Developing Advanced AI Ecosystems to Enhance Diagnosis and Care for Patients with Depression.

Major Depressive Disorder (MDD) has a significant impact on the daily lives of those affected. This concept paper presents a project that aims at addressing MDD challenges through innovative therapy systems. The project consists of two use cases: a multimodal neurofeedback (NFB) therapy and an AI-based virtual therapy assistant (VTA). The multimodal NFB integrates EEG and fNIRS to comprehensively assess brain function. The goal is to develop an open-source NFB toolbox for EEG-fNIRS integration, augmented by the VTA for optimized efficacy. The VTA will be able to collect behavioral data, provide personalized feedback and support MDD patients in their daily lives. This project aims to improve depression treatment by bringing together digital therapy, AI and mobile apps to potentially improve outcomes and accessibility for people living with depression.

Acute Downregulation but Not Genetic Ablation of Murine MCU Impairs Suppressive Capacity of Regulatory CD4 T Cells.

By virtue of mitochondrial control of energy production, reactive oxygen species (ROS) generation, and maintenance of Ca2+ homeostasis, mitochondria play an essential role in modulating T cell function. The mitochondrial Ca2+ uniporter (MCU) is the pore-forming unit in the main protein complex mediating mitochondrial Ca2+ uptake. Recently, MCU has been shown to modulate Ca2+ signals at subcellular organellar interfaces, thus fine-tuning NFAT translocation and T cell activation. The mechanisms underlying this modulation and whether MCU has additional T cell subpopulation-specific effects remain elusive. However, mice with germline or tissue-specific ablation of Mcu did not show impaired T cell responses in vitro or in vivo, indicating that 'chronic' loss of MCU can be functionally compensated in lymphocytes. The current work aimed to specifically investigate whether and how MCU influences the suppressive potential of regulatory CD4 T cells (Treg). We show that, in contrast to genetic ablation, acute siRNA-mediated downregulation of Mcu in murine Tregs results in a significant reduction both in mitochondrial Ca2+ uptake and in the suppressive capacity of Tregs, while the ratios of Treg subpopulations and the expression of hallmark transcription factors were not affected. These findings suggest that permanent genetic inactivation of MCU may result in compensatory adaptive mechanisms, masking the effects on the suppressive capacity of Tregs.

Using preregistration as a tool for transparent fNIRS study design.

Significance: The expansion of functional near-infrared spectroscopy (fNIRS) methodology and analysis tools gives rise to various design and analytical decisions that researchers have to make. Several recent efforts have developed guidelines for preprocessing, analyzing, and reporting practices. For the planning stage of fNIRS studies, similar guidance is desirable. Study preregistration helps researchers to transparently document study protocols before conducting the study, including materials, methods, and analyses, and thus, others to verify, understand, and reproduce a study. Preregistration can thus serve as a useful tool for transparent, careful, and comprehensive fNIRS study design. Aim: We aim to create a guide on the design and analysis steps involved in fNIRS studies and to provide a preregistration template specified for fNIRS studies. Approach: The presented preregistration guide has a strong focus on fNIRS specific requirements, and the associated template provides examples based on continuous-wave (CW) fNIRS studies conducted in humans. These can, however, be extended to other types of fNIRS studies. Results: On a step-by-step basis, we walk the fNIRS user through key methodological and analysis-related aspects central to a comprehensive fNIRS study design. These include items specific to the design of CW, task-based fNIRS studies, but also sections that are of general importance, including an in-depth elaboration on sample size planning. Conclusions: Our guide introduces these open science tools to the fNIRS community, providing researchers with an overview of key design aspects and specification recommendations for comprehensive study planning. As such it can be used as a template to preregister fNIRS studies or merely as a tool for transparent fNIRS study design.

Performance comparison of systemic activity correction in functional near-infrared spectroscopy for methods with and without short distance channels.

