Recognizing depression as an inflammatory disease: The search for endotypes.

Major depressive disorder (MDD) affects millions of individuals worldwide, leading to considerable social and economic costs. Despite advancements in pharmacological treatments, achieving remission remains a key challenge, with a substantial number of patients showing resistance to existing therapies. This resistance is often associated with elevated levels of pro-inflammatory cytokines, suggesting a connection between inflammation, MDD pathophysiology, and treatment efficacy. The observation of increased immune activation in about a quarter of MDD patients resulted in the distinction of inflammatory and non-inflammatory endotypes. While anti-inflammatory treatments show promise in alleviating depression-like symptoms, responses are heterogeneous, thus highlighting the importance of identifying distinct inflammatory endotypes to tailor effective therapeutic strategies. The intestinal microbiome emerges as a crucial modulator of mental health, mediating its effects partially through different immune pathways. Microbiota-derived short-chain fatty acids (SCFAs) significantly impact innate and adaptive immune cells, regulating their differentiation, function, and cellular response. Furthermore, gut-educated immune cells reach the border regions of the central nervous system (CNS), regulating glial cell functions. While the CNS modulates immune responses via efferent parts of the vagus nerve, afferent tracts concurrently transport information on peripheral inflammation back to the brain. This bidirectional communication is particularly relevant in depression, allowing for therapeutic stimulation of the vagus nerve in the context of inflammatory depression endotypes. In this review, we explore the intricate relationship between inflammation and depression, discuss how inflammatory signals are translated into depressive-like symptoms, and highlight immune-modulating therapeutic avenues.

Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy?

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Shorter planning depth and higher response noise during sequential decision-making in old age.

Forward planning is crucial to maximize outcome in complex sequential decision-making scenarios. In this cross-sectional study, we were particularly interested in age-related differences of forward planning. We presumed that especially older individuals would show a shorter planning depth to keep the costs of model-based decision-making within limits. To test this hypothesis, we developed a sequential decision-making task to assess forward planning in younger (age < 40 years; n = 25) and older (age > 60 years; n = 27) adults. By using reinforcement learning modelling, we inferred planning depths from participants' choices. Our results showed significantly shorter planning depths and higher response noise for older adults. Age differences in planning depth were only partially explained by well-known cognitive covariates such as working memory and processing speed. Consistent with previous findings, this indicates age-related shifts away from model-based behaviour in older adults. In addition to a shorter planning depth, our findings suggest that older adults also apply a variety of heuristical low-cost strategies.

The ubiquitin-like modifier FAT10 is degraded by the 20S proteasome in vitro but not in cellulo.

Ubiquitin-independent protein degradation via the 20S proteasome without the 19S regulatory particle has gained increasing attention over the last years. The degradation of the ubiquitin-like modifier FAT10 by the 20S proteasome was investigated in this study. We found that FAT10 was rapidly degraded by purified 20S proteasomes in vitro, which was attributed to the weak folding of FAT10 and the N-terminally disordered tail. To confirm our results in cellulo, we established an inducible RNA interference system in which the AAA-ATPase Rpt2 of the 19S regulatory particle is knocked down to impair the function of the 26S proteasome. Using this system, degradation of FAT10 in cellulo was strongly dependent on functional 26S proteasome. Our data indicate that in vitro degradation studies with purified proteins do not necessarily reflect biological degradation mechanisms occurring in cells and, therefore, cautious data interpretation is required when 20S proteasome function is studied in vitro.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks.

The neuropeptide PACAP alleviates T. gondii infection-induced neuroinflammation and neuronal impairment.

