A promising new treatment approach for major depressive disorder (MDD) targets the microbiota-gut-brain (MGB) axis, which is linked to physiological and behavioral functions affected in MDD. This is ...the first randomized controlled trial to determine whether short-term, high-dose probiotic supplementation reduces depressive symptoms along with gut microbial and neural changes in depressed patients. Patients with current depressive episodes took either a multi-strain probiotic supplement or placebo over 31 days additionally to treatment-as-usual. Assessments took place before, immediately after and again four weeks after the intervention. The Hamilton Depression Rating Sale (HAM-D) was assessed as primary outcome. Quantitative microbiome profiling and neuroimaging was used to detect changes along the MGB axis. In the sample that completed the intervention (probiotics N = 21, placebo N = 26), HAM-D scores decreased over time and interactions between time and group indicated a stronger decrease in the probiotics relative to the placebo group. Probiotics maintained microbial diversity and increased the abundance of the genus Lactobacillus, indicating the effectivity of the probiotics to increase specific taxa. The increase of the Lactobacillus was associated with decreased depressive symptoms in the probiotics group. Finally, putamen activation in response to neutral faces was significantly decreased after the probiotic intervention. Our data imply that an add-on probiotic treatment ameliorates depressive symptoms (HAM-D) along with changes in the gut microbiota and brain, which highlights the role of the MGB axis in MDD and emphasizes the potential of microbiota-related treatment approaches as accessible, pragmatic, and non-stigmatizing therapies in MDD. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.
In major depressive disorder (MDD), cognitive dysfunctions strongly contribute to functional impairments but are barely addressed in current therapies. Novel treatment strategies addressing cognitive ...symptoms in depression are needed. As the gut microbiota-brain axis is linked to depression and cognition, we investigated the effect of a 4-week high-dose probiotic supplementation on cognitive symptoms in depression.
This randomized controlled trial included 60 patients with MDD, of whom 43 entered modified intention-to-treat analysis. A probiotic supplement or indistinguishable placebo containing maltose was administered over 31 days in addition to treatment as usual for depression. Participant scores on the Verbal Learning Memory Test (VLMT), Corsi Block Tapping Test, and both Trail Making Test versions as well as brain-derived neurotrophic factor levels were assessed at 3 different time points: before, immediately after and 4 weeks after intervention. Additionally, brain activation changes during working memory processing were investigated before and immediately after intervention.
We found a significantly improved immediate recall in the VLMT in the probiotic group immediately after intervention, and a trend for a time × group interaction considering all time points. Furthermore, we found a time × group interaction in hippocampus activation during working memory processing, revealing a remediated hippocampus function in the probiotic group. Other measures did not reveal significant changes.
The modest sample size resulting from our exclusion of low-compliant cases should be considered.
Additional probiotic supplementation enhances verbal episodic memory and affects neural mechanisms underlying impaired cognition in MDD. The present findings support the importance of the gut microbiota-brain axis in MDD and emphasize the potential of microbiota-related regimens to treat cognitive symptoms in depression.
clinicaltrials.gov identifier NCT02957591.
The parasitic disease malaria remains a major global public health concern and no truly effective vaccine exists. One approach to the development of a malaria vaccine is to target the asexual blood ...stage that results in clinical symptoms. Most attempts have failed. New antigens such as P27A and P27 have emerged as potential new vaccine candidates. Multiple studies have demonstrated that antigens are more immunogenic and are better correlated with protection when presented on particulate delivery systems. One such particulate delivery system is the self-assembling protein nanoparticle (SAPN) that relies on coiled-coil domains of proteins to form stable nanoparticles. In the past we have used de novo designed amino acid domains to drive the formation of the coiled-coil scaffolds which present the antigenic epitopes on the particle surface.
Here we use naturally occurring domains found in the tex1 protein to form the coiled-coil scaffolding of the nanoparticle. Thus, by engineering P27A and a new extended form of the coiled-coil domain P27 onto the N and C terminus of the SAPN protein monomer we have developed a particulate delivery system that effectively displays both antigens on a single particle that uses malaria tex1 sequences to form the nanoparticle scaffold. These particles are immunogenic in a murine model and induce immune responses similar to the ones observed in seropositive individuals in malaria endemic regions.
