Psychological distress among individuals with a suicide attempt or suicidal ideation and suicide attempts patterns: first two years of the pandemic.

Background: The COVID-19 pandemic and related restrictions may have led to increased stress, particularly in people with mental health problems. Since stress factors play important role in the emergence of suicide attempts (SA) and suicidal ideation (SI), they may have been exacerbated by the pandemic, which could have led to an increased number of suicide attempts. Thus, we first investigated whether the pandemic affected personal stress experiences and appraisal of coping potential in individuals with and without SA and SI. In a second step, we analyzed the frequency and dynamics of SAs by patients admitted to a psychiatric university clinic over a period of four years. Methods: We examined stress experiences and appraisal of coping resources of inpatients recruited between March 2021 and February 2022 with SA (n=38), SI (n=27), and with mood disorder without SA or SI (n=45). In the second study, we investigated the time course of prospectively recorded patients with a suicide attempt (n=399) between January 1st 2018 and December 31st 2021 using interrupted time-series Poisson regression models. Results: There was a significant main effect of group (F[2,107]=6.58, p=0.002) regarding psychological stress levels, which was significantly higher in the SA and SI groups than in the psychiatric control group. No significant differences were found in the appraisal of coping resources or in the frequency of SAs before and during pandemic. However, the pandemic had a significant impact on the seasonal pattern of SAs. Conclusions: The pandemic increased psychological stress levels in individuals with SA and SI, which may be related to SI and do not necessarily result in SA. The pandemic did not affect the overall frequency of SA between March 2020 and December 2021, but interfered with the seasonal pattern of SA occurrence. Effective intervention strategies during a pandemic should include programs to strengthen the psychological resilience of people who are susceptible to mental health problems.

"Mix and match" auto-assembly of glycosyltransferase domains delivers biocatalysts with improved substrate promiscuity.

Glycosyltransferases (GT) catalyze the glycosylation of bioactive natural products, including peptides and proteins, flavonoids, and sterols, and have been extensively used as biocatalysts to generate glycosides. However, the often narrow substrate specificity of wild-type GTs requires engineering strategies to expand it. The GT-B structural family is constituted by GTs that share a highly conserved tertiary structure in which the sugar donor and acceptor substrates bind in dedicated domains. Here, we have used this selective binding feature to design an engineering process to generate chimeric glycosyltransferases that combine auto-assembled domains from two different GT-B enzymes. Our approach enabled the generation of a stable dimer with broader substrate promiscuity than the parent enzymes that were related to relaxed interactions between domains in the dimeric GT-B. Our findings provide a basis for the development of a novel class of heterodimeric GTs with improved substrate promiscuity for applications in biotechnology and natural product synthesis.

A cell-permeable probe for the labelling of a bacterial glycosyltransferase and virulence factor.

Chemical probes for bacterial glycosyltransferases are of interest for applications such as tracking of expression levels, and strain profiling and identification. Existing probes for glycosyltransferases are typically based on sugar-nucleotides, whose charged nature limits their applicability in intact cells. We report the development of an uncharged covalent probe for the bacterial galactosyltransferase LgtC, and its application for the fluorescent labelling of this enzyme in recombinant form, cell lysates, and intact cells. The probe was designed by equipping a previously reported covalent LgtC inhibitor based on a pyrazol-3-one scaffold with a 7-hydroxycoumarin fluorophore. We show that this pyrazol-3-ones scaffold is surprisingly stable in aqueous media, which may have wider implications for the use of pyrazol-3-ones as chemical probes. We also show that the 7-hydroxycoumarin fluorophore leads to an unexpected improvement in activity, which could be exploited for the development of second generation analogues. These results will provide a basis for the development of LgtC-specific probes for the detection of LgtC-expressing bacterial strains.

Impact of Toxoplasma gondii and Human Microbiome on Suicidal Behavior: A Systematic Review.