Significance: Functional near-infrared spectroscopy (fNIRS) is a promising tool for neurofeedback (NFB) or brain-computer interfaces (BCIs). However, fNIRS signals are typically highly contaminated by systemic activity (SA) artifacts, and, if not properly corrected, NFB or BCIs run the risk of being based on noise instead of brain activity. This risk can likely be reduced by correcting for SA, in particular when short-distance channels (SDCs) are available. Literature comparing correction methods with and without SDCs is still sparse, specifically comparisons considering single trials are lacking. Aim: This study aimed at comparing the performance of SA correction methods with and without SDCs. Approach: Semisimulated and real motor task data of healthy older adults were used. Correction methods without SDCs included a simple and a more advanced spatial filter. Correction methods with SDCs included a regression approach considering only the closest SDC and two GLM-based methods, one including all eight SDCs and one using only two a priori selected SDCs as regressors. All methods were compared with data uncorrected for SA and correction performance was assessed with quality measures quantifying signal improvement and spatial specificity at single trial level. Results: All correction methods were found to improve signal quality and enhance spatial specificity as compared with the uncorrected data. Methods with SDCs usually outperformed methods without SDCs. Correction methods without SDCs tended to overcorrect the data. However, the exact pattern of results and the degree of differences observable between correction methods varied between semisimulated and real data, and also between quality measures. Conclusions: Overall, results confirmed that both Δ [ HbO ] and Δ [ HbR ] are affected by SA and that correction methods with SDCs outperform methods without SDCs. Nonetheless, improvements in signal quality can also be achieved without SDCs and should therefore be given priority over not correcting for SA.

Assessment of dynamic cerebral autoregulation in near-infrared spectroscopy using short channels: A feasibility study in acute ischemic stroke patients.

Introduction: In acute ischemic stroke, progressive impairment of cerebral autoregulation (CA) is frequent and associated with unfavorable outcomes. Easy assessment of cerebral blood flow and CA in stroke units bedside tools like near-infrared spectroscopy (NIRS) might improve early detection of CA deterioration. This study aimed to assess dynamic CA with multichannel CW-NIRS in acute ischemic stroke (AIS) patients compared to agematched healthy controls. Methods: CA reaction was amplified by changes in head of bed position. Long- and short channels were used to monitor systemic artery pressure- and intracranial oscillations simultaneously. Gain and phase shift in spontaneous low- and very low-frequency oscillations (LFO, VLFO) of blood pressure were assessed. Results: A total of 54 participants, 27 with AIS and 27 age-matched controls were included. Gain was significantly lower in the AIS group in the LFO range (i) when the upper body was steadily elevated to 30. and (ii) after its abrupt elevation to 30°. No other differences were found between groups. Discussion: This study demonstrates the feasibility of NIRS short channels to measure CA in AIS patients in one single instrument. A lower gain in AIS might indicate decreased CA activity in this pilot study, but further studies investigating the role of NIRS short channels in AIS are needed.

Adaptation of cell spreading to varying fibronectin densities and topographies is facilitated by ß1 integrins.

Cells mechanical behaviour in physiological environments is mediated by interactions with the extracellular matrix (ECM). In particular, cells can adapt their shape according to the availability of ECM proteins, e.g., fibronectin (FN). Several in vitro experiments usually simulate the ECM by functionalizing the surfaces on which cells grow with FN. However, the mechanisms underlying cell spreading on non-uniformly FN-coated two-dimensional substrates are not clarified yet. In this work, we studied cell spreading on variously functionalized substrates: FN was either uniformly distributed or selectively patterned on flat surfaces, to show that A549, BRL, B16 and NIH 3T3 cell lines are able to sense the overall FN binding sites independently of their spatial arrangement. Instead, only the total amount of available FN influences cells spreading area, which positively correlates to the FN density. Immunocytochemical analysis showed that ß1 integrin subunits are mainly responsible for this behaviour, as further confirmed by spreading experiments with ß1-deficient cells. In the latter case, indeed, cells areas do not show a dependency on the amount of available FN on the substrates. Therefore, we envision for ß1 a predominant role in cells for sensing the number of ECM ligands with respect to other focal adhesion proteins.

Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation.

The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.

fMRI-based validation of continuous-wave fNIRS of supplementary motor area activation during motor execution and motor imagery.

Compared to functional magnetic resonance imaging (fMRI), functional near infrared spectroscopy (fNIRS) has several advantages that make it particularly interesting for neurofeedback (NFB). A pre-requisite for NFB applications is that with fNIRS, signals from the brain region of interest can be measured. This study focused on the supplementary motor area (SMA). Healthy older participants (N = 16) completed separate continuous-wave (CW-) fNIRS and (f)MRI sessions. Data were collected for executed and imagined hand movements (motor imagery, MI), and for MI of whole body movements. Individual anatomical data were used to (i) define the regions of interest for fMRI analysis, to (ii) extract the fMRI BOLD response from the cortical regions corresponding to the fNIRS channels, and (iii) to select fNIRS channels. Concentration changes in oxygenated ([Formula: see text]) and deoxygenated ([Formula: see text]) hemoglobin were considered in the analyses. Results revealed subtle differences between the different MI tasks, indicating that for whole body MI movements as well as for MI of hand movements [Formula: see text] is the more specific signal. Selection of the fNIRS channel set based on individual anatomy did not improve the results. Overall, the study indicates that in terms of spatial specificity and task sensitivity SMA activation can be reliably measured with CW-fNIRS.

