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Reversible modification of target proteins by ubiquitin and ubiquitin-like proteins (UBLs) is widely used by eukaryotic cells to control protein fate and cell behaviour1. UFM1 is a UBL that predominantly modifies a single lysine residue on a single ribosomal protein, uL24 (also called RPL26), on ribosomes at the cytoplasmic surface of the endoplasmic reticulum (ER)2,3. UFM1 conjugation (UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are released after ribosome-associated quality-control-mediated splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER3,4. Neither the molecular mechanism by which the UFMylation machinery achieves such precise target selection nor how this ribosomal modification promotes 60S rescue is known. Here we show that ribosome UFMylation in vivo occurs on free 60S and we present sequential cryo-electron microscopy snapshots of the heterotrimeric UFM1 E3 ligase (E3(UFM1)) engaging its substrate uL24. E3(UFM1) binds the L1 stalk, empty transfer RNA-binding sites and the peptidyl transferase centre through carboxy-terminal domains of UFL1, which results in uL24 modification more than 150 Å away. After catalysing UFM1 transfer, E3(UFM1) remains stably bound to its product, UFMylated 60S, forming a C-shaped clamp that extends all the way around the 60S from the transfer RNA-binding sites to the polypeptide tunnel exit. Our structural and biochemical analyses suggest a role for E3(UFM1) in post-termination release and recycling of the large ribosomal subunit from the ER membrane.
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Retículo Endoplasmático , Processamento de Proteína Pós-Traducional , Subunidades Ribossômicas Maiores de Eucariotos , Ubiquitina-Proteína Ligases , Sítios de Ligação , Biocatálise , Microscopia Crioeletrônica , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Membranas Intracelulares/química , Membranas Intracelulares/metabolismo , Membranas Intracelulares/ultraestrutura , Peptidil Transferases/química , Peptidil Transferases/metabolismo , Peptidil Transferases/ultraestrutura , Ligação Proteica , Proteínas Ribossômicas/química , Proteínas Ribossômicas/metabolismo , Proteínas Ribossômicas/ultraestrutura , Subunidades Ribossômicas Maiores de Eucariotos/química , Subunidades Ribossômicas Maiores de Eucariotos/metabolismo , Subunidades Ribossômicas Maiores de Eucariotos/ultraestrutura , RNA de Transferência/metabolismo , Especificidade por Substrato , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/ultraestruturaRESUMO
Hexanucleotide repeat expansions within the gene C9ORF72 are the most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This disease-causing expansion leads to a reduction in C9ORF72 expression levels in patients, suggesting loss of C9ORF72 function could contribute to disease. To further understand the consequences of C9ORF72 deficiency in vivo, we generated a c9orf72 mutant zebrafish line. Analysis of the adult female spinal cords revealed no appreciable neurodegenerative pathology such as loss of motor neurons or increased levels of neuroinflammation. However, detailed examination of adult female c9orf72-/- retinas showed prominent neurodegenerative features, including a decrease in retinal thickness, gliosis, and an overall reduction in neurons of all subtypes. Analysis of rod and cone cells within the photoreceptor layer showed a disturbance in their outer segment structure and rhodopsin mislocalization from rod outer segments to their cell bodies and synaptic terminals. Thus, C9ORF72 may play a previously unappreciated role in retinal homeostasis and suggests C9ORF72 deficiency can induce tissue specific neuronal loss.
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Proteína C9orf72 , Retina , Peixe-Zebra , Animais , Feminino , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Retina/metabolismo , Retina/patologia , Animais Geneticamente Modificados , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/deficiência , Proteínas/genética , Proteínas/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
BACKGROUND: Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence. METHODS: A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire. RESULTS: The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi2(1) = 1.65, p = 0.199, T1: Chi2(1) = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion. CONCLUSIONS: While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers. TRIAL REGISTRATION: https://drks.de/search/de/trial/DRKS00028895.
