Defining desmosomal plakophilin-3 interactions

Plakophilin 3 (PKP3) is a recently described armadillo protein of the desmosomal plaque, which is synthesized in simple and stratified epithelia. We investigated the localization pattern of endogenous and exogenous PKP3 and fragments thereof. The desmosomal binding properties of PKP3 were determined using yeast two-hybrid, coimmunoprecipitation and colocalization experiments. To this end, novel mouse anti-PKP3 mAbs were generated. We found that PKP3 binds all three desmogleins, desmocollin (Dsc) 3a and -3b, and possibly also Dsc1a and -2a. As such, this is the first protein interaction ever observed with a Dsc-b isoform. Moreover, we determined that PKP3 interacts with plakoglobin, desmoplakin (DP) and the epithelial keratin 18. Evidence was found for the presence of at least two DP–PKP3 interaction sites. This finding might explain how lateral DP–PKP interactions are established in the upper layers of stratified epithelia, increasing the size of the desmosome and the number of anchoring points available for keratins. Together, these results show that PKP3, whose epithelial and epidermal desmosomal expression pattern and protein interaction repertoire are broader than those of PKP1 and -2, is a unique multiprotein binding element in the basic architecture of a vast majority of epithelial desmosomes

Phytochemical screening and biological activity studies of five South African indigenous medicinal plants

Different extracts and fractions of five selected indigenous South African medicinal plants, namely, Cissampelos capensis, Geranium incanum and three Gethyllis species, were subjected to phytochemical screening and testing for cytotoxicity using the brine shrimp lethality bioassay, and antimicrobial activity assays against nine microbes, which included three fungal species, three Gram negative and three Gram positive bacteria.The majority of the extracts tested positive for the presence of tannins, phenolics and flavonoids, while in selected cases, phytochemical tests suggested the presence of essential oils, glycosides or alkaloids. The methanol extract of Gethyllis gregoriana displayed the highest cytotoxicity levels. Generally, the highest levels of biological activity were shown to reside in the methanolic extracts, while hexane extracts revealed very low to zero activity. The total tertiary alkaloid (TTA) of C. capensis was mostly active against Bacillus subtilis, a Gram +ve bacteria. The trends observed for the cytotoxicity assay were in agreement with those observed for the antimicrobial assay

International assessment of priority environmental issues for land-based and offshore wind energy development

Non-technical summary. A substantial increase in wind energy deployment worldwide is required to help achieve international targets for decreasing global carbon emissions andlimiting the impacts of climate change. In response to global concerns regarding the environmental effects of wind energy, the International Energy Agency Wind Technical Collaborative Program initiated Task 34 – Working Together to Resolve Environmental Effects of Wind Energy or WREN. As part of WREN, this study performed an international assessment with the global wind energy and environmental community to determine priority environmental issues over the next 5‒10 years and help support collaborative interactions among researchers, developers, regulators, and stakeholders. Technical summary. A systematic assessment was performed using feedback from the international community to identify priority environmental issues for land-based and offshore wind energy development. Given the global nature of wind energy development, feedback was of interest from all countries where such development is underway or planned to help meet United Nations Intergovernmental Panel on Climate Change targets. The assessment prioritized environmental issues over the next 5–10 years associated with wind energy development and received a total of 294 responses from 28 countries. For land-based wind, the highest-ranked issues included turbine collision risk for volant species (birds and bats), cumulative effects on species and ecosystems, and indirect effects such as avoidance and displacement. For offshore wind, the highest-ranked issues included cumulative effects, turbine collision risk, underwater noise (e.g. marine mammals and fish), and displacement. Emerging considerations for these priorities include potential application to future technologies (e.g. larger turbines and floating turbines), new stressors and species in frontier regions, and cumulative effects for multiple projects at a regional scale. For both land-based and offshore wind, effectiveness of minimization measures (e.g. detection and deterrence technologies) and costs for monitoring, minimization, and mitigation were identified as overarching challenges. Social media summary. Turbine collisions and cumulative effects among the international environmental priorities for wind energy development. Environmental; turbines; wildlife; wind energyInternational assessment of priority environmental issues for land-based and offshore wind energy developmentpublishedVersio

