Resilience moderates the relationship between the psychological impact of COVID-19 and anxiety.

Psychological resilience is considered to constitute an important factor for protecting mental health, especially during times of crises, like the COVID-19 pandemic outbreak. However, there is a lack of research on the potential buffering effect of resilience on the psychological impact of COVID-19 as related to mental health. Therefore, the aim of the current study was to examine protective effects of resilience on mental health during the initial stage of the COVID-19 outbreak in Austria. Analysis was based on data collected from 4,113 Austrian residents, who participated in an anonymous online survey. The survey addressed sociodemographic data, the subjective response to COVID-19 (Impact of Event Scale; IES-R), mental health status (Depression Anxiety Stress Scale; DASS-21), and resilience (Resilience-Scale; RS-11). Structural equation modelling showed significant positive associations between the IES-R score and depressive symptoms, stress and anxiety, respectively. Resilience was significantly negatively associated with depression, stress, and anxiety. Furthermore, resilience moderated the relation between the impact of COVID-19 and anxiety symptoms. However, there was no moderating effect of resilience on the relationship between IES-R and both depression and stress. The psychological impact of COVID-19 on anxiety symptoms seems to vary with the level of resilience. Moderating effects of resilience on the relation between impact of COVID-19 and stress and depression symptoms could not be confirmed. Further studies are needed to evaluate the long-term effects of resilience on stress and mental health during the COVID-19 pandemic.

Acute and Chronic Physical Activity Increases Creative Ideation Performance: A Systematic Review and Multilevel Meta-analysis.

BACKGROUND: Physical activity is a health-relevant lifestyle factor associated with various benefits on physical and mental health. Several meta-analyses indicated effects of acute and chronic physical activities on elementary cognitive functions such as executive control processes, memory, and attention. Meta-analytic evidence on the effects of physical activity on creative idea generation, which involves a conglomerate of these elementary cognitive functions, is largely missing. OBJECTIVE: A twofold approach was used to evaluate (1) if there is an association between habitual physical activity and creative ideation and (2) if physical activity interventions (acute and chronic) enhance creative ideation performance. METHODS: Multilevel meta-analytic methods were applied to (1) evaluate the cross-sectional association between creative ideation performance and measures of habitual physical activity and (2) the effect of physical activity on creative ideation performance. Indicators of creative ideation (fluency, flexibility, originality, elaboration, or composite score), creativity domain (verbal, figural), population (adults, children), gender, study quality, and publication year served as moderator variables for both meta-analyses. Analyses of intervention studies additionally examined the moderator variables study design (between, within), time of measurement (during, after), and implementation of intervention (acute, chronic). RESULTS: The applied meta-analytic multilevel analysis indicated a medium effect for cross-sectional studies (r = 0.22, SE = 0.06, p = 0.002, 95% CI [0.10-0.34]) based on 17 effects sizes from seven studies. The pooled effects of 28 intervention studies, providing 115 effect sizes, indicated a medium effect size of Hedges' g = 0.47 (SE = 0.09, p < 0.001, 95% CI [0.30-0.65]). Furthermore, a stronger effect was observed for chronic interventions of several days or weeks in comparison with acute interventions of one single bout. CONCLUSION: This study adds important new meta-analytic evidence on the beneficial role of physical activity beyond mental and physical health outcomes: Physical activity has a positive impact on creative ideation, which expands the literature on the role of physical activity in more elementary cognitive functions such as executive control, memory, and attention. Moderator analyses suggested that chronic interventions showed stronger effects than single bouts of physical activity. Rigorously conducted randomized controlled intervention studies and more cross-sectional studies are needed to broaden the evidence in this nascent field of research.

Life events are associated with elevated heart rate and reduced heart complexity to acute psychological stress.

The current study examined whether the exposure to life events and reported impact of life events are associated with altered cardiac reactivity to an acute psychological stressor. Participants (N = 69) completed the Life Experience Survey (LES) and Positive and Negative Affect Schedule (PANAS) and undertook a standardized social-evaluative stress task. Cardiac activity was measured via heart rate and non-linear heart rate variability (HRV) indices Sample Entropy, SD1, SD2 and SD1/SD2 ratio. Heart rate and non-linear HRV were measured before, during and after stress exposure. Findings suggest higher heart rate reactivity in individuals reporting higher number and impact of negative and total life events. Decreases in Sample Entropy were evident for number as well as impact of life events. No associations were found for SD1, SD2 and SD1/SD2 ratio. Findings suggest that life-events are associated with elevated heart rate and diminished heart rate complexity in response to acute stress.

