Mutations in
ANKRD11
have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To ...understand the pathogenic mechanism that relates
ANKRD11
mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic
ANKRD11
variants in humans, including six reported in this study, and one reported in the
Ankrd11
Yod/
+
mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.
To provide equipercentile equating of physical function (PF) scores from frequently used patient-reported outcome measures (PROMs) in cancer patients to facilitate data pooling and comparisons.
Adult ...cancer patients from five European countries completed the European Organization for Research and Treatment of Cancer (EORTC) computer adaptive test (CAT) Core, EORTC Quality of Life Questionnaire Version 3.0 (QLQ-C30), Functional Assessment of Cancer Therapy - General (FACT-G), 36-item Short Form Health Survey (SF-36), and the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function 20a short form. The R package "equate" was used to establish conversion tables of PF scores on those measures with a bivariate rank correlation of at least 0.75.
In total, 953 patients with cancer (mean age 58.9 years, 54.7% men) participated. Bivariate rank correlations between PF scores from the EORTC CAT Core, EORTC QLQ-C30, SF-36, and PROMIS were all above 0.85, but below 0.69 for the FACT-G. Conversion tables were established for all measures but the FACT-G. These tables indicate which score from one PROM best matches the score from another PROM and provide standard errors of converted scores.
Our analysis indicates that linking of PF scores from both EORTC measures (CAT and QLQ-C30) with PROMIS and SF-36 is possible, whereas the physical domain of the FACT-G seems to be different. The established conversion tables may be used for comparing results or pooling data from clinical studies using different PROMs.
Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental ...retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2(-/y)).
We found that EE delayed and attenuated some neurological alterations presented by Mecp2(-/y) mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models.
We found that EE induced downregulation of several synaptic markers, suggesting that the partial prevention of RTT-associated phenotypes is achieved through a non-conventional transcriptional program.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND AND PURPOSE—Prophylactic treatments that afford neuroprotection against stroke may emerge from the field of preconditioning. Resveratrol mimics ischemic preconditioning, reducing ischemic ...brain injury when administered 2 days before global ischemia in rats. This protection is linked to silent information regulator 2 homologue 1 (Sirt1) and enhanced mitochondrial function possibly through its repression of uncoupling protein 2. Brain-derived neurotrophic factor (BDNF) is another neuroprotective protein associated with Sirt1. In this study, we sought to identify the conditions of resveratrol preconditioning (RPC) that most robustly induce neuroprotection against focal ischemia in mice.
METHODS—We tested 4 different RPC paradigms against a middle cerebral artery occlusion model of stroke. Infarct volume and neurological score were calculated 24 hours after middle cerebral artery occlusion. Sirt1-chromatin binding was evaluated by ChIP-qPCR. Percoll gradients were used to isolate synaptic fractions, and changes in protein expression were determined via Western blot analysis. BDNF concentration was measured using a BDNF-specific ELISA assay.
RESULTS—Although repetitive RPC induced neuroprotection from middle cerebral artery occlusion, strikingly one application of RPC 14 days before middle cerebral artery occlusion showed the most robust protection, reducing infarct volume by 33% and improving neurological score by 28%. Fourteen days after RPC, Sirt1 protein was increased 1.5-fold and differentially bound to the uncoupling protein 2 and BDNF promoter regions. Accordingly, synaptic uncoupling protein 2 level decreased by 23% and cortical BDNF concentration increased 26%.
CONCLUSIONS—RPC induces a novel extended window of ischemic tolerance in the brain that lasts for at least 14 days. Our data suggest that this tolerance may be mediated by Sirt1 through upregulation of BDNF and downregulation of uncoupling protein 2.
Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome characterized ...by high myopia and sensorineural deafness. Our molecular investigation in 3 families led to the identification of 3 homozygous nonsense mutations (p.R181X, p.S297X, and p.Q414X) in SLIT and NTRK-like family, member 6 (SLITRK6), a leucine-rich repeat domain transmembrane protein. All 3 mutant SLITRK6 proteins displayed defective cell surface localization. High-resolution MRI of WT and Slitrk6-deficient mouse eyes revealed axial length increase in the mutant (the endophenotype of myopia). Additionally, mutant mice exhibited auditory function deficits that mirrored the human phenotype. Histological investigation of WT and Slitrk6-deficient mouse retinas in postnatal development indicated a delay in synaptogenesis in Slitrk6-deficient animals. Taken together, our results showed that SLITRK6 plays a crucial role in the development of normal hearing as well as vision in humans and in mice and that its disruption leads to a syndrome characterized by severe myopia and deafness.