Signal Processing in fNIRS: A Case for the Removal of Systemic Activity for Single Trial Data.

Researchers using functional near infrared spectroscopy (fNIRS) are increasingly aware of the problem that conventional filtering methods do not eliminate systemic noise at frequencies overlapping with the task frequency. This is a problem when signals are averaged for analysis, even more so when single trial data are used as in online neurofeedback or BCI applications where insufficiently preprocessed data means feeding back noise instead of brain activity or when looking for brain-behavior relationships on a trial-by-trial basis. For removing this task-related noise statistical approaches have been proposed. Yet as evidence is lacking on how these approaches perform on independent data, choosing one approach over another can be difficult. Here signal quality at the single trial level was considered together with statistical effects to inform this choice. Compared were conventional band-pass filtering and wavelet minimum description length detrending and the combination of both with a more elaborate, published preprocessing approach for a motor execution-motor imagery data set. Temporal consistency between Δ[HbO] and Δ[HbR] and two measures of the spatial specificity of signals that are proposed here served as measures of data quality. Both improved strongly for the combinationed preprocessing approaches. Statistical effects showed a strong tendency toward getting smaller for the combined approaches. This underlines the importance to adequately deal with noise in fNIRS recordings and demonstrates how the quality of statistical correction approaches can be estimated.

MgSc2 Se4 -A Magnesium Solid Ionic Conductor for All-Solid-State Mg Batteries?

Recently, the ternary spinel selenide MgSc2 Se4 was proposed to have high magnesium ion mobility and is therefore an interesting potential candidate as a solid electrolyte in magnesium secondary batteries. To test the properties of the material, a modified solid-state reaction was used to synthesize pure MgSc2 Se4 . Electrochemical characterizations identified detrimental high electronic conductivities, which limit its application as a Mg-conducting solid electrolyte. Two methods were attempted to lower electronic conductivities, including the implementation of Se-rich phases and aliovalent doping, however, with no sufficient improvement. Based on the mixed conducting properties of MgSc2 Se4 , a reversible insertion/extraction of Mg2+ into the spinel structure could be demonstrated.

Expansion of functional personalized cells with specific transgene combinations.

Fundamental research and drug development for personalized medicine necessitates cell cultures from defined genetic backgrounds. However, providing sufficient numbers of authentic cells from individuals poses a challenge. Here, we present a new strategy for rapid cell expansion that overcomes current limitations. Using a small gene library, we expanded primary cells from different tissues, donors, and species. Cell-type-specific regimens that allow the reproducible creation of cell lines were identified. In depth characterization of a series of endothelial and hepatocytic cell lines confirmed phenotypic stability and functionality. Applying this technology enables rapid, efficient, and reliable production of unlimited numbers of personalized cells. As such, these cell systems support mechanistic studies, epidemiological research, and tailored drug development.

Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept.

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate.

Cell type-specific adaptation of cellular and nuclear volume in micro-engineered 3D environments.

Bio-functionalized three-dimensional (3D) structures fabricated by direct laser writing (DLW) are structurally and mechanically well-defined and ideal for systematically investigating the influence of three-dimensionality and substrate stiffness on cell behavior. Here, we show that different fibroblast-like and epithelial cell lines maintain normal proliferation rates and form functional cell-matrix contacts in DLW-fabricated 3D scaffolds of different mechanics and geometry. Furthermore, the molecular composition of cell-matrix contacts forming in these 3D micro-environments and under conventional 2D culture conditions is identical, based on the analysis of several marker proteins (paxillin, phospho-paxillin, phospho-focal adhesion kinase, vinculin, ß1-integrin). However, fibroblast-like and epithelial cells differ markedly in the way they adapt their total cell and nuclear volumes in 3D environments. While fibroblast-like cell lines display significantly increased cell and nuclear volumes in 3D substrates compared to 2D substrates, epithelial cells retain similar cell and nuclear volumes in 2D and 3D environments. Despite differential cell volume regulation between fibroblasts and epithelial cells in 3D environments, the nucleus-to-cell (N/C) volume ratios remain constant for all cell types and culture conditions. Thus, changes in cell and nuclear volume during the transition from 2D to 3D environments are strongly cell type-dependent, but independent of scaffold stiffness, while cells maintain the N/C ratio regardless of culture conditions.

