cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5125264
title: Supplementary Material for: The Gap between Trial Data and Clinical Practice - An Analysis of Case Reports on Bleeding Complications Occurring under Dabigatran and Rivaroxaban Anticoagulation

description: <b><i>Background:</i></b> The novel direct oral anticoagulants (NOA), dabigatran (a thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have shown at least noninferiority compared to warfarin concerning the prevention of stroke and systemic embolism as well as the risk of hemorrhagic complications in large phase III trials in patients with atrial fibrillation (AF). These results have been obtained under regular monitoring of side effects and reinforcement of medication adherence in carefully controlled clinical trials. To what extent they translate into clinical practice is a matter of ongoing research. While postmarketing registers, most prominently the GLORIA-AF registry, are currently recruiting and will not report data for several years, we aimed at extracting risk factors for hemorrhagic complications under NOA from all available case reports and single case series published to date. <b><i>Methods:</i></b> To identify risk factors which increase the risk of hemorrhage under NOA, we performed a PubMed search for both dabigatran and rivaroxaban, as well as three search terms for hemorrhagic complications. The cases of hemorrhagic complications were analyzed for the presence of the following four factors: ‘prescriber errors', ‘unfavorable comedications', ‘renal impairment' and ‘prescription of NOA in the frail elderly'. <b><i>Results and Discussion:</i></b> We found a discrepancy in the frequency of case reports on hemorrhagic complications to the disadvantage of dabigatran which can hardly be attributed to the earlier marketing time of dabigatran alone. As risk factors, we identified prescriber errors, impaired renal function, comedication with antiplatelet drugs or p-glycoprotein inhibitors, old age and low body weight. Strikingly, the majority of the bleeding complications reported in this compilation of case reports showed at least one and in most cases several risk factors. <b><i>Conclusions:</i></b> We should, therefore, carefully select our patients for treatment with the NOA with an emphasis on age, body weight, renal function and comedications and follow them faithfully concerning their medication adherence and eventual side effects.
DOI: 10.6084/m9.figshare.5125252
title: Supplementary Material for: Adult and Near-Adult Height in Patients with Severe Insulin-Like Growth Factor-I Deficiency after Long-Term Therapy with Recombinant Human Insulin-Like Growth Factor-I

description: <b><i>Background:</i></b> Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). <b><i>Aims:</i></b> To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. <b><i>Methods:</i></b> Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. <b><i>Results:</i></b> Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. <b><i>Conclusion:</i></b> Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range.
DOI: 10.6084/m9.figshare.5125255
title: Supplementary Material for: Control of Protein Function through Regulated Protein Degradation: Biotechnological and Biomedical Applications

description: Targeted protein degradation is crucial for the correct function and maintenance of a cell. In bacteria, this process is largely performed by a handful of ATP-dependent machines, which generally consist of two components - an unfoldase and a peptidase. In some cases, however, substrate recognition by the protease may be regulated by specialized delivery factors (known as adaptor proteins). Our detailed understanding of how these machines are regulated to prevent uncontrolled degradation within a cell has permitted the identification of novel antimicrobials that dysregulate these machines, as well as the development of tunable degradation systems that have applications in biotechnology. Here, we focus on the physiological role of the ClpP peptidase in bacteria, its role as a novel antibiotic target and the use of protein degradation as a biotechnological approach to artificially control the expression levels of a protein of interest.
DOI: 10.6084/m9.figshare.5125264.v1
title: Supplementary Material for: The Gap between Trial Data and Clinical Practice - An Analysis of Case Reports on Bleeding Complications Occurring under Dabigatran and Rivaroxaban Anticoagulation

