Dose-response relationship in cognitive behavioral therapy for depression: A nonlinear metaregression analysis.

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).

Enrichment and Quantitation of Dipeptidyl Peptidase IV Inhibitory Peptides in Quinoa upon Systematic Malting.

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.

Conserved quality control mechanisms of mitochondrial protein import.

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.

C9ORF72 Deficiency Results in Neurodegeneration in the Zebrafish Retina.

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.

Modular Assembly of Mitochondrial ß-Barrel Proteins.

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.

Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.

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.

UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.

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.

Promises and Limitations of Current Models for Understanding Barrett's Esophagus and Esophageal Adenocarcinoma.

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.

Characterization of molar mass and conformation of relevant (non-)starch polysaccharides in cereal-based beverages.

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.

[The German Guideline on Liver Transplantation by DGVS and DGAV]. / Lebertransplantation ­ Die deutschsprachige Leitlinie der DGVS und DGAV.

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.

Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.

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.

Liver transplantation for HCC in cirrhosis: Are Milan criteria outdated?

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.

APOL1-mediated monovalent cation transport contributes to APOL1-mediated podocytopathy in kidney disease.

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.

[Influence of guideline recommendations, care structures and individual factors on the use of psychosocial therapies in severely mentally ill people]. / Einfluss von Leitlinienempfehlungen, Versorgungsstrukturen und individuellen Faktoren auf die Inanspruchnahme von psychosozialen Therapien bei schwer psychisch kranken Menschen.

OBJECTIVE: The influence of guideline recommendations and other factors on the utilization of psychosocial interventions in people with severe mental illness was examined. METHODS: Data from a cross-sectional study of 397 people with severe mental illness were analysed descriptively. RESULTS: Patients are less likely to receive therapies with a strong recommendation compared to other levels of recommendation. Various other factors are diffusely associated with utilization rates, but no ubiquitous predictors could be identified across all therapies. CONCLUSION: Current practice in the use of psychosocial interventions does not follow guideline recommendation strength. Interventions with strong recommendations are probably not available across services. Consequently, routine practice is not able to follow guideline recommendations according to their strength. Other consistent predictors could not be identified.

Mitochondrial entry gate as regulatory hub.

Mitochondria import 1000-1300 different precursor proteins from the cytosol. The main mitochondrial entry gate is formed by the translocase of the outer membrane (TOM complex). Molecular coupling and modification of TOM subunits control and modulate protein import in response to cellular signaling. The TOM complex functions as regulatory hub to integrate mitochondrial protein biogenesis and quality control into the cellular proteostasis network.

[Outpatient Medical Rehabilitation Services: A New Socio-Law Perspective In Psychiatric Care]. / Ambulante Leistungen der medizinischen Rehabilitation: Eine neue sozialrechtliche Perspektive in der psychiatrischen Versorgung.

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.

The cost-utility of an intervention for children and adolescents with a parent having a mental illness in the framework of the German health and social care system: a health economic evaluation of a randomized controlled trial.

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.

Mitochondrial complexome and import network.

Mitochondria perform crucial functions in cellular metabolism, protein and lipid biogenesis, quality control, and signaling. The systematic analysis of protein complexes and interaction networks provided exciting insights into the structural and functional organization of mitochondria. Most mitochondrial proteins do not act as independent units, but are interconnected by stable or dynamic protein-protein interactions. Protein translocases are responsible for importing precursor proteins into mitochondria and form central elements of several protein interaction networks. These networks include molecular chaperones and quality control factors, metabolite channels and respiratory chain complexes, and membrane and organellar contact sites. Protein translocases link the distinct networks into an overarching network, the mitochondrial import network (MitimNet), to coordinate biogenesis, membrane organization and function of mitochondria.

COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.

Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.

Advancing Quantification of Water-Extractable Arabinoxylan in Beer: A High-Throughput Approach.

Water-extractable arabinoxylan (WEAX) may cause major problems during clarification processes in a brewery owing to its ability to form gel networks. However, high WEAX contents can also enhance the nutritional quality of the final product as they play an important role in the human diet. Therefore, precise quantification of WEAX is required. Current methods are very time- and resource-consuming as well as limited in the number of samples and in some cases provide low accuracy. Thus, a reproducible high-throughput method for the quantification of WEAX optimized for beer was developed, reaching recovery rates (RRs) of almost 100%. The assay is based on Douglas's colorimetric method. Hydrolysis was conducted using glacial acetic acid to induce the formation of red color complexes resulting from the interaction between pentose degradation products and phloroglucinol. The method was successfully transferred to a multi-mode microplate reader to minimize the loss of color intensity over time and to obtain a high throughput. By using 96-well plates, up to 40% of the previous analysis time could be saved, and a larger number of samples could be analyzed in one batch. The collected data determined xylose as an optimal calibration standard due to high accuracy and reproducibility. The respective AX control standards showed RR within the range of 95-105% without exception. To validate and show the ruggedness of the modified method, WEAX concentration in seven commercial German beers (e.g., lager, pilsner, wheat beer, non-alcoholic beer) was quantified. Interfering hexose sugars that lead to measurement errors when analyzing samples with high amounts of fermentable sugars (e.g., non-alcoholic beer produced by limited fermentation) were eliminated by Saccharomyces diastaticus fermentation. Further investigations were carried out by means of LC-MS in order to obtain additional information about the reddish product in the hydrolyzed samples. In this context, C16H12O6 could be identified as one of numerous condensation products, contributing to the coloring. The collected data showed the impact of diverse factors on the measured AX concentration and helped optimize the experimental procedure for a high sample throughput with precise and highly reproducible results. The proposed quantification method should be primarily used in completely fermented finished beer to emphasize the time aspect. Wort samples and non-alcoholic beer produced by limited fermentation can be also analyzed, but only after fermentation with S. diastaticus.