Autonomic dysfunction in posttraumatic stress disorder indexed by heart rate variability: a meta-analysis.

BACKGROUND: Changes in autonomic nervous system (ANS) function have been observed in a variety of psychological disorders, including posttraumatic stress disorder (PTSD). Analysis of heart rate variability (HRV) provides insight into the functioning of the ANS. Previous research on PTSD found lower HRV in PTSD patients compared to controls, indicating altered sympathetic and parasympathetic activity, but findings are inconsistent. The purpose of this meta-analysis was to examine differences in HRV indices between individuals with PTSD and healthy controls at baseline and during stress. METHODS: The included primary studies present an aggregate of studies analyzing different HRV indices. Examined HRV indices were standard deviation of the normalized NN-intervals (SDNN), root mean square of successive differences (RMSSD), low-frequency (LF) and high-frequency (HF) spectral components, LF/HF ratio, and heart rate (HR). Moderating effects of study design, HRV and PTSD assessment, and sample characteristics were examined via subgroup-analyses and meta-regressions. RESULTS: Random-effects meta-analyses for HRV parameters at rest revealed significant group differences for RMSSD and HF-HRV, suggesting lower parasympathetic activity in PTSD. The aggregated effect size for SDNN was medium, suggesting diminished total variability in PTSD. A small effect was found for LF-HRV. A higher LF/HF ratio was found in the PTSD sample as compared to controls. Individuals with PTSD showed significantly higher HR. During stress, individuals with PTSD showed higher HR and lower HF-HRV, both indicated by small effect sizes. CONCLUSIONS: Findings suggest that PTSD is associated with ANS dysfunction.

Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

Overcoming the global health threat of HIV infection requires continuous pipelines of novel drug candidates. We identified the γ-pyrone polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compound collection. Total synthesis of a structurally diverse group of Aureothin-derivatives successfully identified a lead compound (#7) superior to Aureothin that combines strong anti-HIV activity (IC90<45 nM), photostability and improved cell safety. Compound #7 inhibited de novo virus production from integrated proviruses by blocking the accumulation of HIV RNAs that encode the structural components of virions and include viral genomic RNAs. Thus, the mode-of-action displayed by compound #7 is different from those of all current clinical drugs. Proteomic analysis indicated that compound #7 does not affect global protein expression in primary blood cells and may modulate cellular pathways linked to HIV infection. Compound #7 inhibited multiple HIV genotypes, including HIV-type 1 and 2 and synergistically inhibited HIV in combination with clinical reverse transcriptase and integrase inhibitors. We conclude that compound #7 represents a promising new class of HIV inhibitors that will facilitate the identification of new virus-host interactions exploitable for antiviral attack and holds promise for further drug development.

Prevalence of mental disorders in young refugees and asylum seekers in European Countries: a systematic review.

The European Union member states received about 385,000 asylum applications from children and adolescents below 18 years in 2015, and 398,000 in 2016. The latest political crises and war have led to an upsurge in refugee movements into European countries, giving rise to a re-evaluation of the epidemiology of psychiatric disorders and mental health problems among young refugees and asylum seekers. We systematically searched five electronic databases and reference lists of pertinent review articles. We then screened the results of forward citation tracking of key articles for relevant studies in the field for the period from January 1990 to October 2017. We dually reviewed citations and assessed risk of bias. We reported the results narratively, as meta-analyses were impeded due to high heterogeneity. We included 47 studies covered in 53 articles. Overall, the point prevalence of the investigated psychiatric disorders and mental health problems varied widely among studies (presenting interquartile ranges): for posttraumatic stress disorder between 19.0 and 52.7%, for depression between 10.3 and 32.8%, for anxiety disorders between 8.7 and 31.6%, and for emotional and behavioural problems between 19.8 and 35.0%. The highly heterogeneous evidence base could be improved by international, methodologically comparable studies with sufficiently large sample sizes drawn randomly among specific refugee populations. The prevalence estimates suggest, nevertheless, that specialized mental health care services for the most vulnerable refugee and asylum-seeking populations are needed. REGISTRATION: The systematic review protocol was registered in PROSPERO on October 19th, 2017 with the number: CRD42017080039 and is available from: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=80039.

"A joke a day keeps the doctor away?" Meta-analytical evidence of differential associations of habitual humor styles with mental health.

