Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults.

OBJECTIVES: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. METHODS: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12. RESULTS: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4+) and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed. CONCLUSION: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects.

Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD).

Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention.New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo."

Mitochondrial DNA G15927A and G15928A variations in patients with multiple sclerosis.

BACKGROUND: Modern genetics has offered a fresh perspective on the pathology of Multiple Sclerosis (MS). As mitochondrial DNA (mtDNA) variations are held to be potential contributors to the complex pathobiology of MS, the present study tests the claim that mtDNA G15927A or G15928A variations, or both, are associated with MS in an Iranian population. MATERIALS AND METHODS: Following DNA extraction from blood samples of 100 subjects with relapsing-remitting MS, and 100 healthy unrelated control subjects, PCR-RFLP analyses was carried out by HpaII restriction enzyme reaction. Electrophoresis was then performed with 3% Agarose gel. As the restriction enzyme did not differentiate between two neighboring nucleotide positions (G15927A and G15928A), all PCR products with a variant allele were sequenced to determine the exact position of the variation. RESULTS: The MtDNA G15927A or G15928A variations were observed in 11 of all 100 cases of MS (11%) and in 7 of 100 healthy control subjects (7%) (P = 0.3, OR = 1.6, 95% CI = 0.5-5.2). Having sequenced all the PCR products with the variant allele (11 cases and 7 controls), the mtDNA G15927A variation was found in one of the 100 cases (1%) and 3 of 100 controls (3%) (P = 0.3, OR = 0.3, 95% CI = 0.0-4.1). Therefore, the mtDNA G15928A variation was present in 10 of the 100 cases (10%) and in 4 of 100 controls (4%) (P = 0.09, OR = 2.6, 95% CI = 0.7-12.0). CONCLUSION: Neither mtDNA variation, G15927A or G15928A, was associated with MS in the studied Iranian population. There was a non-significant association of the G15927A and the G15928A variations separately with MS.

Pandora's Box: mitochondrial defects in ischaemic heart disease and stroke.

Ischaemic heart disease and stroke are vascular events with serious health consequences worldwide. Recent genetic and epigenetic techniques have revealed many genetic determinants of these vascular events and simplified the approaches to research focused on ischaemic heart disease and stroke. The pathogenetic mechanisms of ischaemic heart disease and stroke are complex, with mitochondrial involvement (partially or entirely) recently gaining substantial support. Not only can mitochondrial reactive oxygen species give rise to ischaemic heart disease and stroke by production of oxidised low-density lipoprotein and induction of apoptosis, but the impact on pericytes contributes directly to the pathogenesis. Over the past two decades, publications implicate the causative role of nuclear genes in the development of ischaemic heart disease and stroke, in contrast to the potential role of mitochondrial DNA (mtDNA) in the pathophysiology of the disorders, which is much less understood, although recent studies do demonstrate that the involvement of mitochondria and mtDNA in the development of ischaemic heart disease and stroke is likely to be larger than originally thought, with the novel discovery of links among mitochondria, mtDNA and vascular events. Here we explore the molecular events and mtDNA alterations in relation to the role of mitochondria in ischaemic heart disease and stroke.

Evidence for gender-specific endophenotypes in high-functioning autism spectrum disorder during empathy.

Despite remarkable behavioral gender differences in patients with autism spectrum disorder (ASD), and growing evidence for a diminished male : female ratio for the putative "male disorder" ASD, aspects of gender are not addressed accordingly in ASD research. Our study aims at filling this gap by exploring empathy abilities in a group of 28 patients with high-functioning ASD and 28 gender-, age- and education-matched non-autistic subjects, for the first time by means of functional neuroimaging (fMRI). In an event-related fMRI paradigm, emotional ("E") and neutral ("N") video clips presented actors telling self-related short stories. After each clip, participants were asked to indicate their own emotion and its intensity as well as the emotion and intensity perceived for the actor. Behaviorally, we found significantly less empathic responses in the overall ASD group compared with non-autistic subjects, and inadequate emotion recognition for the neutral clips in the female ASD group compared with healthy women. Neurally, increased activation of the bilateral medial frontal gyrus was found in male patients compared with female patients, a pattern which was not present in the non-autistic group. Additionally, autistic women exhibited decreased activation of midbrain and limbic regions compared with non-autistic women, whereas there was no significant difference within the male group. While we did not find a fundamental empathic deficit in autistic patients, our data propose different ways of processing empathy in autistic men and women, suggesting stronger impairments in cognitive aspects of empathy/theory of mind for men, and alterations of social reciprocity for women.