BACKGROUND: Cerebral infection with the protozoan Toxoplasma gondii (T. gondii) is responsible for inflammation of the central nervous system (CNS) contributing to subtle neuronal alterations. Albeit essential for brain parasite control, continuous microglia activation and recruitment of peripheral immune cells entail distinct neuronal impairment upon infection-induced neuroinflammation. PACAP is an endogenous neuropeptide known to inhibit inflammation and promote neuronal survival. Since PACAP is actively transported into the CNS, we aimed to assess the impact of PACAP on the T. gondii-induced neuroinflammation and subsequent effects on neuronal homeostasis. METHODS: Exogenous PACAP was administered intraperitoneally in the chronic stage of T. gondii infection, and brains were isolated for histopathological analysis and determination of pathogen levels. Immune cells from the brain, blood, and spleen were analyzed by flow cytometry, and the further production of inflammatory mediators was investigated by intracellular protein staining as well as expression levels by RT-qPCR. Neuronal and synaptic alterations were assessed on the transcriptional and protein level, focusing on neurotrophins, neurotrophin-receptors and signature synaptic markers. RESULTS: Here, we reveal that PACAP administration reduced the inflammatory foci and the number of apoptotic cells in the brain parenchyma and restrained the activation of microglia and recruitment of monocytes. The neuropeptide reduced the expression of inflammatory mediators such as IFN-γ, IL-6, iNOS, and IL-1ß. Moreover, PACAP diminished IFN-γ production by recruited CD4+ T cells in the CNS. Importantly, PACAP promoted neuronal health via increased expression of the neurotrophin BDNF and reduction of p75NTR, a receptor related to neuronal cell death. In addition, PACAP administration was associated with increased expression of transporters involved in glutamatergic and GABAergic signaling that are particularly affected during cerebral toxoplasmosis. CONCLUSIONS: Together, our findings unravel the beneficial effects of exogenous PACAP treatment upon infection-induced neuroinflammation, highlighting the potential implication of neuropeptides to promote neuronal survival and minimize synaptic prejudice.

Patterns of Alcohol Consumption Among Individuals With Alcohol Use Disorder During the COVID-19 Pandemic and Lockdowns in Germany.

Importance: Alcohol consumption (AC) leads to death and disability worldwide. Ongoing discussions on potential negative effects of the COVID-19 pandemic on AC need to be informed by real-world evidence. Objective: To examine whether lockdown measures are associated with AC and consumption-related temporal and psychological within-person mechanisms. Design, Setting, and Participants: This quantitative, intensive, longitudinal cohort study recruited 1743 participants from 3 sites from February 20, 2020, to February 28, 2021. Data were provided before and within the second lockdown of the COVID-19 pandemic in Germany: before lockdown (October 2 to November 1, 2020); light lockdown (November 2 to December 15, 2020); and hard lockdown (December 16, 2020, to February 28, 2021). Main Outcomes and Measures: Daily ratings of AC (main outcome) captured during 3 lockdown phases (main variable) and temporal (weekends and holidays) and psychological (social isolation and drinking intention) correlates. Results: Of the 1743 screened participants, 189 (119 [63.0%] male; median [IQR] age, 37 [27.5-52.0] years) with at least 2 alcohol use disorder (AUD) criteria according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) yet without the need for medically supervised alcohol withdrawal were included. These individuals provided 14 694 smartphone ratings from October 2020 through February 2021. Multilevel modeling revealed significantly higher AC (grams of alcohol per day) on weekend days vs weekdays (ß = 11.39; 95% CI, 10.00-12.77; P < .001). Alcohol consumption was above the overall average on Christmas (ß = 26.82; 95% CI, 21.87-31.77; P < .001) and New Year's Eve (ß = 66.88; 95% CI, 59.22-74.54; P < .001). During the hard lockdown, perceived social isolation was significantly higher (ß = 0.12; 95% CI, 0.06-0.15; P < .001), but AC was significantly lower (ß = -5.45; 95% CI, -8.00 to -2.90; P = .001). Independent of lockdown, intention to drink less alcohol was associated with lower AC (ß = -11.10; 95% CI, -13.63 to -8.58; P < .001). Notably, differences in AC between weekend and weekdays decreased both during the hard lockdown (ß = -6.14; 95% CI, -9.96 to -2.31; P = .002) and in participants with severe AUD (ß = -6.26; 95% CI, -10.18 to -2.34; P = .002). Conclusions and Relevance: This 5-month cohort study found no immediate negative associations of lockdown measures with overall AC. Rather, weekend-weekday and holiday AC patterns exceeded lockdown effects. Differences in AC between weekend days and weekdays evinced that weekend drinking cycles decreased as a function of AUD severity and lockdown measures, indicating a potential mechanism of losing and regaining control. This finding suggests that temporal patterns and drinking intention constitute promising targets for prevention and intervention, even in high-risk individuals.

