Visual outcomes and predictors in optic pathway glioma: a single centre study

BACKGROUND/AIMS: Optic pathway gliomas (OPGs) may cause progressive visual loss despite chemotherapy. Newer, less toxic treatments might be given earlier, depending on visual prognosis. We aimed to investigate the prognostic value of visual evoked potentials (VEP) and optical coherence tomography (OCT). METHODS: A retrospective study of OPG patients (treated 2003–2017) was conducted. Primary outcome was PEDIG category visual acuity in better and worse eyes (good  = 0.7 logMAR). Binary logistic regression analysis was used to identify predictors of these outcomes. RESULTS: 60 patients (32 Neurofibromatosis type 1 [NF1] and 28 sporadic) had median presentation age 49 months (range 17–183) (NF1) and 27 months (range 4–92) (sporadic). Median follow up was 82 months (range 12–189 months). At follow up 24/32 (75%) of NF1 children and 14/28 (50%) of sporadic children had good better eye visual acuity and 11/32 (34%) of NF1 children and 15/28 (54%) of sporadics had poor worse eye acuity. Mean peripapillary retinal nerve fibre layer (RNFL) thickness predicted good better eye final acuity (OR 0.799, 95%CI 0.646–0.987, p = 0.038). Presenting with visual symptoms (OR 0.22 95% CI 0.001–0.508, p = 0.017) and poorer VEP scores (OR 2.35 95% CI 1.1–5.03, p = 0.027) predicted poor worse eye final acuity. 16 children had homonymous hemianopias at follow up, predicted by poor presenting binocular VEP score (OR 1.449 95%CI 1.052–1.995, p = 0.02). CONCLUSIONS: We found that both RNFL thickness on OCT and VEP were useful in predicting future visual acuity and vision and potentially in planning treatment. We had a high prevalence of homonymous hemianopia

Spatially-resolved electronic and vibronic properties of single diamondoid molecules

Diamondoids are a unique form of carbon nanostructure best described as hydrogen-terminated diamond molecules. Their diamond-cage structures and tetrahedral sp3 hybrid bonding create new possibilities for tuning electronic band gaps, optical properties, thermal transport, and mechanical strength at the nanoscale. The recently-discovered higher diamondoids (each containing more than three diamond cells) have thus generated much excitement in regards to their potential versatility as nanoscale devices. Despite this excitement, however, very little is known about the properties of isolated diamondoids on metal surfaces, a very relevant system for molecular electronics. Here we report the first molecular scale study of individual tetramantane diamondoids on Au(111) using scanning tunneling microscopy and spectroscopy. We find that both the diamondoid electronic structure and electron-vibrational coupling exhibit unique spatial distributions characterized by pronounced line nodes across the molecular surfaces. Ab-initio pseudopotential density functional calculations reveal that the observed dominant electronic and vibronic properties of diamondoids are determined by surface hydrogen terminations, a feature having important implications for designing diamondoid-based molecular devices.Comment: 16 pages, 4 figures. to appear in Nature Material

A randomised controlled trial among cleaners-Effects on strength, balance and kinesiophobia

<p>Abstract</p> <p>Background</p> <p>Cleaners constitute a job group with poor health and low socioeconomic resources. Therefore, there is a great need for scientifically documented health promoting initiatives for cleaners. However, both workplace initiatives and high quality intervention studies are lacking. The aim of this study was to evaluate the effects of a 3-month workplace trial with interventions to improve physical or cognitive behavioural resources among cleaners.</p> <p>Methods</p> <p>A cluster randomised controlled trial was conducted among 294 female cleaners from 9 workplaces. The participants were allocated to three groups: Physical coordination training (PCT, n = 95), Cognitive behavioural theory-based training (CBTr, n = 99) and Reference group (REF, n = 100). Interventions were conducted during work hours for an average of 1 hour/week. Muscle strength was measured by maximal voluntary contractions in trunk/extension, and shoulder abduction/elevation. Postural balance was measured on a force platform. Kinesiophobia was measured with Tampa Scale for Kinesiophobia. Test and questionnaires were completed at baseline and at 3-month follow-up and analyses followed the intention-to-treat (ITT) principle with last observation carried forward in case of missing data at follow-up. Reports and analyses are given on true observations as well.</p> <p>Results</p> <p>ITT-analyses revealed that PCT improved strength of the trunk (p < .05) and postural balance (p < .05) compared to CBTr and REF. Based on true observations the strength and balance improvements corresponded to ~20% and ~16%, respectively. ITT-analyses showed that CBTr reduced kinesiophobia compared to PCT and REF (p < .05). Based on true observations, the improvement corresponded to a ~16% improvement.</p> <p>Conclusion</p> <p>This workplace-based intervention study including PCT and CBTr among cleaners improved strength and postural balance from PCT, and kinesiophobia from CBTr. The improved strength, postural balance and kinesiophobia may improve the cleaners' tolerance for high physical work demands. Future studies should investigate the potential in the combination of PCT and CBTr in a workplace intervention.</p> <p>Trial registration</p> <p>Current controlled trials <a href="http://www.controlled-trials.com/ISRCTN96241850">ISRCTN96241850</a></p