Humor and mental health are interconnected as is evidenced by a large number of studies. However, associations are only small and inconsistent as the operationalization of humor poses a methodological challenge. The Humor Styles Questionnaire (HSQ) differentiates four humor styles that might be beneficial or harmful to mental health. The aim of the present study was to meta-analytically aggregate studies using the HSQ to assess the associations of different humor styles with four areas of mental health (self-esteem, life satisfaction, optimism, depression). An extensive electronic database literature search identified 37 studies that reported correlations between the HSQ scales and the four areas of mental health in 45 independent samples (total N = 12,734). In total, 16 meta-analyses were conducted. Moderating effects of participant age, sex, and geographic region were examined via subgroup analyses and meta-regression. Humor styles differed in terms of their associations with mental health. Health-promoting humor styles were overall positively correlated with mental health (small-to-medium effect sizes). Self-defeating humor was overall negatively correlated with mental health. Aggressive humor was overall unrelated with mental health. Moderator analyses suggested geographic differences (Eastern vs. Western samples) and sex differences for some of these associations. Fostering specific humor styles may be beneficial for mental health. In addition, observing the habitual use of humor styles might help therapists to develop a better understanding of their clients. Differences in the utilization and the correlates of humor styles in Eastern and Western societies, and sex differences, need to be addressed in future research.

Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes.

Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.

Dual role of the chromatin-binding factor PHF13 in the pre- and post-integration phases of HIV-1 replication.

Viruses interact with multiple host cell factors. Some of these are required to promote viral propagation, others have roles in inhibiting infection. Here, we delineate the function of the cellular factor PHF13 (or SPOC1), a putative HIV-1 restriction factor. Early in the HIV-1 replication cycle PHF13 increased the number of integrated proviral copies and the number of infected cells. However, after HIV-1 integration, high levels of PHF13 suppressed viral gene expression. The antiviral activity of PHF13 is counteracted by the viral accessory protein Vpr, which mediates PHF13 degradation. Altogether, the transcriptional master regulator and chromatin binding protein PHF13 does not have purely repressive effects on HIV-1 replication, but also promotes viral integration. By the functional characterization of the dual role of PHF13 during the HIV-1 replication cycle, we reveal a surprising and intricate mechanism through which HIV-1 might regulate the switch from integration to viral gene expression. Furthermore, we identify PHF13 as a cellular target specifically degraded by HIV-1 Vpr.

Potent in vitro antiviral activity of Cistus incanus extract against HIV and Filoviruses targets viral envelope proteins.

Novel therapeutic options are urgently needed to improve global treatment of virus infections. Herbal products with confirmed clinical safety features are attractive starting material for the identification of new antiviral activities. Here we demonstrate that Cistus incanus (Ci) herbal products inhibit human immunodeficiency virus (HIV) infections in vitro. Ci extract inhibited clinical HIV-1 and HIV-2 isolates, and, importantly, a virus isolate with multiple drug resistances, confirming broad anti-HIV activity. Antiviral activity was highly selective for virus particles, preventing primary attachment of the virus to the cell surface and viral envelope proteins from binding to heparin. Bioassay-guided fractionation indicated that Ci extract contains numerous antiviral compounds and therefore has favorably low propensity to induce virus resistance. Indeed, no resistant viruses emerged during 24 weeks of continuous propagation of the virus in the presence of Ci extracts. Finally, Ci extracts also inhibited infection by virus particles pseudotyped with Ebola and Marburg virus envelope proteins, indicating that antiviral activity of Ci extract extends to emerging viral pathogens. These results demonstrate that Ci extracts show potent and broad in vitro antiviral activity against viruses that cause life-threatening diseases in humans and are promising sources of agents that target virus particles.

Benefits of listening to a recording of euphoric joint music making in polydrug abusers.

BACKGROUND AND AIMS: Listening to music can have powerful physiological and therapeutic effects. Some essential features of the mental mechanism underlying beneficial effects of music are probably strong physiological and emotional associations with music created during the act of music making. Here we tested this hypothesis in a clinical population of polydrug abusers in rehabilitation listening to a previously performed act of physiologically and emotionally intense music making. METHODS: Psychological effects of listening to self-made music that was created in a previous musical feedback intervention were assessed. In this procedure, participants produced music with exercise machines (Jymmin) which modulate musical sounds. RESULTS: The data showed a positive effect of listening to the recording of joint music making on self-efficacy, mood, and a readiness to engage socially. Furthermore, the data showed the powerful influence of context on how the recording evoked psychological benefits. The effects of listening to the self-made music were only observable when participants listened to their own performance first; listening to a control music piece first caused effects to deteriorate. We observed a positive correlation between participants' mood and their desire to engage in social activities with their former training partners after listening to the self-made music. This shows that the observed effects of listening to the recording of the single musical feedback intervention are influenced by participants recapitulating intense pleasant social interactions during the Jymmin intervention. CONCLUSIONS: Listening to music that was the outcome of a previous musical feedback (Jymmin) intervention has beneficial psychological and probably social effects in patients that had suffered from polydrug addiction, increasing self-efficacy, mood, and a readiness to engage socially. These intervention effects, however, depend on the context in which the music recordings are presented.