Persisting Microbiota and Neuronal Imbalance Following T. gondii Infection Reliant on the Infection Route.

Toxoplasma gondii is a highly successful parasite capable of infecting all warm-blooded animals. The natural way of infection in intermediate hosts is the oral ingestion of parasite-contaminated water or food. In murine experimental models, oral infection (p.o.) of mice with T. gondii is applied to investigate mucosal and peripheral immune cell dynamics, whereas intraperitoneal infection (i.p.) is frequently used to study peripheral inflammation as well as immune cell - neuronal interaction in the central nervous system (CNS). However, the two infection routes have not yet been systematically compared along the course of infection. Here, C57BL/6 mice were infected p.o. or i.p. with a low dose of T. gondii cysts, and the acute and chronic stages of infection were compared. A more severe course of infection was detected following i.p. challenge, characterized by an increased weight loss and marked expression of proinflammatory cytokines particularly in the CNS during the chronic stage. The elevated proinflammatory cytokine expression in the ileum was more prominent after p.o. challenge that continued following the acute phase in both i.p. or p.o. infected mice. This resulted in sustained microbial dysbiosis, especially after p.o. challenge, highlighted by increased abundance of pathobionts from the phyla proteobacteria and a reduction of beneficial commensal species. Further, we revealed that in the CNS of i.p. infected mice CD4 and CD8 T cells displayed higher IFNγ production in the chronic stage. This corresponded with an increased expression of C1q and CD68 in the CNS and reduced expression of genes involved in neuronal signal transmission. Neuroinflammation-associated synaptic alterations, especially PSD-95, VGLUT, and EAAT2 expression, were more pronounced in the cortex upon i.p. infection highlighting the profound interplay between peripheral inflammation and CNS homeostasis.

Type 1 innate lymphoid cells regulate the onset of Toxoplasma gondii-induced neuroinflammation.

Cerebral infections are restrained by a complex interplay of tissue-resident and recruited peripheral immune cells. Whether innate lymphoid cells (ILCs) are involved in the orchestration of the neuroinflammatory dynamics is not fully understood. Here, we demonstrate that ILCs accumulate in the cerebral parenchyma, the choroid plexus, and the meninges in the onset of cerebral Toxoplasma gondii infection. Antibody-mediated depletion of conventional natural killer (cNK) cells and ILC1s in the early stage of infection results in diminished cytokine and chemokine expression and increased cerebral parasite burden. Using cNK- and ILC1-deficient murine models, we demonstrate that exclusively the lack of ILC1s affects cerebral immune responses. In summary, our results provide evidence that ILC1s are an early source of IFN-γ and TNF in response to cerebral T. gondii infection, thereby inducing host defense factors and initiating the development of a neuroinflammatory response.

Immune response and pathogen invasion at the choroid plexus in the onset of cerebral toxoplasmosis.

BACKGROUND: Toxoplasma gondii (T. gondii) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood-brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), the main structure forming the blood-cerebrospinal fluid (CSF) barrier (BCSFB) have not been addressed. METHODS: To investigate T. gondii invasion at the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analyzed for parasite burden. Additionally, immuno-stained brain sections and three-dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro. RESULTS: Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo, which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo, which was extended over the infection course. CONCLUSIONS: Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.

Antibiotic-induced gut dysbiosis leads to activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus.