Neural correlates of moral reasoning in autism spectrum disorder.

In our study, we tried to clarify whether patients with autism spectrum disorder (ASD) reveal different moral decision patterns as compared to healthy subjects and whether common social interaction difficulties in ASD are reflected in altered brain activation during different aspects of moral reasoning. 28 patients with high-functioning ASD and 28 healthy subjects matched for gender, age and education took part in an event-related functional magnetic resonance imaging study. Participants were confronted with textual dilemma situations followed by proposed solutions to which they could agree or disagree. On a neural level, moral decision making was associated with activation in anterior medial prefrontal regions, the temporo-parietal junction and the precuneus for both groups. However, while patients and healthy controls did not exhibit significant behavioral differences, ASD patients showed decreased activation in limbic regions, particularly the amygdala, as well as increased activation in the anterior and the posterior cingulate gyrus during moral reasoning. Alterations of brain activation in patients might thus indicate specific impairments in empathy. However, activation increases in brain regions associated with the 'default mode network' and self-referential cognition also provide evidence for an altered way of patients' cerebral processing with regard to decision making based on social information.

The neurobiology of suicide - A Review of post-mortem studies.

The neurobiology of suicidal behaviour, which constitutes one of the most serious problems both in psychiatry and general medical practice, still remains to a large degree unclear. As a result, scientists constantly look for new opportunities of explaining the causes underlying suicidality. In order to elucidate the biological changes occurring in the brains of the suicide victims, studies based on post-mortem brain tissue samples are increasingly being used. These studies employ different research methods to provide an insight into abnormalities in brain functioning on various levels, including gene and protein expression, neuroplasticity and neurotransmission, as well as many other areas. The aim of this paper to summarize the available data on the post-mortem studies, to provide an overview of main research directions and the most up-to-date findings, and to indicate the possibilities of further research in this field.

Matrix metalloproteinases in autism spectrum disorders.

Autism Spectrum Disorders (ASD) are group of developmental disabilities with a complex neurobiological basis including putative changes in the immune system. They are characterized by pervasive qualitative abnormalities in social interactions, communication, and stereotyped behaviour. Matrix metalloproteinases (MMPs) represent a group of proteases which play an important role in neuroinflammation and neurodevelopment. Therefore, they possibly have a crucial function in the etiopathology of ASD. In this review, we summarize the plausibility of the hypothesis that MMPs are involved in the neuropathology of ASD. Possible pathways through which MMPs can contribute to the pathogenesis of ASD are discussed including neuroinflammatory mechanisms inclusive of mediating neuropathological effects of infections, the associations between MMPs and other biomarkers such as cytokines, chemokines and neurotrophic factors. Despite sufficient evidence for such an involvement of MMPs in the neuropathology of ASD, they have not yet been extensively studied in this context. Thus, further research in this field is not only urgently needed but also very promising and may also lead to new therapeutic approaches.

Methyl- and acetyltransferases are stable epigenetic markers postmortem.

Postmortem brain tissue has been reported to be suitable to delineate regional pattern of possible disturbances underlying epigenetic functionality. However, from many parameters that have been detected in postmortem brain regions it is noteworthy that an effect of postmortem interval (PMI), storage time and premortem parameters should not be underestimated. Our previous investigation revealed that tryptophan (TRP) levels in postmortem brain tissue is affected by PMI and storage time. Since, alteration in TRP levels are assumed to be due to protein degradation, we further investigated whether TRP correlates to variables such as RNA, proteins and DNA modulators. In addition, we aimed to elucidate whether established postmortem variables may influence epigenetic parameters. These were investigated in well characterized postmortem human brain tissue originating from the European Brain Bank consortium II (BNEII). We could confirm previous findings, in which some protein levels alter because of prolonged PMI. Similarly, we demonstrated an influence of increased storage period on TRP levels, which might indicate degradation of proteins. Still not all proteins degrade in a similar manner, therefore a specific analysis for the protein of interest would be recommended. We found that methyltransferase- and acetyltransferase-activities were relatively preserved with PMI and storage duration. In conclusion, preservation of acetyltransferase- and methyltransferase-activities provides possible evidence of stability for epigenetic studies using postmortem tissue.