FeV2S4 as a high capacity electrode material for sodium-ion batteries.

Iron vanadium sulfide (FeV2S4) was synthesized via a high temperature solid state reaction and was investigated as a cheap anode material for Na and Li ion batteries. Discharge capacities as high as 723 mA h g(-1) (Na) and 890 mA h g(-1) (Li) were found for half-cell measurements at room temperature. The capacity of the Na-FeV2S4 system remained constant at 529 mA h g(-1) after the 10th cycle with an area capacity of 2.7 mA h cm(-2) being very close to that of conventional Li-ion technology.

Conversion reactions for sodium-ion batteries.

Research on sodium-ion batteries has recently been rediscovered and is currently mainly focused on finding suitable electrode materials that enable cell reactions of high energy densities combined with low cost. Naturally, an assessment of potential electrode materials requires a rational comparison with the analogue reaction in lithium-ion batteries. In this paper, we systematically discuss the broad range of different conversion reactions for sodium-ion batteries based on their basic thermodynamic properties and compare them with their lithium analogues. Capacities, voltages, energy densities and volume expansions are summarized to sketch out the scope for future studies in this research field. We show that for a given conversion electrode material, replacing lithium by sodium leads to a constant shift in cell potential ΔE°(Li-Na) depending on the material class. For chlorides ΔE°(Li-Na) equals nearly zero. The theoretical energy densities of conversion reactions of sodium with fluorides or chlorides as positive electrode materials typically reach values between 700 W h kg(-1) and 1000 W h kg(-1). Next to the thermodynamic assessment, results on several conversion reactions between copper compounds (CuS, CuO, CuCl, CuCl2) and sodium are being discussed. Reactions with CuS and CuO were chosen because these compounds are frequently studied for conversion reactions with lithium. Chlorides are interesting because of ΔE°(Li-Na)≈ 0 V. As a result of chloride solubility in the electrolyte, the conversion process proceeds at defined potentials under rather small kinetic limitations.

Filamentous network mechanics and active contractility determine cell and tissue shape.

For both cells and tissues, shape is closely correlated with function presumably via geometry-dependent distribution of tension. In this study, we identify common shape determinants spanning cell and tissue scales. For cells whose sites of adhesion are restricted to small adhesive islands on a micropatterned substrate, shape resembles a sequence of inward-curved circular arcs. The same shape is observed for fibroblast-populated collagen gels that are pinned to a flat substrate. Quantitative image analysis reveals that, in both cases, arc radii increase with the spanning distance between the pinning points. Although the Laplace law for interfaces under tension predicts circular arcs, it cannot explain the observed dependence on the spanning distance. Computer simulations and theoretical modeling demonstrate that filamentous network mechanics and contractility give rise to a modified Laplace law that quantitatively explains our experimental findings on both cell and tissue scales. Our model in conjunction with actomyosin inhibition experiments further suggests that cell shape is regulated by two different control modes related to motor contractility and structural changes in the actin cytoskeleton.

Characterization of native and reconstituted exosome complexes from the hyperthermophilic archaeon Sulfolobus solfataricus.

The eukaryotic exosome is a protein complex with essential functions in processing and degradation of RNA. Exosome-like complexes were recently found in Archaea. Here we characterize the exosome of Sulfolobus solfataricus. Two exosome fractions can be discriminated by density gradient centrifugation. We show that the Cdc48 protein is associated with the exosome from the 30S-50S fraction but not with the exosome of the 11.3S fraction. While only some complexes contain Cdc48, the archaeal DnaG-like protein was found to be a core exosome subunit in addition to Rrp4, Rrp41, Rrp42 and Csl4. Assays with depleted extracts revealed that the exosome is responsible for major ribonucleolytic activity in S. solfataricus. Various complexes consisting of the Rrp41-Rrp42 hexameric ring and Rrp4, Csl4 and DnaG were reconstituted. Dependent on their composition, different complexes showed variations in RNase activity indicating functional interdependence of the subunits. The catalytic activity of these complexes and of the native exosome can be ascribed to the Rrp41-Rrp42 ring, which degrades RNA phosphorolytically. Rrp4 and Csl4 do not exhibit any hydrolytic RNase activity, either when assayed alone or in context of the complex, but influence the activity of the archaeal exosome.