We demonstrate that our P27/P27A-SAPNs induce an immune response akin to the one in seropositive individuals in Burkina Faso. Since P27 is highly conserved among different Plasmodium species, these novel SAPNs may even provide cross-protection between Plasmodium falciparum and Plasmodium vivax the two major human malaria pathogens. As the SAPNs are also easy to manufacture and store they can be delivered to the population in need without complication thus providing a low cost malaria vaccine.
Depression is a debilitating disorder, and at least one third of patients do not respond to therapy. Associations between gut microbiota and depression have been observed in recent years, opening ...novel treatment avenues. Here, we present the first two patients with major depressive disorder ever treated with fecal microbiota transplantation as add-on therapy. Both improved their depressive symptoms 4 weeks after the transplantation. Effects lasted up to 8 weeks in one patient. Gastrointestinal symptoms, constipation in particular, were reflected in microbiome changes and improved in one patient. This report suggests further FMT studies in depression could be worth pursuing and adds to awareness as well as safety assurance, both crucial in determining the potential of FMT in depression treatment.
Various supra-molecular structures form by self-assembly of proteins in a symmetric fashion. Examples of such structures are viruses, some bacterial micro-compartments and eukaryotic vaults. ...Peptide/protein-based nanoparticles are emerging in synthetic biology for a variety of biomedical applications, mainly as drug targeting and delivery systems or as vaccines. Our self-assembling peptide nanoparticles (SAPNs) are formed by a single peptide chain that consists of two helical coiled-coil segments connected by a short linker region. One helix is forming a pentameric coiled coil while the other is forming a trimeric coiled coil.
Here, we were studying in vitro and in silico the effect of the chain length and of point mutations near the linker region between the pentamer and the trimer on the self-assembly of the SAPNs. 60 identical peptide chains co-assemble to form a spherical nanoparticle displaying icosahedral symmetry. We have stepwise reduced the size of the protein chain to a minimal chain length of 36 amino acids. We first used biochemical and biophysical methods on the longer constructs followed by molecular dynamics simulations to study eleven different smaller peptide constructs. We have identified one peptide that shows the most promising mini-nanoparticle model in silico.
An approach of in silico modeling combined with in vitro testing and verification yielded promising peptide designs: at a minimal chain length of only 36 amino acids they were able to self-assemble into proper nanoparticles. This is important since the production cost increases more than linearly with chain length. Also the size of the nanoparticles is significantly smaller than 20 nm, thus reducing the immunogenicity of the particles, which in turn may allow to use the SAPNs as drug delivery systems without the risk of an anaphylactic shock.
Abstract We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated ...the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N = 43 participants with depression, from which N = 19 received the probiotic supplement and N = 24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1β, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.
New imaging techniques such as hybrid imaging of ultrasound and FDG-PET/CT are available but not yet investigated for node staging. The aim of the study was to evaluate the feasibility and added ...diagnostic value of real-time image-fused ultrasound-guided fine-needle aspiration with FDG-PET/CT data for node staging.
Ninety-six patients who were referred for cervical lymph node staging with FDG-PET/CT before ultrasound were prospectively included. After routine ultrasound-guided fine-needle aspiration, all FDG-PET-positive nodes were marked on FDG-PET/CT, and real-time image fusing of ultrasound and FDG-PET/CT was performed using the electromagnetic navigation system PercuNav. Already-punctured nodes were confirmed to be PET-positive, and additional fused-ultrasound-guided fine-needle aspiration was performed in previously missed PET-positive nodes.
Of 96 patients, 87 (91%) patients had suspicious nodes requiring fine-needle aspiration cytology. Ultrasound-guided fine-needle aspiration was performed in 175 nodes. Cytology was inconclusive in 9/175 (5%) nodes, and 85/166 (51%) nodes were malignant. Target planning was performed in 201 PET-positive nodes; 195/201 (97%) of those nodes were fused successfully. Twenty of 175 ultrasound-guided fine-needle aspiration nodes turned out to be FDG-PET-negative, and 149/175 (85%) of the fused ultrasound-guided fine-needle aspiration nodes were confirmed to be FDG-PET-positive. Of 201 PET-positive nodes, 46 (23%) were additionally identified, and fused ultrasound-guided fine-needle aspiration was performed. Cytology was inconclusive in 4/46 nodes (9%), and 13/42 (31%) nodes were malignant.