Antibiotics are widely applied for the treatment of bacterial infections, but their long-term use may lead to gut flora dysbiosis and detrimental effects on brain physiology, behavior as well as cognitive performance. Still, a striking lack of knowledge exists concerning electrophysiological correlates of antibiotic-induced changes in gut microbiota and behavior. Here, we investigated changes in the synaptic transmission and plasticity together with behaviorally-relevant network activities from the hippocampus of antibiotic-treated mice. Prolonged antibiotic treatment led to a reduction of myeloid cell pools in bone marrow, circulation and those surveilling the brain. Circulating Ly6Chi inflammatory monocytes adopted a proinflammatory phenotype with increased expression of CD40 and MHC II. In the central nervous system, microglia displayed a subtle activated phenotype with elevated CD40 and MHC II expression, increased IL-6 and TNF production as well as with an increased number of Iba1 + cells in the hippocampal CA3 and CA1 subregions. Concomitantly, we detected a substantial reduction in the synaptic transmission in the hippocampal CA1 after antibiotic treatment. In line, carbachol-induced cholinergic gamma oscillation were reduced upon antibiotic treatment while the incidence of hippocampal sharp waves was elevated. These alterations were associated with the global changes in the expression of neurotrophin nerve growth factor and inducible nitric oxide synthase, both of which have been shown to influence cholinergic system in the hippocampus. Overall, our study demonstrates that antibiotic-induced dysbiosis of the gut microbiome and subsequent alteration of the immune cell function are associated with reduced synaptic transmission and gamma oscillations in the hippocampus, a brain region that is critically involved in mediation of innate and cognitive behavior.

Perceptual Learning of Object Recognition in Simulated Retinal Implant Perception - The Effect of Video Training.

Purpose: Retinal implants (RIs) provide new vision for patients suffering from photoreceptor degeneration in the retina. The limited vision gained by RI, however, leaves room for improvement by training regimes. Methods: Two groups of normal-sighted participants were respectively trained with videos or still images of daily objects in a labeling task. Object appearance was simulated to resemble RI perception. In Experiment 1, the training effect was measured as the change in performance during the training, and the same labeling task was conducted after 1 week to test the retention. In Experiment 2 with a different pool of participants, a reverse labeling task was included before (pre-test) and after the training (post-test) to show if the training effect could be generalized into a different task context. Results: Both groups showed improved object recognition through training that was maintained for a week, and the video group showed better improvement (Experiment 1). Both groups showed improved object recognition in a different task that was maintained for a week, but the video group did not show better retention than the image group (Experiment 2). Conclusions: Training with video materials leads to more improvement than training with still images in simulated RI perception, but this better improvement was specific to the trained task. Translational Relevance: We recommend videos as better training materials than still images for patients with RIs to improve object recognition when the task-goal is highly specific. We also propose here that achieving highly specific training goals runs the risk of limiting the generalization of the training effects.

Influenza A Virus (H1N1) Infection Induces Microglial Activation and Temporal Dysbalance in Glutamatergic Synaptic Transmission.

Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms, such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression. Previous experiments using IAV/H1N1 infection models have shown impaired hippocampal neuronal morphology and cognitive abilities, but the underlying pathways have not been fully described. In this study, we demonstrate that infection with a low-dose non-neurotrophic H1N1 strain of IAV causes ample peripheral immune response followed by a temporary blood-brain barrier disturbance. Although histological examination did not reveal obvious pathological processes in the brains of IAV-infected mice, detailed multidimensional flow cytometric characterization of immune cells uncovered subtle alterations in the activation status of microglial cells. More specifically, we detected an altered expression pattern of major histocompatibility complex classes I and II, CD80, and F4/80 accompanied by elevated mRNA levels of CD36, CD68, C1QA, and C3, suggesting evolved synaptic pruning. To closer evaluate how these profound changes affect synaptic balance, we established a highly sensitive multiplex flow cytometry-based approach called flow synaptometry. The introduction of this novel technique enabled us to simultaneously quantify the abundance of pre- and postsynapses from distinct brain regions. Our data reveal a significant reduction of VGLUT1 in excitatory presynaptic terminals in the cortex and hippocampus, identifying a subtle dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations. IMPORTANCE Influenza A virus (IAV) causes mainly respiratory tract disease with fever and fatigue but is also associated with behavioral alterations in humans. Here, we demonstrate that infection with a low-dose non-neurotrophic H1N1 strain of IAV causes peripheral immune response followed by a temporary blood-brain barrier disturbance. Characterization of immune cells uncovered subtle alterations in the activation status of microglia cells that might reshape neuronal synapses. We established a highly sensitive multiplex flow cytometry-based approach called flow synaptometry to more closely study the synapses. Thus, we detected a specific dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations.