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Fidelidade a Diretrizes , Esquizofrenia , Humanos , Masculino , Feminino , Adulto , Alemanha , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto/normas , Inquéritos e Questionários , Conhecimentos, Atitudes e Prática em SaúdeRESUMO
Mitochondria carry out essential functions for the cell, including energy production, various biosynthesis pathways, formation of co-factors and cellular signalling in apoptosis and inflammation. The functionality of mitochondria requires the import of about 900-1300 proteins from the cytosol in baker's yeast Saccharomyces cerevisiae and human cells, respectively. The vast majority of these proteins pass the outer membrane in a largely unfolded state through the translocase of the outer mitochondrial membrane (TOM) complex. Subsequently, specific protein translocases sort the precursor proteins into the outer and inner membranes, the intermembrane space and matrix. Premature folding of mitochondrial precursor proteins, defects in the mitochondrial protein translocases or a reduction of the membrane potential across the inner mitochondrial membrane can cause stalling of precursors at the protein import apparatus. Consequently, the translocon is clogged and non-imported precursor proteins accumulate in the cell, which in turn leads to proteotoxic stress and eventually cell death. To prevent such stress situations, quality control mechanisms remove non-imported precursor proteins from the TOM channel. The highly conserved ubiquitin-proteasome system of the cytosol plays a critical role in this process. Thus, the surveillance of protein import via the TOM complex involves the coordinated activity of mitochondria-localized and cytosolic proteins to prevent proteotoxic stress in the cell.
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In Germany, organ allocation is based on the MELD-system and lab-MELD is usually low in patients with hepatocellular carcinoma (HCC) in cirrhosis. Higher medical urgency can be achieved by standard exception for HCC (SE-HCC), if Milan criteria (MC) are met. Noteworthy, UNOS T2 reflects MC, but excludes singular lesions < 2 cm. Thus, SE-HCC is awarded to patients with one lesion between 2 and 5 cm or 2 to 3 lesions between 1 and 3 cm. These criteria are static and do not reflect biological properties of HCC.We present a retrospective cohort of 111 patients, who underwent liver transplantation at UKSH, Campus Kiel between 2007 and 2017. No difference was found in overall survival for patient cohorts using Milan, UCSF, up-to-seven, and French-AFP criteria. However, there was a significantly reduced survival, if microvascular invasion was detected in the explanted organ and in patients with HCC-recurrence. The exclusive use of static selection criteria including MC appear to limit the access to liver transplantation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/cirurgia , Estudos Retrospectivos , Neoplasias Hepáticas/cirurgia , Cirrose Hepática/diagnóstico , Cirrose Hepática/cirurgiaRESUMO
Background and Objectives: Anastomotic insufficiencies (AI) and perforations of the upper gastrointestinal tract (uGIT) result in high morbidity and mortality. Endoscopic stent placement and endoluminal vacuum therapy (EVT) have been established as surgical revision treatment options. The Eso-Sponge® is the only licensed EVT system with limitations in treating small defects (<10 mm). Therefore, a fistula sponge (FS) was developed for the treatment of such defects as a new therapeutic approach. The aim of this study was to evaluate both EVT options' indications, success rates, and complications in a retrospective, comparative approach. Materials and Methods: Between 01/2018 and 01/2021, the clinical data of patients undergoing FS-EVT or conventional EVT (cEVT; Eso-Sponge®, Braun Melsungen, Melsungen, Germany) due to AI/perforation of the uGIT were recorded. Indication, diameter of leakage, therapeutic success, and complications during the procedure were assessed. FSs were prepared using a nasogastric tube and a porous drainage film (Suprasorb® CNP, Lohmann & Rauscher, Rengsdorf, Germany) sutured to the distal tip. Results: A total of 72 patients were included (20 FS-EVT; 52 cEVT). FS-EVT was performed in 60% suffering from AI (cEVT = 68%) and 40% from perforation (cEVT = 32%; p > 0.05). FS-EVT's duration was significantly shorter than cEVT (7.6 ± 12.0 d vs. 15.1 ± 14.3 d; p = 0.014). The mean diameter of the defect was 9 mm in the FS-EVT group compared to 24 mm in cEVT (p < 0.001). Therapeutic success was achieved in 90% (FS-EVT) and 91% (cEVT; p > 0.05). Conclusions: EVT comprises an efficient treatment option for transmural defects of the uGIT. In daily clinical practice, fistulas < 10 mm with large abscess formations poses a special challenge since intraluminal cEVT usually is ineffective. In these cases, the concept of extraluminal FS placement is safe and effective.