A two-domain elevator mechanism for sodium/proton antiport

Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general

Pancreas Whole Tissue Transcriptomics Highlights the Role of the Exocrine Pancreas in Patients With Recently Diagnosed Type 1 Diabetes

Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from the laser-captured pancreatic islets of the DiViD patients and non-diabetic organ donors were analyzed together with the original dataset to confirm the results and to get further insights into the potential disease-associated differences between the exocrine and the endocrine pancreas. First, higher expression of the core acinar cell genes, encoding for digestive enzymes, was detected in the whole pancreas of the DiViD patients when compared to non-diabetic controls. Second, In the pancreatic islets, upregulation of immune and inflammation related genes was observed in the DiViD patients when compared to non-diabetic controls, in line with earlier publications, while an opposite trend was observed for several immune and inflammation related genes at the whole pancreas tissue level. Third, strong downregulation of the regenerating gene family (REG) genes, linked to pancreatic islet growth and regeneration, was observed in the exocrine acinar cell dominated whole-pancreas data of the DiViD patients when compared with the non-diabetic controls. Fourth, analysis of unique features in the transcriptomes of each DiViD patient compared with the other DiViD patients, revealed elevated expression of central antiviral immune response genes in the whole-pancreas samples, but not in the pancreatic islets, of one DiViD patient. This difference in the extent of antiviral gene expression suggests different statuses of infection in the pancreas at the time of sampling between the DiViD patients, who were all enterovirus VP1+ in the islets by immunohistochemistry based on earlier studies. The observed features, indicating differences in the function, status and interplay between the exocrine and the endocrine pancreas of recent onset T1D patients, highlight the importance of studying both compartments for better understanding of the molecular mechanisms of T1D.publishedVersionPeer reviewe

Pancreas Whole Tissue Transcriptomics Highlights the Role of the Exocrine Pancreas in Patients With Recently Diagnosed Type 1 Diabetes

Although type 1 diabetes (T1D) is primarily a disease of the pancreatic beta-cells, understanding of the disease-associated alterations in the whole pancreas could be important for the improved treatment or the prevention of the disease. We have characterized the whole-pancreas gene expression of patients with recently diagnosed T1D from the Diabetes Virus Detection (DiViD) study and non-diabetic controls. Furthermore, another parallel dataset of the whole pancreas and an additional dataset from the laser-captured pancreatic islets of the DiViD patients and non-diabetic organ donors were analyzed together with the original dataset to confirm the results and to get further insights into the potential disease-associated differences between the exocrine and the endocrine pancreas. First, higher expression of the core acinar cell genes, encoding for digestive enzymes, was detected in the whole pancreas of the DiViD patients when compared to non-diabetic controls. Second, In the pancreatic islets, upregulation of immune and inflammation related genes was observed in the DiViD patients when compared to non-diabetic controls, in line with earlier publications, while an opposite trend was observed for several immune and inflammation related genes at the whole pancreas tissue level. Third, strong downregulation of the regenerating gene family (REG) genes, linked to pancreatic islet growth and regeneration, was observed in the exocrine acinar cell dominated whole-pancreas data of the DiViD patients when compared with the non-diabetic controls. Fourth, analysis of unique features in the transcriptomes of each DiViD patient compared with the other DiViD patients, revealed elevated expression of central antiviral immune response genes in the whole-pancreas samples, but not in the pancreatic islets, of one DiViD patient. This difference in the extent of antiviral gene expression suggests different statuses of infection in the pancreas at the time of sampling between the DiViD patients, who were all enterovirus VP1+ in the islets by immunohistochemistry based on earlier studies. The observed features, indicating differences in the function, status and interplay between the exocrine and the endocrine pancreas of recent onset T1D patients, highlight the importance of studying both compartments for better understanding of the molecular mechanisms of T1D.</p