High salt diet-induced proximal tubular phenotypic changes and sodium-glucose cotransporter-2 expression are coordinated by cold shock Y-box binding protein-1.

High salt diet (HSD) is a hallmark of blood pressure elevations, weight gain and diabetes onset in the metabolic syndrome. In kidney, compensatory mechanisms are activated to balance salt turnover and maintain homeostasis. Data on the long-term effects of HSD with respect to tubular cell functions and kidney architecture that exclude confounding indirect blood pressure effects are scarce. Additionally we focus on cold shock Y-box binding protein-1 as a tubular cell protective factor. A HSD model (4% NaCl in chow; 1% NaCl in water) was compared to normal salt diet (NSD, standard chow) over 16 months using wild type mice and an inducible conditional whole body knockout for cold shock Y-box binding protein-1 (BL6J/N, Ybx1). HSD induced no difference in blood pressure over 16 months, comparing NSD/HSD and Ybx1 wild type/knockout. Nevertheless, marked phenotypic changes were detected. Glucosuria and subnephrotic albuminuria ensued in wild type animals under HSD, which subsided in Ybx1-deficient animals. At the same time megalin receptors were upregulated. The sodium-glucose cotransporter-2 (SGLT2) was completely downregulated in wild type HSD animals that developed glucosuria. In Ybx1 knockouts, expression of AQP1 and SGLT2 was maintained under HSD; proximal tubular widening and glomerular tubularization developed. Concurrently, amino aciduria of neutral and hydrophobic amino acids was seen. In vitro translation confirmed that YB-1 translationally represses Sglt2 transcripts. Our data reveal profound effects of HSD primarily within glomeruli and proximal tubular segments. YB-1 is regulated by HSD and orchestrates HSD-dependent changes; notably, sets reabsorption thresholds for amino acids, proteins and glucose.

The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis.

Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I/II-peptide complexes, which are required for the induction of T cell responses. The control of Toxoplasma gondii infection relies on Interferon-γ (IFNγ)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (ß1i/LMP2, ß2i/MECL-1 and ß5i/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8+ T cells were reduced in Toxoplasma gondii-infected TKO mice. Furthermore, impaired IFNγ, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated T. gondii burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits ß1i/LMP2, ß2i/MECL-1 and ß5i/LMP7 for the control of cerebral Toxoplasma gondii infection and subsequent neuroinflammation.

Optogenetic and chemogenetic insights into the neurocircuitry of depression-like behaviour: A systematic review.

Major depressive disorder (MDD) and its treatment are challenges for global health. Optogenetics and chemogenetics are driving MDD research forward by unveiling causal relations between cell-type-specific control of neurons and depressive-like behaviour in rodents. Using a systematic search process, in this review, a set of 43 original studies applying optogenetic or chemogenetic techniques in rodent models of depression was identified. Our aim was to provide an examination of all available studies elucidating central neuronal mechanisms leading to depressive-like behaviour in rodents and thereby unveiling the most promising routes for future research. A complex interacting network of relevant structures, in which central circuitries causally related to depressive-like behaviour are implicated, has been identified. As most relevant structures emerge: medial prefrontal cortex, anterior cingulate cortex, amygdala, nucleus accumbens, ventral tegmental area, hippocampus and raphe nuclei. Further evidence, though examined by only few studies, emerges for structures like the lateral habenula, or medial dorsal thalamus. Most of the identified brain areas have previously been associated with MDD neuropathology, but now evidence can be provided for causal pathological mechanisms within a complex cortico-limbic reward circuitry. However, the studies also show conflicting results concerning the mechanisms underlying the causal involvement of specific circuitries. Comparability of studies is partly limited since even small deviations in methodological approaches lead to different outcomes. Factors influencing study outcomes were identified and need to be considered in future studies (e.g. frequency used for stimulation, time and duration of stimulation, limitations of applied animal models of MDD).