Regulatory T cells increased while IL-1ß decreased during antidepressant therapy.

BACKGROUND: Regulatory T cells (Tregs, CD4(+)CD25(hi)) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1ß, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4(+)CD25(hi) Tregs in these immunological processes during antidepressant therapy. METHODS: 16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctor's choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1ß, and measured IL-1ß, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4(+)CD25(hi) Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21). RESULTS: HAMD-21 score, IL-1ß serum levels as well as LPS-stimulated IL-1ß and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4(+)CD25(hi) cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed. CONCLUSIONS: The increase in CD4(+)CD25(hi) Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.

Tryptophan is a marker of human postmortem brain tissue quality.

Postmortem human brain tissue is widely used in neuroscience research, but use of tissue originating from different brain bank centers is considered inaccurate because of possible heterogeneity in sample quality. There is thus a need for well-characterized markers to assess the quality of postmortem brain tissue. Toward this aim, we determined tryptophan (TRP) concentrations, phosphofructokinase-1 and glutamate decarboxylase activities in 119 brain tissue samples. These neurochemical parameters were tested in samples from autopsied individuals, including control and pathological cases provided by 10 different brain bank centers. Parameters were assessed for correlation with agonal state, postmortem interval, age and gender, brain region, preservation and freezing methods, storage conditions and storage time, RNA integrity, and tissue pH value. TRP concentrations were elevated significantly (p = 0.045) with increased postmortem interval; which might indicate increased protein degradation. Therefore, TRP concentration might be one useful and convenient marker for estimating the quality of human postmortem brain tissue.

Effects of acute nicotine on brain function in healthy smokers and non-smokers: estimation of inter-individual response heterogeneity.

The present study used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms of nicotine effects on antisaccades (an oculomotor measure of the conflict between a reflexive response and a spatially complex volitional response) and prosaccades (involving reflexive overt attentional shifts). Given the known inter-individual variability in drug response we aimed to identify oculomotor variables and brain areas in which significant inter-individual heterogeneity in response to nicotine is observed. To do so we calculated within-session intraclass correlation (ICC) coefficients over measurements obtained before and after nicotine/placebo administration and reasoned that a significant reduction in ICC with nicotine compared to placebo would reflect the operation of significant inter-individual response heterogeneity. Thirteen light-to-moderate smokers and 11 non-smokers completed fMRI during antisaccades before and after subcutaneous injection of 12 microg/kg nicotine or saline placebo in a double-blind, randomised, cross-over design. All participants were healthy, right-handed males. Nicotine and placebo were given on separate occasions approximately 1 week apart with time of injection kept constant. Nicotine significantly reduced antisaccade latencies in both groups. At the level of brain function, during antisaccades the blood oxygen level dependent (BOLD) response in the left frontal eye field was non-significantly reduced by nicotine while it significantly increased following placebo in non-smokers, but there was no discernible effect in smokers. During prosaccades, it was found that deactivation areas (posterior cingulate gyrus and precuneus; right superior temporal gyrus) showed enhanced deactivations following nicotine administration in both groups. ICC analysis identified significant inter-individual response heterogeneity in antisaccade reflexive errors in smokers, and in a number of brain regions, particularly in non-smokers. These findings suggest that nicotine has beneficial effects at the cognitive level and leads to reductions in task-related activations and further decreases of BOLD in deactivation areas. The comparison of within-session ICCs across drug conditions suggests that the effects of nicotine are subject to inter-individual variability at behavioural and neural levels.

From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.

Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative post-mortem study.