description: <b><i>Background:</i></b> The novel direct oral anticoagulants (NOA), dabigatran (a thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have shown at least noninferiority compared to warfarin concerning the prevention of stroke and systemic embolism as well as the risk of hemorrhagic complications in large phase III trials in patients with atrial fibrillation (AF). These results have been obtained under regular monitoring of side effects and reinforcement of medication adherence in carefully controlled clinical trials. To what extent they translate into clinical practice is a matter of ongoing research. While postmarketing registers, most prominently the GLORIA-AF registry, are currently recruiting and will not report data for several years, we aimed at extracting risk factors for hemorrhagic complications under NOA from all available case reports and single case series published to date. <b><i>Methods:</i></b> To identify risk factors which increase the risk of hemorrhage under NOA, we performed a PubMed search for both dabigatran and rivaroxaban, as well as three search terms for hemorrhagic complications. The cases of hemorrhagic complications were analyzed for the presence of the following four factors: ‘prescriber errors', ‘unfavorable comedications', ‘renal impairment' and ‘prescription of NOA in the frail elderly'. <b><i>Results and Discussion:</i></b> We found a discrepancy in the frequency of case reports on hemorrhagic complications to the disadvantage of dabigatran which can hardly be attributed to the earlier marketing time of dabigatran alone. As risk factors, we identified prescriber errors, impaired renal function, comedication with antiplatelet drugs or p-glycoprotein inhibitors, old age and low body weight. Strikingly, the majority of the bleeding complications reported in this compilation of case reports showed at least one and in most cases several risk factors. <b><i>Conclusions:</i></b> We should, therefore, carefully select our patients for treatment with the NOA with an emphasis on age, body weight, renal function and comedications and follow them faithfully concerning their medication adherence and eventual side effects.
DOI: 10.6084/m9.figshare.5125249
title: Supplementary Material for: Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q

description: <b><i>Background/Aims:</i></b> In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. <b><i>Methods:</i></b> We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. <b><i>Results:</i></b> Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 <i>(HK1)</i> and one missense variant in the coding region of <i>DNA2</i>. <b><i>Conclusion:</i></b> Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. <i>HK1</i> is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
DOI: 10.6084/m9.figshare.5125255.v1
title: Supplementary Material for: Control of Protein Function through Regulated Protein Degradation: Biotechnological and Biomedical Applications

description: Targeted protein degradation is crucial for the correct function and maintenance of a cell. In bacteria, this process is largely performed by a handful of ATP-dependent machines, which generally consist of two components - an unfoldase and a peptidase. In some cases, however, substrate recognition by the protease may be regulated by specialized delivery factors (known as adaptor proteins). Our detailed understanding of how these machines are regulated to prevent uncontrolled degradation within a cell has permitted the identification of novel antimicrobials that dysregulate these machines, as well as the development of tunable degradation systems that have applications in biotechnology. Here, we focus on the physiological role of the ClpP peptidase in bacteria, its role as a novel antibiotic target and the use of protein degradation as a biotechnological approach to artificially control the expression levels of a protein of interest.
DOI: 10.6084/m9.figshare.5125246
title: Supplementary Material for: Skin Microbiome Imbalance in Patients with STAT1/STAT3 Defects Impairs Innate Host Defense Responses

description: <b><i>Background:</i></b> Chronic mucocutaneous candidiasis (CMC) and hyper-IgE syndrome (HIES) are primary immunodeficiencies mainly caused by mutations in <i>STAT1</i> and <i>STAT3</i>, respectively. CMC and HIES patients have an increased risk for skin and mucosal infections with fungal pathogens and <i>Staphylococcus aureus</i>. However, it is unknown whether the genetic defects in these patients also affect the skin and mucosal microbiome, which in turn may influence host defense mechanisms. <b><i>Methods:</i></b> The skin and oral microbiome of CMC and HIES patients was compared to that of healthy controls at five body sites using 16S rRNA sequencing. The influence of skin colonizers on the immune response was investigated using in vitro experiments. <b><i>Results:</i></b> The microbiome of CMC and HIES patients contained more Gram-negative bacteria, especially <i>Acinetobacter </i>spp.<i>,</i> and less of the normal <i>Corynebacterium </i>spp. compared to healthy controls. Exposure of human primary leukocytes to <i>Acinetobacter</i> suppressed the cytokine response to <i>Candida albicans </i>and <i>S. aureus,</i> while the normal corynebacteria did not suppress cytokine responses. <b><i>Discussion:</i></b> These results demonstrate that central mediators of immune responses like STAT1 and STAT3 not only directly influence immune responses, but also result in changes in the skin microbiome that in turn can amplify the defective immune response against fungal and microbial pathogens.
DOI: 10.6084/m9.figshare.5125249.v1
title: Supplementary Material for: Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10q