BACKGROUND: Suicide remains a persistent global health challenge, resisting widespread prevention efforts. According to previous findings, toxoplasmosis is particularly associated with altered decision making, which could lead to risk-taking behavior, thereby increasing the likelihood for suicidal behavior (SB). In addition, discussion about the role of microbiome in psychiatric disorders has emerged lately, which also makes it relevant to investigate its role in the context of SB. Therefore, two systematic reviews are integrated in this paper, and the existing knowledge is comprehensively summarized regarding the association between microbial pathogens and SB. METHODS: We conducted a systematic search with keywords including SB and Toxoplasma gondii (Suicid* AND Toxoplasm*) and microbiome (Suicid* AND Microbiome AND Microbiota) throughout PubMed and Scopus to retrieve related studies up to 9 November 2023, identifying 24 eligible records. The subjects of the included studies had to have fulfilled the criteria of an SB disorder as defined by DSM-5, and death cases needed to have been defined as suicide. RESULTS: Most studies reported significant association between toxoplasmosis and SB, suggesting a higher likelihood of SB in the infected population. Regarding the microbiome, only very few studies investigated an association between SB and alterations in the microbiome. Based on six included studies, there were some indications of a link between changes in the microbiome and SB. CONCLUSION: The cognitive aspects of decision making in T. gondii-infected individuals with SB should be further investigated to unravel the underlying mechanisms. Further sufficiently powered studies are needed to establish a link between SB and alterations in the microbiome.

No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy.

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration-which is shorter than current recommendations.

Facial expressions of pain: the role of the serotonergic system.

RATIONALE: Although interest in the neurobiology of facial communication of pain has increased over the last decades, little is known about which neurotransmitter systems might be involved in regulating facial expressions of pain. OBJECTIVES: We aim to investigate whether the serotonergic system (5-HT), which has been implicated in various aspects of pain processing as well as in behavioral response inhibition, might play a role in facial expressions of pain. Using acute tryptophan depletion (ATD) to manipulate 5-HT function, we examined its effects on facial and subjective pain responses. METHODS: In a double-blind, placebo-controlled within-subject design, 27 participants received either an ATD or a control drink in two separate sessions. Approximately 5-h post-oral consumption, we assessed pain thresholds (heat, pressure) as well as facial and subjective responses to phasic heat pain. Moreover, situational pain catastrophizing and mood were assessed as affective state indicators. RESULTS: ATD neither influenced pain thresholds nor self-report ratings, nor catastrophizing or mood. Only facial responses were significantly affected by ATD. ATD led to a decrease in pain-indicative as well as in pain-non-indicative facial responses to painful heat, compared to the control condition. CONCLUSIONS: Decrease in brain 5-HT synthesis via ATD significantly reduced facial responses to phasic heat pain; possibly due to (i) diminished disposition to display social behavior or due to (ii) decreased facilitation of excitatory inputs to the facial motor neuron.

Altered brain network organization in adults with Asperger's syndrome: decreased connectome transitivity and assortativity with increased global efficiency.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that persists into adulthood with both social and cognitive disturbances. Asperger's syndrome (AS) was a distinguished subcategory of autism in the DSM-IV-TR defined by specific symptoms including difficulties in social interactions, inflexible thinking patterns, and repetitive behaviour without any delay in language or cognitive development. Studying the functional brain organization of individuals with these specific symptoms may help to better understand Autism spectrum symptoms. Methods: The aim of this study is therefore to investigate functional connectivity as well as functional network organization characteristics using graph-theory measures of the whole brain in male adults with AS compared to healthy controls (HC) (AS: n = 15, age range 21-55 (mean ± sd: 39.5 ± 11.6), HC: n = 15, age range 22-57 [mean ± sd: 33.5 ± 8.5]). Results: No significant differences were found when comparing the region-by-region connectivity at the whole-brain level between the AS group and HC. However, measures of "transitivity," which reflect local information processing and functional segregation, and "assortativity," indicating network resilience, were reduced in the AS group compared to HC. On the other hand, global efficiency, which represents the overall effectiveness and speed of information transfer across the entire brain network, was increased in the AS group. Discussion: Our findings suggest that individuals with AS may have alterations in the organization and functioning of brain networks, which could contribute to the distinctive cognitive and behavioural features associated with this condition. We suggest further research to explore the association between these altered functional patterns in brain networks and specific behavioral traits observed in individuals with AS, which could provide valuable insights into the underlying mechanisms of its symptomatology.

Altered brain dynamic in major depressive disorder: state and trait features.

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.

Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings.SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

Neural Correlates of Impaired Cognitive Control in Individuals with Methamphetamine Dependence: An fMRI Study.