A new model for post-integration latency in macroglial cells to study HIV-1 reservoirs of the brain.

OBJECTIVE: Macroglial cells like astrocytes are key targets for the formation of HIV-1 reservoirs in the brain. The 'shock-and-kill' HIV-1 cure strategy proposes eradication of reservoirs by clinical treatment with latency reversing agents (LRAs). However, virus activation may endanger the brain, due to limited cell turnover, viral neurotoxicity and poor penetration of antiretroviral drugs. Since the brain is not accessible to clinical sampling, we established an experimental model to investigate the LRA effects on HIV-1 latency in macroglial reservoirs. DESIGN: Human neural stem cells (HNSC.100) were used to generate a system that models HIV-1 transcriptional latency in proliferating progenitor, as well as differentiated macroglial cell populations and latency-modulating effects of LRAs and compounds targeting HIV-1 transcription were analysed. METHODS: HNSCs were infected with pseudotyped Env-defective HIV-1 viruses. HIV-1 DNA and RNA levels were quantified by qPCR. Expression of latent GFP-reporter viruses was analysed by confocal microscopy and flow cytometry. NF-κB signalling was investigated by confocal microscopy and chromatin immunoprecipitation. RESULTS: Two of the eight well known LRAs (tumour necrosis factor-alpha, suberoylanilide hydroxamic acid) reactivated HIV-1 in latently infected HNSCs. Tumour necrosis factor-alpha reactivated HIV-1 in progenitor and differentiated populations, whereas suberoylanilide hydroxamic acid was more potent in progenitors. Pre-treatment with inhibitors of key HIV-1 transcription factors (NF-κB, Cdk9) suppressed HIV-1 reactivation. CONCLUSION: We conclude that latent HIV-1 in macroglial reservoirs can be activated by selected LRAs. Identification of small molecules that suppress HIV-1 reactivation supports functional cure strategies. We propose using the HNSC model to develop novel strategies to enforce provirus quiescence in the brain.

Aqueous extracts of the marine brown alga Lobophora variegata inhibit HIV-1 infection at the level of virus entry into cells.

In recent years, marine algae have emerged as a rich and promising source of molecules with potent activities against various human pathogens. The widely distributed brown alga Lobophora variegata that is often associated with tropical coral reefs exerts strong antibacterial and antiprotozoal effects, but so far has not been associated with specific anti-viral activities. This study investigated potential HIV-1 inhibitory activity of L. variegata collected from different geographical regions, using a cell-based full replication HIV-1 reporter assay. Aqueous L. variegata extracts showed strong inhibitory effects on several HIV-1 strains, including drug-resistant and primary HIV-1 isolates, and protected even primary cells (PBMC) from HIV-1-infection. Anti-viral potency was related to ecological factors and showed clear differences depending on light exposition or epiphyte growth. Assays addressing early events of the HIV-1 replication cycle indicated that L. variegata extracts inhibited entry of HIV-1 into cells at a pre-fusion step possibly by impeding mobility of virus particles. Further characterization of the aqueous extract demonstrated that even high doses had only moderate effects on viability of cultured and primary cells (PBMCs). Imaging-based techniques revealed extract effects on the plasma membrane and actin filaments as well as induction of apoptosis at concentrations exceeding EC50 of anti-HIV-1 activity by more than 400 fold. In summary, we show for the first time that L. variegata extracts inhibit HIV-1 entry, thereby suggesting this alga as promising source for the development of novel HIV-1 inhibitors.

The root extract of the medicinal plant Pelargonium sidoides is a potent HIV-1 attachment inhibitor.