An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells

Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells

Promoter- and cell-specific epigenetic regulation of CD44, Cyclin D2, GLIPR1 and PTEN by Methyl-CpG binding proteins and histone modifications

<p>Abstract</p> <p><it>Background</it></p> <p>The aim of the current study was to analyze the involvement of methyl-CpG binding proteins (MBDs) and histone modifications on the regulation of CD44, Cyclin D2, GLIPR1 and PTEN in different cellular contexts such as the prostate cancer cells DU145 and LNCaP, and the breast cancer cells MCF-7. Since global chromatin changes have been shown to occur in tumours and regions of tumour-associated genes are affected by epigenetic modifications, these may constitute important regulatory mechanisms for the pathogenesis of malignant transformation.</p> <p><it>Methods</it></p> <p>In DU145, LNCaP and MCF-7 cells mRNA expression levels of CD44, Cyclin D2, GLIPR1 and PTEN were determined by quantitative RT-PCR at the basal status as well as after treatment with demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor Trichostatin A. Furthermore, genomic DNA was bisulfite-converted and sequenced. Chromatin immunoprecipitation was performed with the stimulated and unstimulated cells using antibodies for MBD1, MBD2 and MeCP2 as well as 17 different histone antibodies.</p> <p><it>Results</it></p> <p>Comparison of the different promoters showed that MeCP2 and MBD2a repressed promoter-specifically Cyclin D2 in all cell lines, whereas in MCF-7 cells MeCP2 repressed cell-specifically all methylated promoters. Chromatin immunoprecipitation showed that all methylated promoters associated with at least one MBD. Treatment of the cells by the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) caused dissociation of the MBDs from the promoters. Only MBD1v1 bound and repressed methylation-independently all promoters. Real-time amplification of DNA immunoprecipitated by 17 different antibodies showed a preferential enrichment for methylated lysine of histone H3 (H3K4me1, H3K4me2 and H3K4me3) at the particular promoters. Notably, the silent promoters were associated with unmodified histones which were acetylated following treatment by 5-aza-CdR.</p> <p><it>Conclusions</it></p> <p>This study is one of the first to reveal the histone code and MBD profile at the promoters of CD44, Cyclin D2, GLIPR1 and PTEN in different tumour cells and associated changes after stimulation with methylation inhibitor 5-aza-CdR.</p

Modeling a New Water Channel That Allows SET9 to Dimethylate p53

SET9, a protein lysine methyltransferase, has been thought to be capable of transferring only one methyl group to target lysine residues. However, some reports have pointed out that SET9 can dimethylate Lys372 of p53 (p53-K372) and Lys4 of histone H3 (H3-K4). In order to understand how p53 can be dimethylated by SET9, we measured the radius of the channel that surrounds p53-K372, first on the basis of the crystal structure of SET9, and we show that the channel is not suitable for water movement. Second, molecular dynamic (MD) simulations were carried out for 204 ns on the crystal structure of SET9. The results show that water leaves the active site of SET9 through a new channel, which is made of G292, A295, Y305 and Y335. In addition, the results of molecular docking and MD simulations indicate that the new water channel continues to remain open when S-adenosyl-L-methionine (AdoMet) or S-adenosyl-L-homocysteine (AdoHcy) is bound to SET9. The changes in the radii of these two channels were measured in the equilibrium phase at the constant temperature of 300 K. The results indicate that the first channel still does not allow water to get into or out of the active site, but the new channel is large enough to allow this water to circulate. Our results indicate that water can be removed from the active site, an essential process for allowing the dimethylation reaction to occur