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Trato Gastrointestinal Superior , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Trato Gastrointestinal Superior/cirurgia , Tratamento de Ferimentos com Pressão Negativa/métodos , Tratamento de Ferimentos com Pressão Negativa/instrumentação , Estudos de Coortes , Resultado do Tratamento , Tampões de Gaze Cirúrgicos , Idoso de 80 Anos ou mais , Fístula Anastomótica/terapia , AdultoRESUMO
Arabinoxylans, ß-glucans, and dextrins influence the brewing industry's filtration process and product quality. Despite their relevance, only a maximum concentration of ß-glucans is recommended. Nevertheless, filtration problems are still present, indicating that although the chemical concentration is essential, other parameters should be investigated. Molar mass and conformation are important polymer physical characteristics often neglected in this industry. Therefore, this research proposes an approach to physically characterize enzymatically isolated beer polysaccharides by asymmetrical flow field-flow fractionation coupled to multi-angle light scattering and differential refractive index detector. Based on the obtained molar masses, root-mean-square radius (rrms from MALS), and hydrodynamic radius (rhyd), conformational properties such as apparent density (ρapp) and rrms/rhyd can be calculated based on their molar mass and size. Consequently, the ρapp and rrms/rhyd behavior hints at the different structures within each polysaccharide. The rrms/rhyd 1.2 and high ρapp values on low molar mass dextrins (1-2·105 g/mol) indicate branches, while aggregated structures at high molar masses on arabinoxylans and ß-glucans (2·105 -6·106 g/mol) are due to an increase of ρapp and a rrms/rhyd (0.6-1). This methodology provides a new perspective to analyze starch and non-starch polysaccharides in cereal-based beverages since different physical characteristics could influence beer's filtration and sensory characteristics.
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Fracionamento por Campo e Fluxo , beta-Glucanas , Grão Comestível , Dextrinas , Polissacarídeos , Amido/química , Fracionamento por Campo e Fluxo/métodos , Espalhamento de RadiaçãoRESUMO
Mitochondrial ß-barrel proteins fulfill crucial roles in the biogenesis and function of the cell organelle. They mediate the import and membrane insertion of proteins and transport of small metabolites and ions. All ß-barrel proteins are made as precursors on cytosolic ribosomes and are imported into mitochondria. The ß-barrel proteins fold and assemble with partner proteins in the outer membrane. The in vitro import of radiolabelled proteins into isolated mitochondria is a powerful tool to investigate the import of ß-barrel proteins, the folding of the ß-barrel proteins, and their assembly into protein complexes. Altogether, the in vitro import assay is a versatile and crucial assay to analyze the mechanisms of the biogenesis of mitochondrial ß-barrel proteins.
