact on Health-Related Quality of Life (HRQoL) in Primary Sclerosing Cholangitis (PSC). OBJECTIVES: We aimed to assess Bone Mineral Density (BMD), physical activity and incidence of fragility fractures in patients with PSC. We also sought associations between prior fractures and HRQoL. PATIENTS AND METHODS: The study was performed on 33 patients (11 females, 22 males) aged 35.3 ± 13 years. HRQoL was assessed by Short Form (SF)-36, Primary Biliary Cirrhosis (PBC)-40 and PBC-27 questionnaires. BMD was measured by densitometry in the lumbar spine and hip. Physical activity was assessed by questionnaire. RESULTS: In 32% of patients, BMD measured in the hip or spine was below 1.0 Standard Deviation. A history of fragility fractures (distal forearm and ribs) was reported in six patients (18%). In SF-36 assessment, patients with fractures had lower scores in the role functioning, general health and vitality domains and Physical Component Summary (PCS) than those without fractures. Prior fractures adjusted for gender and PSC duration were associated with lower PCS and Mental Component Summary (MCS) scores. Symptoms and fatigue (assessed by PBC) and prior fractures were inversely associated with MCS (P = 0.007). CONCLUSIONS: In middle-aged subjects with PSC, we found a high rate of non-vertebral fractures and a moderately decreased BMD in lumbar spine and hip. Fragility fractures had an impact on physical and mental aspects of HRQoL.