INTRODUCTION: A growing body of evidence suggests that the glial cell line-derived neurotrophic factor (GDNF) is involved in the aetiopathology of mood disorders. GDNF is a neurotrophic factor from the transforming growth factor-beta-family, playing a role in cell development and function in the limbic system. This is the first study to examine GDNF concentration in different brain regions of patients with depressive disorder (DD). MATERIAL AND METHODS: We used sandwich-ELISA-technique to ascertain GDNF concentration and Lowry assay for overall protein levels in post-mortem brain tissue of 7 patients with recurrent depressive disorder and 14 individuals without any neurological or psychiatric diagnoses. We included cortical regions as well as limbic area's (hippocampus, entorhinal cortex) basal ganglia (putamen, caudate nucleus), thalamus and cingulated gyrus. RESULTS: We found a significant increase in GDNF concentration in the parietal cortex of patients with DD compared to the control group. In other regions the trend of an increased GDNF concentration did not reach statistical difference. DISCUSSION: This proof of concept study supports previous findings of an alteration of the GDNF in patients with depressive disorder. However, for the first time a significant increase of GDNF in a cortical brain area was found in DD.

Catechol-O-methyltransferase (COMT) val158met genotype is associated with BOLD response as a function of task characteristic.

The catechol-O-methyltransferase (COMT) val(158)met single nucleotide polymorphism (rs4680) has been shown to be associated with brain activation during a number of neurocognitive and emotional tasks. The present study evaluated genotypic associations with brain function during measurement of cognitive stability (prosaccades) and plasticity (antisaccades). A total of 36 healthy volunteers were genotyped for rs4680 and underwent functional magnetic resonance imaging (fMRI) at 1.5 T. Individuals with at least one val(158) allele (val(158) carriers, N=24) showed lower blood oxygen level-dependent (BOLD) response in ventromedial and dorsomedial prefrontal cortex during antisaccades compared to val(158) noncarriers, whereas met(158) homozygotes (N=12) showed lower BOLD response in a cluster in the posterior cingulate and precuneus during prosaccades compared to val(158) carriers. These findings suggest that associations of COMT val(158)met genotype with brain function may be mediated by task characteristics. The findings may be compatible with a hypothesis on the role of COMT val(158)met genotype in tonic and phasic dopamine levels in brain and differential effects on cognitive measures of stability (eg prosaccades) and plasticity (eg antisaccades).

Misattribution bias of threat-related facial expressions is related to a longer duration of illness and poor executive function in schizophrenia and schizoaffective disorder.

BACKGROUND: While it is known that patients with schizophrenia recognize facial emotions, specifically negative emotions, less accurately, little is known about how they misattribute these emotions to other emotions and whether such misattribution biases are associated with symptoms, course of the disorder, or certain cognitive functions. METHOD: Outpatients with schizophrenia or schizoaffective disorder (n=73) and healthy controls (n=30) performed a computerised Facial Emotion Attribution Test and Wisconsin Card Sorting Test (WCST). Patients were also rated on the Positive and Negative Syndrome Scale (PANSS). RESULTS: Patients were poor at recognizing fearful and angry emotions and attributed fear to angry and angry to neutral expressions. Fear-as-anger misattributions were predicted independently by a longer duration of illness and WCST perseverative errors. CONCLUSION: The findings show a bias towards misattributing fearful and angry facial emotions. The propensity for fear-as-anger misattribution biases increases as the length of time that the disorder is experienced increases and a more rigid style of information processing is used. This, at least in part, may be perpetuated by subtle fearfulness expressed by others while interacting with people with schizophrenia.

Serotonin transporter gene polymorphism and personality traits in primary alcohol dependence.

We tested the hypothesis of an association between the serotonin transporter (5-HTT) gene regulatory region polymorphism and the Temperament and Character Inventory (TCI) personality dimension of Harm Avoidance. For the study, 124 subjects seeking inpatient treatment for primary alcohol dependence were grouped by their 5-HTT genotype and assessed with the TCI. Genotypes differed statistically significantly in Harm Avoidance but not in any other personality trait. This gives support to the hypothesis that the TCI temperament Harm Avoidance is associated with serotonergic neurotransmission in primary alcohol dependence.