Global HIV-1 treatment would benefit greatly from safe herbal medicines with scientifically validated novel anti-HIV-1 activities. The root extract from the medicinal plant Pelargonium sidoides (PS) is licensed in Germany as the herbal medicine EPs®7630, with numerous clinical trials supporting its safety in humans. Here we provide evidence from multiple cell culture experiments that PS extract displays potent anti-HIV-1 activity. We show that PS extract protects peripheral blood mononuclear cells and macrophages from infection with various X4 and R5 tropic HIV-1 strains, including clinical isolates. Functional studies revealed that the extract from PS has a novel mode-of-action. It interferes directly with viral infectivity and blocks the attachment of HIV-1 particles to target cells, protecting them from virus entry. Analysis of the chemical footprint of anti-HIV activity indicates that HIV-1 inhibition is mediated by multiple polyphenolic compounds with low cytotoxicity and can be separated from other extract components with higher cytotoxicity. Based on our data and its excellent safety profile, we propose that PS extract represents a lead candidate for the development of a scientifically validated herbal medicine for anti-HIV-1 therapy with a mode-of-action different from and complementary to current single-molecule drugs.

Severe acute respiratory syndrome coronavirus replication is severely impaired by MG132 due to proteasome-independent inhibition of M-calpain.

The ubiquitin-proteasome system (UPS) is involved in the replication of a broad range of viruses. Since replication of the murine hepatitis virus (MHV) is impaired upon proteasomal inhibition, the relevance of the UPS for the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) was investigated in this study. We demonstrate that the proteasomal inhibitor MG132 strongly inhibits SARS-CoV replication by interfering with early steps of the viral life cycle. Surprisingly, other proteasomal inhibitors (e.g., lactacystin and bortezomib) only marginally affected viral replication, indicating that the effect of MG132 is independent of proteasomal impairment. Induction of autophagy by MG132 treatment was excluded from playing a role, and no changes in SARS-CoV titers were observed during infection of wild-type or autophagy-deficient ATG5(-/-) mouse embryonic fibroblasts overexpressing the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2). Since MG132 also inhibits the cysteine protease m-calpain, we addressed the role of calpains in the early SARS-CoV life cycle using calpain inhibitors III (MDL28170) and VI (SJA6017). In fact, m-calpain inhibition with MDL28170 resulted in an even more pronounced inhibition of SARS-CoV replication (>7 orders of magnitude) than did MG132. Additional m-calpain knockdown experiments confirmed the dependence of SARS-CoV replication on the activity of the cysteine protease m-calpain. Taken together, we provide strong experimental evidence that SARS-CoV has unique replication requirements which are independent of functional UPS or autophagy pathways compared to other coronaviruses. Additionally, this work highlights an important role for m-calpain during early steps of the SARS-CoV life cycle.

Cell type-specific cleavage of nucleocapsid protein by effector caspases during SARS coronavirus infection.

The epidemic outbreak of severe acute respiratory syndrome (SARS) in 2003 was caused by a novel coronavirus (CoV), designated SARS-CoV. The RNA genome of SARS-CoV is complexed by the nucleocapsid protein (N) to form a helical nucleocapsid. Besides this primary function, N seems to be involved in apoptotic scenarios. We show that upon infection of Vero E6 cells with SARS-CoV, which elicits a pronounced cytopathic effect and a high viral titer, N is cleaved by caspases. In contrast, in SARS-CoV-infected Caco-2 cells, which show a moderate cytopathic effect and a low viral titer, this processing of N was not observed. To further verify these observations, we transiently expressed N in different cell lines. Caco-2 and N2a cells served as models for persistent SARS-CoV infection, whereas Vero E6 and A549 cells did as prototype cell lines lytically infected by SARS-CoV. The experiments revealed that N induces the intrinsic apoptotic pathway, resulting in processing of N at residues 400 and 403 by caspase-6 and/or caspase-3. Of note, caspase activation is highly cell type specific in SARS-CoV-infected as well as transiently transfected cells. In Caco-2 and N2a cells, almost no N-processing was detectable. In Vero E6 and A549 cells, a high proportion of N was cleaved by caspases. Moreover, we examined the subcellular localization of SARS-CoV N in these cell lines. In transfected Vero E6 and A549 cells, SARS-CoV N was localized both in the cytoplasm and nucleus, whereas in Caco-2 and N2a cells, nearly no nuclear localization was observed. In addition, our studies indicate that the nuclear localization of N is essential for its caspase-6-mediated cleavage. These data suggest a correlation among the replication cycle of SARS-CoV, subcellular localization of N, induction of apoptosis, and the subsequent activation of caspases leading to cleavage of N.