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Proteínas Mitocondriais , Proteínas de Saccharomyces cerevisiae , Proteínas Mitocondriais/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Mitocôndrias/metabolismo , Transporte Proteico , Proteínas de Transporte da Membrana Mitocondrial/metabolismoRESUMO
BACKGROUND & AIMS: This review was developed to provide a thorough and effective update on models relevant to esophageal metaplasia, dysplasia, and carcinogenesis, focusing on the advantages and limitations of different models of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). METHODS: This expert review was written on the basis of a thorough review of the literature combined with expert interpretation of the state of the field. We emphasized advances over the years 2012-2023 and provided detailed information related to the characterization of established human esophageal cell lines. RESULTS: New insights have been gained into the pathogenesis of BE and EAC using patient-derived samples and single-cell approaches. Relevant animal models include genetic as well as surgical mouse models and emphasize the development of lesions at the squamocolumnar junction in the mouse stomach. Rat models are generated using surgical approaches that directly connect the small intestine and esophagus. Large animal models have the advantage of including features in human esophagus such as esophageal submucosal glands. Alternatively, cell culture approaches remain important in the field and allow for personalized approaches, and scientific rigor can be ensured by authentication of cell lines. CONCLUSIONS: Research in BE and EAC remains highly relevant given the morbidity and mortality associated with cancers of the tubular esophagus and gastroesophageal junction. Careful selection of models and inclusion of human samples whenever possible will ensure relevance to human health and disease.
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Adenocarcinoma , Esôfago de Barrett , Modelos Animais de Doenças , Neoplasias Esofágicas , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Humanos , Animais , Adenocarcinoma/patologia , Camundongos , RatosRESUMO
The equality of mentally ill people with somatically ill people and the provision of community care were central topics of the Psychiatry-Enquête. With regard to medical rehabilitation services, this goal has not been implemented to date. The amendments to the Ninth Book of the Social Code (SGB IX) made by the Federal Participation Act (BTHG) again open up the possibility of making outreach medical rehabilitation services accessible to people with severe mental illnesses.
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Transtornos Mentais , Pacientes Ambulatoriais , Humanos , Alemanha , Psicoterapia , Transtornos Mentais/reabilitaçãoRESUMO
The S2k guideline "Liver Transplantation", jointly developed by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the German Society of General and Visceral Surgery (DGAV), represents the first German-language guideline for the care of adult patients before and after liver transplantation. This guideline has been crafted through a collaborative, consensus-based approach, involving experts from various disciplines. It integrates current scientific insights and clinical experience to ensure optimal care for patients undergoing liver transplantation. Targeting health care professionals in diagnostics and therapy, patient advocates, affected individuals, and their families, the guideline aims to establish a framework for common decisions in clinical practice.
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Gastroenterologia , Transplante de Fígado , Humanos , Consenso , AlemanhaRESUMO
Food-derived peptides with an inhibitory effect on dipeptidyl peptidase IV (DPP-IV) can be used as an additive treatment for type 2 diabetes. The inhibitory potential of food depends on technological protein hydrolysis and gastrointestinal digestion, as the peptides only act after intestinal resorption. The effect of malting as a hydrolytic step on the availability of these peptides in grains has yet to be investigated. In this study, quinoa was malted under systematic temperature, moisture, and time variations. In the resulting malts, the DPP-IV inhibition reached a maximum of 45.02 (±10.28) %, whereas the highest overall concentration of literature-known inhibitory peptides was 4.07 µmol/L, depending on the malting parameters. After in vitro gastrointestinal digest, the inhibition of most malts, as well as the overall concentration of inhibitory peptides, could be increased significantly. Additionally, the digested malts showed higher values in both the inhibition and the peptide concentration than the unmalted quinoa. Concerning the malting parameters, germination time had the highest impact on the inhibition and the peptide concentration after digest. An analysis of the protein sizes before and after malting gave first hints toward the origin of these peptides, or their precursors, in quinoa.