No association between cumulative traumatic experiences and sex in risk for posttraumatic stress disorder among human immunodeficiency virus-positive adults

This study examined the association between the type and number of traumatic experiences and the conditional risk for posttraumatic stress disorder (PTSD), stratified by sex, in human immunodeficiency virus (HIV). We evaluated 465 (114 male and 350 female) HIV-positive adults attending HIV clinics in Cape Town, South Africa. Demographic and clinical data were collected, and the participants were screened for current PTSD and traumatic event exposure using the Mini-International Neuropsychiatric Interview and the Life Events Checklist, respectively. The highest attributable risk for PTSD was derived from sexual assault (17.4%) and transport accidents (16.9%). Only sexual assault was significantly (p = 0.002) associated with current PTSD. Although sex had no effect on the prediction of current PTSD, HIVinfected men tended to experience more lifetime traumas than HIV-infected women, with the men having significantly higher rates of exposure than women to physical assault (p = 0.018) and assault with a weapon (p = 0.001). These data highlight the importance of considering trauma type in contributing to the burden of PTSD in HIV-infected adults.Web of Scienc

Development of the Tilburg Pregnancy Distress Scale: the TPDS

Contains fulltext : 96807.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Pregnant women with high levels of stress, depression and/or anxiety are at increased risk for adverse perinatal outcomes and impaired neurologic and emotional development of the offspring. Pregnancy specific instruments to measure psychological functioning during gestation are scarce and do not define items based on in-depth interviews of pregnant and recently delivered women. The current study developed a pregnancy specific scale that measures psychological functioning using in-depth interviews. METHODS: Three focus groups were formed to discuss issues most relevant to pregnancy distress; 22 candidate items were derived for pilot testing (study I, n = 419) its psychometric properties by means of explorative factor analyses (EFA). This resulted in a 17-item TPDS which was further explored by confirmatory factor analyses (CFA) and concurrent and construct validity assessment (study II, n = 454). RESULTS: EFA in study I suggested a two component solution (negative affect (NA) and partner involvement (PI)). CFA in study II resulted in a higher order model of the NA subscale into three more subscales: NA regarding confinement, delivery and general health. TPDS, EPDS and GAD-7 were all significantly correlated. CONCLUSIONS: The TPDS constitutes a valid and user friendly instrument to assess pregnancy distress. In addition to its proven ability to pick up pregnancy specific negative affect it also includes an important sub-scale measuring perceived partner involvement

Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18–65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e., six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia

67P/C-G inner coma dust properties from 2.2 au inbound to 2.0 auoutbound to the Sun

GIADA (Grain Impact Analyzer and Dust Accumulator) on-board the Rosetta space probe is designed to measure the momentum, mass and speed of individual dust particles escaping the nucleus of comet 67P/Churyumov-Gerasimenko (hereafter 67P). From 2014 August to 2016 June, Rosetta escorted comet 67P during its journey around the Sun. Here, we focus on GIADA data taken between 2015 January and 2016 February which included 67P's perihelion passage. To better understand cometary activity and more specifically the presence of dust structures in cometary comae, we mapped the spatial distribution of dust density in 67P's coma. In this manner, we could track the evolution of high-density regions of coma dust and their connections with nucleus illumination conditions, namely tracking 67P's seasons. We also studied the link between dust particle speeds and their masses with respect to heliocentric distance, i.e. the level of cometary activity. This allowed us to derive a global and a local correlation of the dust particles' speed distribution with respect to the H2O production rate. © 2016 The Authors.Peer Reviewe

Involvement of VDAC, Bax and Ceramides in the Efflux of AIF from Mitochondria during Curcumin-Induced Apoptosis

Contains fulltext : 80085.pdf (publisher's version ) (Open Access)BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process. PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion. CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought