Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem ...system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.
This study aimed to compare cognitive and memory abilities between older adults with and without autism over the age of 50. Twenty-eight individuals with autism and 29 typically developing (TD) older ...adults took part in the current study. Participants’ cognitive and memory abilities were assessed by WAIS-IV and WMS-IV. Older autistic adults were found to have poorer performance in processing speed and visual working memory, but they performed at a similar level as TD controls in all other domains. Poorer processing speed and visual working memory are also often found to be associated with age-related decline in neurotypical adults. Longitudinal studies are warranted to explore how the combination of ageing and autism affects cognitive functioning in older adults.
This study aims at evaluating the symptom response, response duration, and toxicity of single dose palliative liver radiotherapy (RT) for symptomatic HCC patients. We reviewed unresectable HCC ...patients treated with palliative RT in our institution. Eligible patients were unsuitable or refractory to trans-arterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT), with an index symptom of pain or abdominal discomfort. The primary outcome was the percentage of patients with clinical improvement of index symptom at 1 month. Secondary outcomes were response duration, toxicities, alpha-feto protein (AFP) response, and radiological response. Fifty-two patients were included in the study. The index symptom was pain in 34 patients (65.4%), and abdominal discomfort (34.6%) in 18 patients. At 1 month, 51.9% of patients had improvement of symptoms. Median time to symptom progression was 89 days (range: 12-392 days). Treatment was well tolerated with only 2 patients (3.8%) developing grade 3 GI toxicities. AFP response, radiological response rate, and disease control rate at 3 months were 48.6%, 15.1%, and 54.5% respectively. Half of the patients had improvement of index symptoms after receiving palliative liver RT with median response duration of 3 months. The treatment was well tolerated with minimal toxicities.
Teacher stress and burnout have a detrimental effect on the stability of the teaching workforce. However, the possible consequences of teacher burnout on teaching quality and on student learning ...outcomes are less clear, especially in special education settings. We applied Maslach and Leiter’s (1999) model to understand the direct effects of burnout on teaching in general and stress arising from interaction with a specific student on the individualized education program (IEP) outcomes of young children with autism spectrum disorder. We also examined indirect effects through teaching quality and student engagement. The results indicated that one of the three components of burnout—teacher personal accomplishment—was directly related to IEP outcomes, a distal effect, whereas stress was directly related to teaching quality and student engagement, which were more proximal effects. In addition, teacher stress, emotional exhaustion, and depersonalization had indirect effects on IEP outcomes through teaching quality and student engagement.
Background
A key step in clinical flow cytometry data analysis is gating, which involves the identification of cell populations. The process of gating produces a set of reportable results, which are ...typically described by gating definitions. The non‐standardized, non‐interpreted nature of gating definitions represents a hurdle for data interpretation and data sharing across and within organizations. Interpreting and standardizing gating definitions for subsequent analysis of gating results requires a curation effort from experts. Machine learning approaches have the potential to help in this process by predicting expert annotations associated with gating definitions.
Methods
We created a gold‐standard dataset by manually annotating thousands of gating definitions with cell type and functional marker annotations. We used this dataset to train and test a machine learning pipeline able to predict standard cell types and functional marker genes associated with gating definitions.
Results
The machine learning pipeline predicted annotations with high accuracy for both cell types and functional marker genes. Accuracy was lower for gating definitions from assays belonging to laboratories from which limited or no prior data was available in the training. Manual error review ensured that resulting predicted annotations could be reused subsequently as additional gold‐standard training data.
Conclusions
Machine learning methods are able to consistently predict annotations associated with gating definitions from flow cytometry assays. However, a hybrid automatic and manual annotation workflow would be recommended to achieve optimal results.
Autism is a neurodevelopmental condition that affects individuals across their lifetime, though the effects of ageing in older adulthood are poorly understood to date. This systematic review assessed ...six characteristics in older autistic adults (cognitive functioning, co-occurring difficulties, autism symptom severity, social integration, adaptive functioning, language processing). A total of 41 studies met inclusion criteria, 16 of which included autistic adults with intellectual disability, and three were longitudinal in nature. Findings show differing effects of ageing across the six domains. Factors contributing to discrepancies such as age and IQ differences, methodology and healthy survivor effect are discussed. The need for more longitudinal studies to investigate changes across developmental stages alongside other limitations, future directions and clinical implications are discussed.
Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of midbrain dopaminergic neurons, the pathogenetic mechanisms of which remain unclear. Mitochondrial dysfunction, which ...has long been implicated in sporadic PD, has recently been highlighted as a key pathological cause, particularly with the identification of mutations in the PTEN-induced putative kinase (pink1), parkin and htrA2 (also known as omi) genes that are linked to PD. Studies in Drosophila melanogaster have shown that pink1 and parkin act in a common genetic pathway that maintains mitochondrial integrity, but other upstream or downstream components of this pathway are currently unknown. Using ectopic expression in the Drosophila eye as an assay, we have investigated the involvement of the mitochondrial protease encoded by omi in the Pink1/Parkin pathway and found that it acts genetically downstream of pink1 but functions independently of Parkin. Using the same approach, we also found that Rhomboid-7, a mitochondrial protease not previously implicated in PD, acts as an upstream component of this pathway, and showed that it is required to cleave the precursor forms of both Pink1 and Omi. These data further elucidate the composition of the Pink1 pathway and suggest that regulated intramembrane proteolysis is involved in its regulation.
Radiotherapy with electrons is commonly applied to the tumor bed after whole-breast radiotherapy following breast conservation surgery for breast cancer patients. However, the radiation dose to ...adjacent organs-at-risk (OARs) and conformity of planning target volume (PTV) cannot be optimized. In this study, we examine the feasibility of using modulated electron bolus (MEB) to improve PTV conformity and reduce the dose to these OARs. Twenty-seven patients with left breast cancer were retrospectively selected in this study. For each patient, a tangential photon plan in RayStation treatment planning system with prescription of 26 Gy in 5 fractions was created as base plan. Two electron plans, one without bolus and one with MEB using Adaptiiv software based on the PTV were created. Various dosimetric parameters of OARs including left lung, heart, left anterior descending artery (LAD) and ribs and the conformity indices of PTV of these 2 electron plans together with the base plans were compared. Statistically significant decreases in the dosimetric parameters (V
, V
, V
, and mean dose) of the ipsilateral left lung and the heart were observed with MEB. The median maximum dose to the LAD and the ribs decreased by 6.2% and 4.5% respectively. The median conformity index was improved by 14.3% with median increases of monitor units by 1.7%. Our results show that MEB is feasible resulting in reduction of doses to the predefined OARs and an improved conformity of PTV. By using 3D printing, MEB might be considered as an alternative to conventional electron boost.
Purpose
Idasanutlin is a selective small-molecule MDM2 antagonist. It activates the tumor suppressor TP53 and is in phase 3 clinical trial for acute myeloid leukemia. Nonclinical studies have shown ...that glucuronidation is the major metabolizing mechanism for idasanutlin and UGT1A3 is the major metabolizing enzyme. There are reported examples of UGT polymorphisms associated with drug metabolism or response. Thus, the aim of this analysis is to investigate if UGT polymorphism is associated with idasanutlin pharmacokinetics.
Method
Idasanutlin clearance was derived and normalized from two phase I studies. Its clearance level was compared between patients with different genotypes at 44 non-monomorphic UGT SNPs. Several single-locus and multi-locus association analysis, including haplotype association analysis and pairwise SNP interaction (epistasis) analyses were performed to investigate if there is any association between UGT genotypes and idasanutlin clearance.
Results and conclusion
A total of 69 patients who have both idasanutlin pharmacokinetic data and UGT genotyping data were analyzed for association. The major clearance enzyme for idasanutlin, UGT1A3, has no association with idasanutlin clearance. Further single-locus and multi-locus association analyses also suggest that no significant UGT polymorphism association with idasanutlin clearance can be detected with the current datasets. However, the possibility of association with rare allele(s) of UGT family genes cannot be excluded due to the limited sample size of the current phase I studies.
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