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Chenopodium quinoa , Inibidores da Dipeptidil Peptidase IV , Peptídeos , Chenopodium quinoa/química , Inibidores da Dipeptidil Peptidase IV/química , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/metabolismo , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Manipulação de Alimentos , Germinação , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Hidrólise , Sementes/química , Sementes/metabolismo , Humanos , DigestãoRESUMO
INTRODUCTION: For over two decades, abdominal surgical procedures have been safely performed robotically. After the first patent expiration, alternative robotic systems entered the market. The Dexter Robotic System™ is a small-format, modular, and robotic platform consisting of a surgeon's console, two patient carts with instrument arms, and one endoscope arm. We report our initial experiences with Dexter since its installation at our visceral surgery department. METHODS: The system and surgical setup are described. Demographic and perioperative data of all operated patients as well as the system docking times were analyzed. RESULTS: From 56 procedures performed with Dexter, the most common ones included cholecystectomy (n = 15), inguinal hernia repair (TAPP; unilateral n = 15; bilateral n = 3), and right oncologic hemicolectomy (n = 15). The median docking time was 6 min (2-16 min) and was reduced to 4 min in the last tertile of procedures performed. CONCLUSIONS: In our experience, Dexter can be implemented without any major challenges, and visceral surgical procedures of simple to medium complexity can be performed safely. The simplicity and accessibility of the system along with the ease of switching between robotics and laparoscopy could be particularly suitable for beginners in robotic surgery.
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OBJECTIVE: Evidence on the optimal "dose" of cognitive behavioral therapy (CBT) for treating major depressive disorder is sparse. This analysis aimed to evaluate the dose-response curve in CBT using a nonlinear approach, whereby "dose" was defined as number of treatment sessions. The dose-response curve of CBT was compared to other psychotherapies and pharmacological treatments for depression. METHOD: A systematic review and metaregression analysis of randomized controlled trials (RCTs) examining the efficacy of CBT in adults with acute depression was conducted. Treatment arms examining other psychosocial or pharmacological interventions were also analyzed. Cubic spline metaregression techniques were used to model nonlinear dose-response curves. RESULTS: Seventy-two studies and 7,377 participants were included. Modeling the dose-response curve between change of depression symptom severity and the number of CBT sessions resulted in a nonlinear curve characterized by a strong improvement in symptom severity from baseline within the first eight sessions. Symptom reduction continues in the further course of the treatment, but at a slower pace. A similar pattern of symptom development was found for other therapies as well, although the prominence of early improvement and overall effect sizes vary across treatment arms. CONCLUSION: Results imply a general tendency for the strongest alleviation of depressive symptom severity in early stages of CBT treatment, thus, if aiming at symptom alleviation, speak for short CBT interventions. However, these findings have to be discussed in the light of the limited data regarding the sustainability of treatment effects in short-term therapies and effects beyond symptomatic changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Terapia Cognitivo-Comportamental , Transtorno Depressivo Maior , Humanos , Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo Maior/terapia , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
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Mitocôndrias , Membranas Mitocondriais , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Fosfolipídeos/metabolismo , Transporte de Elétrons , Cardiolipinas/metabolismoRESUMO
The majority of mitochondrial precursor proteins are imported through the Tom40 ß-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for ß-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.
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Proteínas de Membrana Transportadoras , Proteínas de Saccharomyces cerevisiae , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Transporte/metabolismo , Transporte ProteicoRESUMO
Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.
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Apolipoproteína L1 , Nefropatias , Compostos Organotiofosforados , Camundongos , Animais , Humanos , Apolipoproteína L1/genética , Células HEK293 , Variação Genética , Nefropatias/genética , Camundongos TransgênicosRESUMO
To predict the achievable product volume with respect to the gas retention capacity of the gluten matrix in wheat flour doughs, strain hardening evaluation is crucial. But assessing these structure hardening phenomena in wheat flour dough systems is still a challenging task. In this work, a simple shear method applied to kneaded dough samples was tested and compared to biaxial extension tests performed with a lubricated squeezing flow method. The comparability of shear-induced structure hardening with biaxial extension tests was shown. Structure hardening and breakdown after overload were visualized using shear flow and a comparison of the obtained shear flow over Hencky strain curve peaks. To predict the behavior of the analyzed flours according to their composition, a correlation analysis of the flour and dough properties was performed. The influence of the HMW glutenin subunits on the sensitivity of the dough matrix according to the applied shear speed (0.1 and 1.0 mm/s) could be shown with a correlation coefficient of 0.94. The LMW glutenin subunits, on the other hand, showed a high correlation coefficient of 0.89 with the achievable network connectivity parameter z [-] gained from frequency sweep testing.