description: <b><i>Background/Aims:</i></b> In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. <b><i>Methods:</i></b> We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. <b><i>Results:</i></b> Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 <i>(HK1)</i> and one missense variant in the coding region of <i>DNA2</i>. <b><i>Conclusion:</i></b> Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. <i>HK1</i> is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
DOI: 10.6084/m9.figshare.5125237
title: Supplementary Material for: Neuronal Nitric Oxide Synthase-Derived Nitric Oxide Is Involved in Gastric Mucosal Hyperemic Response to Capsaicin in Rats

description: <b><i>Background and Aims:</i></b> Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin-sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. <b><i>Methods:</i></b> Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. <b><i>Results:</i></b> The nNOS inhibitor N<sup>5</sup>-[imino(propylamino)methyl]-L-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N<sup>5</sup>-(1-iminomethyl)-L-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N<sup>G</sup>-nitro-L-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. <b><i>Conclusion:</i></b> We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin.
DOI: 10.6084/m9.figshare.5125243
title: Supplementary Material for: Strategies for a Direct Characterization of Phosphoproteins on Hydroxyapatite Surfaces

description: We show in this work how systems formed by phosphoproteins on calcium phosphate surfaces can be <i>directly</i> characterized, in real time, in liquid medium, without the need for elution or labeling. Specifically, we show how this is possible by applying three different techniques: ellipsometry, quartz crystal microbalance with dissipation, and atomic force microscopy-based friction force spectroscopy. We apply these techniques to study two different model systems, i.e. those formed upon the adsorption of two model phosphoproteins (κ- and ß-casein) on hydroxyapatite (HA) surfaces. Information on the kinetics of adsorption, surface excess, viscoelasticity, water content, thickness of the layers, and protein-surface interaction is provided. Results indicate that both phosphoproteins form homogeneous elastic highly hydrated monolayers on the HA surfaces, the strength of ß-casein layers being higher by approximately a factor of 4. Based on the experimental results, models for the conformation of κ- and ß-casein molecules adsorbed on HA surfaces are proposed.
DOI: 10.6084/m9.figshare.5125234
title: Supplementary Material for: Evaluations of the Selectivities of the Diacylglycerol Kinase Inhibitors R59022 and R59949 Among Diacylglycerol Kinase Isozymes Using a New Non-Radioactive Assay Method

description: Ten mammalian diacylglycerol kinase (DGK) isozymes (a-γ) have been identified. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of pathophysiological functions. Thus, it is important to be able to easily check DGK activity in each pathophysiological event. Moreover, the conventional DGK assay is quite laborious because it requires the use of a radioisotope and thin-layer chromatography including multiple extraction steps. In order to minimize the laborious procedures, we established a non-radioactive, single well, two-step DGK assay system. We demonstrated that, compared to the conventional method, the new assay system has comparable sensitivity and much higher efficiency, and is effective in detecting potential agents with high reliability (Z'-factor = 0.69 ± 0.12; n = 3). Using the newly developed assay, we comprehensively evaluated the DGK isozyme selectivities of commercially available DGK inhibitors, R59022 and R59949, in vitro. We found that among 10 isozymes, R59022 strongly inhibited type I DGKa and moderately attenuated type III DGKe and type V DGKθ, and that R59949 strongly inhibited type I DGK a and γ, and moderately attenuated type II DGK d and γ.
DOI: 10.6084/m9.figshare.5125237.v1
title: Supplementary Material for: Neuronal Nitric Oxide Synthase-Derived Nitric Oxide Is Involved in Gastric Mucosal Hyperemic Response to Capsaicin in Rats