Real-time ultrasound image fusion with FDG-PET-positive nodes is feasible in cervical lymph nodes, and fused ultrasound-guided fine-needle aspiration increases the number of malignant nodes detected.
Adequate sanitation, wastewater treatment and irrigation infrastructure often lacks in urban areas of developing countries. While treated, nutrient-rich reuse water is a precious resource for crop ...production in dry regions, excessive salinity might harm the crops. The aim of this study was to quantify, from a system perspective, the nutrient and salt flows a new infrastructure connecting water supply, sanitation, wastewater treatment and nutrient-rich water reuse for the irrigation of agriculture, from a system perspective. For this, we developed and applied a quantitative assessment method to understand the benefits and to support the management of the new water infrastructure in an urban area in semi-arid Namibia. The nutrient and salt flows, as affected by sanitation user behavior, were quantified by mathematical material flow analysis that accounts for the low availability of suitable and certain data in developing countries, by including data ranges and by assessing the effects of different assumptions in cases. Also the nutrient and leaching requirements of a crop scheme were calculated. We found that, with ideal sanitation use, 100% of nutrients and salts are reclaimed and the slightly saline reuse water is sufficient to fertigate 10 m2/cap/yr (90% uncertainty interval 7–12 m2/cap/yr). However, only 50% of the P contained in human excreta could be finally used for crop nutrition. During the pilot phase fewer sanitation users than expected used slightly more water per capita, used the toilets less frequently and practiced open defecation more frequently. Therefore, it was only possible to reclaim about 85% of nutrients from human excreta, the reuse water was non-saline and contained less nutrient so that the P was the limiting factor for crop fertigation. To reclaim all nutrients from human excreta and fertigate a larger agricultural area, sanitation user behavior needs to be improved. The results and the methodology of this study can be generalized and used worldwide in other semi-arid regions requiring irrigation for agriculture as well as urban areas in developing countries with inadequate sanitation infrastructure.
•Our quantitative assessment supports the design/operation of water reuse infrastructures.•The nutrient ratio (N, P, K, Ca, Mg) in wastewater differs from that required by crops.•Little reuse water and P, while too much N, K, Ca and Mg are available for crops.•Reuse water is generated to fertigate crops on 10 m2/cap (7–12 m2/cap) per year.•50% of P from human excreta is finally reused by crops.
Integrated assessments that aim to support sustainable natural resources management require analysing how biophysical systems are impacted by human actions. These analyses are often performed by ...modelling the physical system, while human actions are prescribed as scenarios and introduced into the physical models by varying the model input. To achieve a more thorough analysis of the human system component in participatory integrated assessments, we developed a semi-quantitative approach for actor-based modelling which focuses on modelling actions of societal actors based on their problem perceptions but also computes the resulting changes of physical system variables. Our approach is intended to support transdisciplinary research and identification of sustainable development options in problem fields with high levels of uncertainty or ignorance, together with the actors that are being modelled. Actor-based modelling is done using an enhanced version of the DANA software. DANA allows modelling the actors in a specific problem field by representing the perception of each actor by directed graphs, and by computing optimal actions from the perspective of each actor. These perception graphs are semi-quantitative causal maps, which can easily be discussed among stakeholders in a participatory process. DANA was extended to support, in addition to actor modelling, the other two steps in actor-based modelling, modelling of actions and modelling of factors. Modelling of actions refers to determining the actions of each actor under certain scenario assumptions, taking into account the diverse problem perceptions of the individual actors in the problem field, the action of the other actors and exogenous changes. Modelling of factors refers to calculating, in a semi-quantitative way, the resulting changes of physical variables (e.g. pollutant emissions), which may serve as input to physical models. We applied actor-based modelling in an integrated assessment of mobile organic xenobiotics in rivers. Our study shows that actor-based modelling allows generating scientifically better founded and more transparent scenarios of the drivers of change in integrated assessments, in particular because they are based on a structured analysis of the actors' problem perceptions.
► We developed a semi-quantitative approach for actor-based modelling. ► Our approach focuses on modelling actions of actors based on their problem perceptions. ► We applied the method in an integrated assessment of mobile organic xenobiotics. ► The method allows generating scientifically better founded and more transparent scenarios.
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