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BACKGROUND: Children of families with a parent with a mental illness have an increased risk of developing social and mental health problems resulting in decreased quality of life. Therefore, children and adolescents living in families with a parent with mental illness are regarded as a target group for preventive interventions. To date, only a few economic evaluation studies for interventions directed at preventing the intergenerational transmission of mental health problems exist. In this investigation we estimated the cost utility of an intervention for the support of children and adolescents with a parent having a mental illness from the perspective of the German health and social care system. METHODS: We randomly assigned a total of 214 families with 337 children and adolescents to the intervention (INT) group (108/170) or the control (TAU) group (106/167). Families in the intervention group received on average eight intervention sessions (50-90 min) over 6 months. We estimated total cost of illness by means of the Children and Adolescent Mental Health Service Receipt Inventory (CAMHSRI) over 24 months. For the estimation of Quality-Adjusted Live Years (QALYs) we applied the KIDSCREEN-10. For estimating the incremental cost-utility of the intervention compared to treatment as usual we used the net-benefit approach. RESULTS: We estimated the annual cost of illness amounting to 3784.59 (SD 8581.11) in the TAU group and 3264.44 (SD 9431.89) in the INT group. The annual cost difference between INT and TAU was - 516.14 (SE 1124.95) which was not significant (p ≤ 0.05). We estimated the average QALY to be 0.759 (SD 0.073) in the TAU group and 0.763 (SD 0.072). The QALY difference between INT and TAU was 0.0037 (SE 0.0092) which was not significant (p ≤ 0.05). The incremental cost utility ratio (ICUR) indicated that the gain of one additional year in full health by means of the intervention was associated with the saving of 139.49. However, the stochastic insecurity of the ICUR did not allow a unique decision about the cost-utility of the intervention. CONCLUSIONS: More information on the economic value of the intervention for families with a parent with mental illness in comparison to treatment as usual in Germany is needed. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02308462; German Clinical Trials Register: DRKS00006806.
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Introdução: Dirigir automóvel é importante para manter a independência, autonomia e qualidade de vida e requer a integridade das funções cognitivas, as quais tendem a diminuir com o envelhecimento, podendo interferir nas habilidades necessárias para a direção segura. Testes neuropsicológicos permitem detectar deficiências cognitivas e junto com o uso de simuladores de direção podem auxiliar a identificar o risco de acidentes e infrações. Objetivo: Investigar a relação entre o desempenho de idosos em um simulador de direção e em testes cognitivos. Métodos: Trinta e quatro condutores com mais de 65 anos foram submetidos a exercícios em um simulador de direção e avaliados cognitivamente. Resultados: Contatou-se associação entre o desempenho nas tarefas no simulador e o funcionamento cognitivo. Conclusão: O uso de testes cognitivos, em especial os que avaliam atenção e memória revelam-se promissores na identificação de idosos que possam apresentar problemas no trânsito.
Introduction: Driving cars is an important to maintain the independence, autonomy and quality of life and that requires the integrity of the cognitive functions, which tend to decline with aging, and may interfere in the skills needed for safe driving. Neuropsychological tests can detect cognitive impairment and together with the use of driving simulators can help to identify the risk of accidents and violations. Objective: To investigate the relation between the performance of the elderly in a driving simulator and in cognitive tests. Methods: Thirty-four drivers over 65 years were evaluated through exercises on the driving simulator and cognitively. Results: It was found an association between performance on tasks in the simulator and cognitive functioning. Conclusion: The use of cognitive tests, especially that evaluate attention and memory functions, are promising in the identification of elderly people who may present traffic problems.