We previously demonstrated that in Alzheimer's disease (AD) patients, European apolipoprotein E (APOE) ε4 carriers express significantly more APOE ε4 in their brains than African AD carriers. We ...examined single nucleotide polymorphisms near APOE with significant frequency differences between African and European/Japanese APOE ε4 haplotypes that could contribute to this difference in expression through regulation. Two enhancer massively parallel reporter assay (MPRA) approaches were performed, supplemented with single fragment reporter assays. We used Capture C analyses to support interactions with the APOE promoter. Introns within TOMM40 showed increased enhancer activity in the European/Japanese versus African haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. Identification of the mechanisms for differential regulatory function for APOE expression between African and European/Japanese haplotypes could lead to therapeutic targets for APOE ε4 carriers.
Introduction
Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). ...Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences.
Methods
Single‐nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.
Results
A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44‐46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P < 1.8E–317) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE ε4 expression and specific to ELA, is suggestive of A1 reactive astrocytes.
Discussion
AD patients with ELA expressed significantly greater levels of APOE than ALA APOE ε4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE ε4 carriers.
Patient-reported physical function (PF) is a key endpoint in cancer clinical trials. Using complex statistical methods, common metrics have been developed to compare scores from different ...patient-reported outcome (PRO) measures, but such methods do not account for possible differences in questionnaire content. Therefore, the aim of our study was a content comparison of frequently used PRO measures for PF in cancer patients.
Relying on the framework of the International Classification of Functioning, Disability and Health (ICF) we categorized the item content of the physical domains of the following measures: EORTC CAT Core, EORTC QLQ-C30, SF-36, PROMIS Cancer Item Bank for Physical Function, PROMIS Short Form for Physical Function 20a, and the FACT-G. Item content was linked to ICF categories by two independent reviewers.
The 118 items investigated were assigned to 3 components ('d - Activities and Participation', 'b - Body Functions', and 'e - Environmental Factors') and 11 first-level ICF categories. All PF items of the EORTC measures but one were assigned to the first-level ICF categories 'd4 - Mobility' and 'd5 - Self-care', all within the component 'd - Activities and Participation'. The SF-36 additionally included item content related to 'd9 - Community, social and civic life' and the PROMIS Short Form for Physical Function 20a also included content related to 'd6 - domestic life'. The PROMIS Cancer Item Bank (v1.1) covered, in addition, two first-level categories within the component 'b - Body Functions'. The FACT-G Physical Well-being scale was found to be the most diverse scale with item content partly not covered by the ICF framework.
Our results provide information about conceptual differences between common PRO measures for the assessment of PF in cancer patients. Our results complement quantitative information on psychometric characteristics of these measures and provide a better understanding of the possibilities of establishing common metrics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this article was to establish thresholds for clinical importance (TCIs) for the European Organisation for Research and Treatment of Cancer (EORTC) Computer Adaptive Testing (CAT) Core ...measure, the new adaptive version of the EORTC QLQ-C30.
For our diagnostic study, we recruited cancer patients with mixed diagnoses and treatments from six European countries. Patients completed the EORTC CAT Core and a questionnaire with anchor items assessing criteria for clinical importance (limitations in everyday life, need for help/care, and worries by the patient/family/partner) for each EORTC CAT Core domain. We used a binary variable summarizing the anchor items for determining TCIs and for calculating the area under the curve (AUC) in receiving operator characteristic analysis as a measure of diagnostic accuracy.
Using data from 498 cancer patients (mean age 60.4 years, 55.2% women), we established TCIs for the 14 domains of the EORTC CAT Core. Median AUC across domains was 0.93 (range 0.84–0.94). Median sensitivity and specificity of the TCIs were 0.91 (range 0.80–0.96) and 0.77 (range 0.66–0.84), respectively. TCIs and AUCs were largely consistent across patient groups.
We have generated TCIs for the 14 functional health and symptom domains of the EORTC CAT Core. The EORTC CAT Core showed high diagnostic accuracy in identifying clinically important symptoms and functional impairments.
Rett syndrome (RTT) is a disorder that affects patients' ability to communicate, move and behave. RTT patients are characterized by impaired language, stereotypic behaviors, frequent seizures, ataxia ...and sleep disturbances, with the onset of symptoms occurring after a period of seemingly normal development. RTT is caused by mutations in methyl-CpG binding protein 2 (MECP2), an X-chromosome gene encoding for MeCP2, a protein that regulates gene expression. MECP2 generates two alternative splice variants encoding two protein isoforms that differ only in the N-terminus. Although no functional differences have been identified for these splice variants, it has been suggested that the RTT phenotype may occur in the presence of a functional MeCP2-e2 protein. This suggests that the two isoforms might be functionally distinct. Supporting this notion, the two variants show regional and age-related differences in transcript abundance. Here, we show that transgenic expression of either the MeCP2-e1 or MeCP2-e2 splice variant results in prevention of development of RTT-like phenotypic manifestations in a mouse model lacking Mecp2. Our results indicate that the two MeCP2 splice variants can substitute for each other and fulfill the basic functions of MeCP2 in the mouse brain.
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