description: <b><i>Background and Aims:</i></b> Activation of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin leads to gastric hyperemic response through capsaicin-sensitive sensory nerves and nitric oxide (NO). The aim of the present study is to examine which isoform of nitric oxide synthase (NOS)/NO is involved in the hyperemic response to capsaicin in the rat stomach. <b><i>Methods:</i></b> Gastric mucosal blood flow (GMBF) was measured by laser Doppler flowmetry in rats. The localizations of TRPV1 and neuronal NOS (nNOS) in the rat gastric mucosa were detected by immunohistochemical staining. <b><i>Results:</i></b> The nNOS inhibitor N<sup>5</sup>-[imino(propylamino)methyl]-L-ornithine substantially reduced GMBF during capsaicin application, whereas the endothelial NOS (eNOS) inhibitor N<sup>5</sup>-(1-iminomethyl)-L-ornithine did not affect the effect of capsaicin during the application. The nonselective NOS inhibitor N<sup>G</sup>-nitro-L-arginine methyl ester apparently inhibited the capsaicin-induced GMBF, while the inducible NOS inhibitor 1400W did not affect GMBF response to capsaicin. The immunohistochemical studies revealed nerve fibers coexpressing TRPV1 and nNOS around blood vessels in the gastric submucosa. <b><i>Conclusion:</i></b> We demonstrated for the first time that nNOS/NO is involved in gastric hyperemic responses to capsaicin.
DOI: 10.6084/m9.figshare.5125240
title: Supplementary Material for: Clinical Characteristics of C9ORF72-Linked Frontotemporal Lobar Degeneration

description: <b><i>Background:</i></b> The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the <i>C9ORF72</i> gene. The frequency of the <i>C9ORF72</i> expansion in Finland is among the highest in the world. <b><i>Methods:</i></b> We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded <i>C9ORF72</i>. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E <i>(APOE)</i> genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier. <b><i>Results:</i></b> The <i>C9ORF72</i> expansion was present in 20 of 70 (29%) probands. Significant associations with the <i>C9ORF72</i> expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The <i>APOE</i> ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers. <b><i>Conclusion:</i></b> In line with the suggested <i>C9ORF72</i> core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to <i>C9ORF72</i>-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis.
DOI: 10.6084/m9.figshare.5125231
title: Supplementary Material for: Elevated Serum Aminotransferases Secondary to Rippling Muscle Disease

description: A 43-year-old man was referred by his general practitioner to the hepatology clinic with deranged serum aminotransferases, discovered as part of routine blood tests. The objective was to identify the cause of elevated serum aminotransferases in this patient in a systematic manner. Thorough history and physical examination revealed a background history of rippling muscle disease secondary to caveolin-3 protein deficiency, with typical clinical signs. There was a positive family history of musculoskeletal disease in the patient's father and brother. Previous diagnostic tests performed to investigate the patient's musculoskeletal symptoms, including muscle biopsies, were revisited. Subsequent systematic investigations such as blood tests, liver ultrasound scan and Fibroscan® were performed to exclude potential causes of the deranged serum aminotransferases. Liver biopsy was not performed. A consistent pattern of chronic low-grade elevations of serum aminotransferases, less than three times the upper limit of the normal range, was found. This was associated with a consistently elevated serum creatine kinase and normal renal function tests. Previous muscle biopsies had revealed chronic degenerative and regenerative changes suggestive of a focal necrotizing myopathy. Liver ultrasound scan and Fibroscan® were normal. With exclusion of other liver diseases and identification of profoundly elevated serum creatine kinase concentration, the deranged aminotransferases were attributed to rippling muscle disease.
DOI: 10.6084/m9.figshare.5125243.v1
title: Supplementary Material for: Strategies for a Direct Characterization of Phosphoproteins on Hydroxyapatite Surfaces

description: We show in this work how systems formed by phosphoproteins on calcium phosphate surfaces can be <i>directly</i> characterized, in real time, in liquid medium, without the need for elution or labeling. Specifically, we show how this is possible by applying three different techniques: ellipsometry, quartz crystal microbalance with dissipation, and atomic force microscopy-based friction force spectroscopy. We apply these techniques to study two different model systems, i.e. those formed upon the adsorption of two model phosphoproteins (κ- and ß-casein) on hydroxyapatite (HA) surfaces. Information on the kinetics of adsorption, surface excess, viscoelasticity, water content, thickness of the layers, and protein-surface interaction is provided. Results indicate that both phosphoproteins form homogeneous elastic highly hydrated monolayers on the HA surfaces, the strength of ß-casein layers being higher by approximately a factor of 4. Based on the experimental results, models for the conformation of κ- and ß-casein molecules adsorbed on HA surfaces are proposed.