Autoantibody Formation and Mapping of Immunogenic Epitopes against Cold-Shock-Protein YB-1 in Cancer Patients and Healthy Controls.

Cold shock Y-box binding protein-1 participates in cancer cell transformation and mediates invasive cell growth. It is unknown whether an autoimmune response against cancerous human YB-1 with posttranslational protein modifications or processing develops. We performed a systematic analysis for autoantibody formation directed against conformational and linear epitopes within the protein. Full-length and truncated recombinant proteins from prokaryotic and eukaryotic cells were generated. Characterization revealed a pattern of spontaneous protein cleavage, predominantly with the prokaryotic protein. Autoantibodies against prokaryotic, but not eukaryotic full-length and cleaved human YB-1 protein fragments were detected in both, healthy volunteers and cancer patients. A mapping of immunogenic epitopes performed with truncated E. coli-derived GST-hYB-1 proteins yielded distinct residues in the protein N- and C-terminus. A peptide array with consecutive overlapping 15mers revealed six distinct antigenic regions in cancer patients, however to a lesser extent in healthy controls. Finally, a protein cleavage assay was set up with recombinant pro- and eukaryotic-derived tagged hYB-1 proteins. A distinct cleavage pattern developed, that is retarded by sera from cancer patients. Taken together, a specific autoimmune response against hYB-1 protein develops in cancer patients with autoantibodies targeting linear epitopes.

Combining convolutional neural networks and star convex cuts for fast whole spine vertebra segmentation in MRI.

BACKGROUND AND OBJECTIVE: We propose an automatic approach for fast vertebral body segmentation in three-dimensional magnetic resonance images of the whole spine. Previous works are limited to the lower thoracolumbar section and often take minutes to compute, which is problematic in clinical routine, for study data sets with numerous subjects or when the cervical or upper thoracic spine is to be analyzed. METHODS: We address these limitations by a novel graph cut formulation based on vertebra patches extracted along the spine. For each patch, our formulation incorporates appearance and shape information derived from a task-specific convolutional neural network as well as star-convexity constraints that ensure a topologically correct segmentation of each vertebra. When segmenting vertebrae individually, ambiguities will occur due to overlapping segmentations of adjacent vertebrae. We tackle this problem by novel non-overlap constraints between neighboring patches based on so-called encoding swaps. The latter allow us to obtain a globally optimal multi-label segmentation of all vertebrae in polynomial time. RESULTS: We validated our approach on two data sets. The first contains T1- and T2-weighted whole spine images of 64 subjects with varying health conditions. The second comprises 23 T2-weighted thoracolumbar images of young healthy adults and is publicly available. Our method yielded Dice coefficients of 93.8 â€¯±â€¯ 2.6% and 96.0 â€¯±â€¯ 1.0% for both data sets with a run time of 1.35 â€¯±â€¯ 0.08 s and 0.90 â€¯±â€¯ 0.03 s per vertebra on consumer hardware. A complete whole spine segmentation took 32.4 ±â€¯1.92 s on average. CONCLUSIONS: Our results are superior to those of previous works at a fraction of their run time, which illustrates the efficiency and effectiveness of our whole spine segmentation approach.

Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner.

BACKGROUND: It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes. METHODS: Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation. RESULTS: Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1ß) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism. CONCLUSION: Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.