Impaired cognitive and behavioral control has often been observed in people who use methamphetamine (MA). However, a comprehensive understanding of the neural substrates underlying these impairments is still lacking. The goal of the present study was to study the neural correlates of impaired cognitive control in individuals with MA dependence according to DSM-IV criteria. Eighteen individuals with MA dependence and 21 healthy controls were investigated using Stroop task, fMRI, and an impulsivity questionnaire. Overall, patients were found to have significantly poorer accuracy on the Stroop task and higher self-rated impulsivity. Comparing brain activations during the task, decreased activation in the dorsolateral prefrontal cortex (DLPFC), anterior midcingulate cortex (aMCC), and dorsal striatum was observed in individuals with MA dependence, compared to healthy controls. Altered fMRI signal in DLPFC and aMCC significantly correlated with impaired behavioral task performance in individuals with MA dependence. Furthermore, significantly lower and pronounced brain activations in the MA group were additionally detected in several sensory cortical regions, i.e., in the visual, auditory, and somatosensory cortices. The results of the current study provide evidence for the negative impact of chronic crystal meth consumption on the proper functioning of the fronto-cingulate and striatal brain regions, presumably underlying the often-observed deficits in executive functions in individuals with MA use disorder. As a new finding, we also revealed abnormal activation in several sensory brain regions, suggesting the negative effect of MA use on the proper neural activity of these regions. This blunted activation could be the cause of the observed deficits in executive functions and the associated altered brain activation in higher-level brain networks.

Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review.

Background: More than 2% of the general population experience suicidal ideas each year and a large number of them will attempt suicide. Evidence-based therapeutic options to manage suicidal crisis are currently limited. Objectives: The aim of this study was to overview the findings on the use of ketamine and esketamine for the treatment of suicidal ideas and acts. Design: Systematic review. Data Sources and methods: PubMed, article references, and Clinicaltrials.gov up to June 30, 2022. Meta-analyses published within the last 2 years were also reviewed. Results: We identified 12 randomized controlled trials with reduction of suicidal ideation as the primary objective and 14 trials as secondary objectives. Intravenous racemic ketamine was superior to control drugs (placebo or midazolam) within the first 72 h, in spite of large placebo effects. Adverse events were minor and transient. In contrast, intranasal esketamine did not differ from placebo in large-scale studies. Limitations, clinical considerations, and opportunities for future research include the following points: large placebo effects when studying suicidal ideation reduction; small concerns about blinding quality due to dissociative effects; no studies on the risk/prevention of suicidal acts and mortality; lack of studies beyond affective disorders; no studies in adolescents and older people; lack of knowledge of long-term side effects, notably liability for abuse; no robust predictive markers; limited understanding of the mechanisms of ketamine on suicidal ideas; need for improved assessment of suicidal ideation in clinical trials; need for studies in outpatient settings, emergency room, and liaison consultation; need for research on ketamine administration; limited knowledge on the positive and negative effects of concomitant treatments. Conclusion: Overall, there is compelling evidence for a favorable short-term benefit-risk balance with intravenous racemic ketamine but not intranasal esketamine. The place of ketamine will have to be defined within a multimodal care strategy for suicidal patients. Caution remains necessary for clinical use, and pharmacovigilance will be essential.

Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies.

The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD. We obtained resting-state functional magnetic resonance imaging data from the REST-meta-MDD (N = 2338) and PsyMRI (N = 1039) consortia. Classification of functional connectivity matrices was done using support vector machines (SVM) and graph convolutional neural networks (GCN), and performance was evaluated using 5-fold cross-validation. Features were visualized using GCN-Explainer, an ablation study and univariate t-testing. The results showed a mean classification accuracy of 61% for MDD versus controls. Mean accuracy for classifying (non-)medicated subgroups was 62%. Sex classification accuracy was substantially better across datasets (73-81%). Visualization of the results showed that classifications were driven by stronger thalamic connections in both datasets, while nearly all other connections were weaker with small univariate effect sizes. These results suggest that whole brain resting-state connectivity is a reliable though poor biomarker for MDD, presumably due to disease heterogeneity as further supported by the higher accuracy for sex classification using the same methods. Deep learning revealed thalamic hyperconnectivity as a prominent neurophysiological signature of depression in both multicenter studies, which may guide the development of biomarkers in future studies.

Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine.

Ketamine shows rapid antidepressant effects peaking 24 h after administration. The antidepressant effects may occur through changes in glutamatergic metabolite levels and resting-state functional connectivity (rsFC) within the default mode network (DMN). A multistage drug effect of ketamine has been suggested, inducing acute effects on dysfunctional network configuration and delayed effects on homeostatic synaptic plasticity. Whether the DMN-centered delayed antidepressant-related changes are associated with the immediate changes remains unknown. Thirty-five healthy male participants (25.1 ± 4.2 years) underwent 7 T magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (rsfMRI) before, during, and 24 h after a single S-ketamine or placebo infusion. Changes in glutamatergic measures and rsFC in the DMN node pregenual anterior cingulate cortex (pgACC) were examined. A delayed rsFC decrease of the pgACC to inferior parietal lobe (family-wise error corrected p (pFWEc) = 0.018) and dorsolateral prefrontal cortex (PFC; pFWEc = 0.002) was detected that was preceded by an immediate rsFC increase of the pgACC to medial PFC (pFWEc < 0.001) and dorsomedial PFC (pFWEc = 0.005). Additionally, the immediate rsFC reconfigurations correlated with the delayed pgACC glutamate (Glu) level increase (p = 0.024) after 24 h at trend level (p = 0.067). Baseline measures of rsFC and MRS were furthermore associated with the magnitude of the respective delayed changes (p's < 0.05). In contrast, the delayed changes were not associated with acute psychotomimetic side effects or plasma concentrations of ketamine and its metabolites. This multimodal study suggests an association between immediate S-ketamine-induced network effects and delayed brain changes at a time point relevant in its clinical context.

Investigating the Clinical Profile of Suicide Attempters Who Used a Violent Suicidal Means.

In our study, we aimed to explore the profile of the high-risk subgroup of suicide attempters that used a violent means compared to suicide attempters that chose a non-violent suicide means. Therefore, we recruited a sample of inpatients with recent suicide attempts in three psychiatric hospitals in Thuringia, Germany. We used a structured clinical interview to assess the psychiatric diagnoses, sociodemographic data, and characteristics of the suicide attempt. Furthermore, we used several validated clinical questionnaires to measure suicidal ideations, suicide intent, depression severity, hopelessness, impulsivity, aggression, anger expression, and childhood trauma. We compared 41 individuals using violent means to 59 using non-violent means with univariate and multivariate statistical analyses. We found significantly (corrected for multiple comparisons) higher levels of impulsivity-related sensation-seeking in violent suicide attempters in univariate and multivariate analyses, and additionally in anger expression directed inward at an uncorrected statistical threshold. Besides that, there were no significant differences between the two groups. We assume that underlying neurocognitive mechanisms, such as impaired decision-making processes and/or differences in risk/loss assessment, could explain the higher levels of questionnaire-based sensation-seeking in subjects who use violent suicide means. Further research is needed, including neuroimaging and biochemical techniques, to gain more insight into the mechanisms underlying the choice of a suicidal means.

Generation and Characterization of Native and Sialic Acid-Deficient IgE.

Efficient characterization of IgE antibodies and their glycan structures is required for understanding their function in allergy and in the emerging AllergoOncology field for antibody immunotherapy. We report the generation, glyco-profiling and functional analysis of native and sialic acid-deficient glyco-engineered human IgE. The antibodies produced from human embryonic kidney cells were purified via a human IgE class-specific affinity matrix and structural integrity was confirmed by SDS-PAGE and size-exclusion chromatography (SEC). Purified IgEs specific for the tumor-associated antigens Chondroitin Sulfate Proteoglycan 4 (CSPG4-IgE) and Human Epidermal Growth Factor Receptor 2 (HER2-IgE) were devoid of by-products such as free light chains. Using neuraminidase-A, we generated sialic acid-deficient CSPG4-IgE as example glyco-engineered antibody. Comparative glycan analyses of native and glyco-engineered IgEs by Hydrophilic interaction liquid chromatography (HILIC)-high performance liquid chromatography (HPLC) indicated loss of sialic acid terminal residues and differential glycan profiles. Native and glyco-engineered CSPG4-IgEs recognized Fc receptors on the surface of human FcεRI-expressing rat basophilic leukemia RBL-SX38 cells, and of CD23/FcεRII-expressing human RPMI-8866 B-lymphocytes and bound to CSPG4-expressing A2058 human melanoma cells, confirming Fab-mediated recognition. When cross-linked on the cell surface, both IgEs triggered RBL-SX38 degranulation. We demonstrate efficient generation and functional competence of recombinant native and sialic acid-deficient IgEs.

Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies.

Suicide is the 14th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.

Relapse Prevention Intervention after Suicidal Event (RISE): Feasibility study of a psychotherapeutic short-term program for inpatients after a recent suicide attempt.

Recent research suggests that treating only mental disorders may not be sufficient to reduce the risk for future suicidal behavior in patients with a suicide attempt(s). It is therefore necessary to pay special therapeutic attention to past suicidal acts. Thus, the newly developed RISE (Relapse Prevention Intervention after Suicidal Event) program was built on the most effective components of existing psychotherapeutic and psychosocial interventions according to our current meta-analysis. The RISE program consists of five individual sessions designed for the acute psychiatric inpatient setting. The main goals of the treatment are to decrease future suicidal events and to improve patients' ability to cope with future suicidal crises. In the present study, feasibility and acceptance of the RISE program were investigated as well as its clinical effects on suicidal ideations, mental pain, self-efficacy and depressive symptoms. We recruited a sample of 27 inpatients of the Department of Psychiatry and Psychotherapy, University Hospital Jena, Germany. The final sample consisted of 20 patients hospitalized for a recent suicide attempt, including 60 percent of multiple attempters. The data collection included a structured interview and a comprehensive battery of questionnaires to evaluate the feasibility and acceptance of the RISE program as well as associated changes in clinical symptoms. A follow-up examination was carried out after 6 months. Considering the low dropout rate and the overall positive evaluation, the RISE program was highly accepted in a sample of severely impaired patients. The present study also demonstrated that the levels of suicidal ideations, mental pain, depressive symptoms, and hopelessness decreased significantly after RISE. Since all of these clinical parameters are associated with the risk of future suicidal behavior, a potential suicide-preventive effect of the intervention can be inferred from the present findings. The positive results of the follow-up assessment after 6 months point in the same direction. In addition, RISE treatment increased self-efficacy in patients, which is an important contributor for better coping with future suicidal crises. Thus, present study demonstrate that RISE is a suitable therapy program for the treatment of patients at high risk for suicidal behavior in an acute inpatient setting.

Defined stereoisomers of 2″-amino NAD+ and their activity against human sirtuins and a bacterial (ADP-ribosyl) transferase.

Nicotinamide adenine dinucleotide (NAD+) is an important biomolecule with essential roles at the intersection of energy metabolism, epigenetic regulation and cell signalling. Synthetic analogues of NAD+ are therefore of great interest as chemical tools for medicinal chemistry, chemical biology and drug discovery. Herein, we report the chemical synthesis and full analytical characterisation of three stereoisomers of 2″-amino NAD+, and their biochemical evaluation against two classes of NAD+-consuming enzymes: the human sirtuins 1-3, and the bacterial toxin TccC3. To rationalise the observed activities, molecular docking experiments were carried out with SIRT1 and SIRT2, which identified the correct orientation of the pyrophosphate linkage as a major determinant for activity in this series. These results, together with results from stability tests and a conformational analysis, allow, for the first time, a side-by-side comparison of the chemical and biochemical features, and analytical properties, of different 2″-amino NAD+ stereoisomers. Our findings provide insight into the recognition of co-substrate analogues by sirtuins, and will greatly facilitate the application of these important NAD+ analogues as chemical tool compounds for mechanistic studies with these as well as other NAD+-dependent enyzmes.

The differential association between local neurotransmitter levels and whole-brain resting-state functional connectivity in two distinct cingulate cortex subregions.

We examined the association between rsFC and local neurotransmitter levels in the pregenual anterior cingulate cortex (pgACC) and the anterior mid-cingulate cortex (aMCC) by varying rsFC-strengths at the whole-brain level. Our results showed region-dependent directionality of associations in the investigated ACC subdivisions.