Biosynthetic reconstitution of deoxysugar phosphoramidate metalloprotease inhibitors using an N-P-bond-forming kinase

Baulig A, Helmle I, Bader M, et al. Biosynthetic reconstitution of deoxysugar phosphoramidate metalloprotease inhibitors using an N-P-bond-forming kinase. CHEMICAL SCIENCE. 2019;10(16):4486-4490.Phosphoramidon is a potent metalloprotease inhibitor and a widespread tool in cell biology research. It contains a dipeptide backbone that is uniquely linked to a 6-deoxysugar via a phosphoramidate bridge. Herein, we report the identification of a gene cluster for the formation of phosphoramidon and its detailed characterization. In vitro reconstitution of the biosynthesis established TalE as a phosphoramidate-forming kinase and TalC as the glycosyltransferase which installs the L-rhamnose moiety by phosphoester linkage

KCTD12 Auxiliary Proteins Modulate Kinetics of GABAB Receptor-Mediated Inhibition in Cholecystokinin-Containing Interneurons

Cholecystokinin-expressing interneurons (CCK-INs) mediate behavior state-dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However, it remains unclear to what extent GABAB receptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy, we found that CCK-INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins, whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently, whole-cell recordings revealed slow GABABR-mediated inhibitory postsynaptic currents (IPSCs) in most CCK-INs. In spite of the higher surface density of GABABRs in CCK-INs than in CA1 principal cells, the amplitudes of IPSCs were comparable, suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK-INs were diverse, comprising perisomatic-targeting basket cells (BCs), as well as dendrite-targeting (DT) interneurons, including a previously undescribed DT type. GABABR-mediated IPSCs in CCK-INs were large in BCs, but small in DT subtypes. In response to prolonged activation, GABABR-mediated currents displayed strong desensitization, which was absent in KCTD12-deficient mice. This study highlights that GABABRs differentially control CCK-IN subtypes, and the kinetics and desensitization of GABABR-mediated currents are modulated by KCTD12 proteins

Sustainable protected areas: Synergies between biodiversity conservation and socioeconomic development

1. Reconciling conservation and socioeconomic development goals is key to sustainability but remains a source of fierce debate. Protected areas (PAs) are believed to play an essential role in achieving these seemingly conflicting goals. Yet, there is limited evidence as to whether PAs are actually achieving the two goals simultaneously. 2. Here, we investigate when and to what extent synergies or trade‐offs between biodiversity conservation and local socioeconomic development occur. To explore these relationships, we collected data across a wide range of socioeconomic settings through face‐to‐face survey with PA managers from 114 African and European PAs using structured questionnaire. 3. We found synergies between biodiversity conservation and socioeconomic development for 62% of the PAs, albeit with significant differences between African (55%) and European PAs (75%). Moreover, the sustainability of PAs in conserving biodiversity was strongly correlated with the empowerment of the PA management and the involvement of local communities in PA planning and decision‐making processes. 4. Our results demonstrate that for PAs to promote synergies between biodiversity conservation and local socioeconomic development, and to enhance their long‐term sustainability, they should invest in the empowerment of their respective management and involvement of local communities in their planning and management activities

Sustainable protected areas: Synergies between biodiversity conservation and socioeconomic development

1. Reconciling conservation and socioeconomic development goals is key to sus- tainability but remains a source of fierce debate. Protected areas (PAs) are be- lieved to play an essential role in achieving these seemingly conflicting goals. Yet, there is limited evidence as to whether PAs are actually achieving the two goals simultaneously. 2. Here, we investigate when and to what extent synergies or trade- offs between biodiversity conservation and local socioeconomic development occur. To ex- plore these relationships, we collected data across a wide range of socioeco- nomic settings through face-to-face survey with PA managers from 114 African and European PAs using structured questionnaire. 3. We found synergies between biodiversity conservation and socioeconomic development for 62% of the PAs, albeit with significant differences between African (55%) and European PAs (75%). Moreover, the sustainability of PAs in conserving biodiversity was strongly correlated with the empowerment of the PA management and the involvement of local communities in PA planning and decision-making processes. 4. Our results demonstrate that for PAs to promote synergies between biodiver- sity conservation and local socioeconomic development, and to enhance their long-term sustainability, they should invest in the empowerment of their respec- tive management and involvement of local communities in their planning and management activitie

SpEYEders: Adults’ and children’s affective responses during immersive playful gaze interactions transforming virtual spiders

Specific phobias like spider phobia represent a frequent mental health problem in children and adolescents, demanding innovative prevention and treatment approaches. We therefore develop an eye tracking supported Virtual Reality serious game for school-aged children, realizing gaze interactions to promote attention towards, and positive experiences during exposure to spiders. Within pilot studies in adults (n=30) and children (n=14) without fear of spiders, we assessed positive and negative affect during prototype gaze feedback through five different variants: If gazed for few seconds, the virtual spider changed into a shrunk, a rainbow coloured, or dying spider, or morphed into a smileyball, or speaks friendly. We found the highest positive affect for the rainbow and smileyball variant, followed by the shrunk and friendly speaking variant. In contrast, the dying variant was excluded due to the possible induction of negative affect. Findings indicate eligible variants for the further development of the VR serious game

Streptocollin, a Type IV Lanthipeptide Produced by Streptomyces collinus Tü 365

Lanthipeptides are ribosomally synthesized and post-translationally modified microbial secondary metabolites. Here, we report the identification and isolation of streptocollin from Streptomyces collinus Tü 365, a new member of class IV lanthipeptides. Insertion of the constitutive ermE* promoter upstream of the lanthipeptide synthetase gene stcL resulted in peptide production. The streptocollin gene cluster was heterologously expressed in S. coelicolor M1146 and M1152 with 3.5- and 5.5-fold increased yields, respectively. The structure and ring topology of streptocollin were determined by high resolution MS/MS analysis. Streptocollin contains four macrocyclic rings, with one lanthionine and three methyllanthionine residues. To the best of our knowledge, this is the first report on the isolation of a class IV lanthipeptide in preparative amounts, and on the successful heterologous expression of a class IV lanthipeptide gene cluster

Educational inequalities in diabetes mortality across Europe in the 2000s : the interaction with gender

To evaluate educational inequalities in diabetes mortality in Europe in the 2000s, and to assess whether these inequalities differ between genders. Data were obtained from mortality registries covering 14 European countries. To determine educational inequalities in diabetes mortality, age-standardised mortality rates, mortality rate ratios, and slope and relative indices of inequality were calculated. To assess whether the association between education and diabetes mortality differs between genders, diabetes mortality was regressed on gender, educational rank and 'gender x educational rank'. An inverse association between education and diabetes mortality exists in both genders across Europe. Absolute educational inequalities are generally larger among men than women; relative inequalities are generally more pronounced among women, the relative index of inequality being 2.8 (95 % CI 2.0-3.9) in men versus 4.8 (95 % CI 3.2-7.2) in women. Gender inequalities in diabetes mortality are more marked in the highest than the lowest educated. Education and diabetes mortality are inversely related in Europe in the 2000s. This association differs by gender, indicating the need to take the socioeconomic and gender dimension into account when developing public health policies.Peer reviewe

The dynamics of root cap sloughing in Arabidopsis is regulated by peptide signalling

The root cap protects the stem cell niche of angiosperm roots from damage. In Arabidopsis, lateral root cap (LRC) cells covering the meristematic zone are regularly lost through programmed cell death, while the outermost layer of the root cap covering the tip is repeatedly sloughed. Efficient coordination with stem cells producing new layers is needed to maintain a constant size of the cap. We present a signalling pair, the peptide IDA-LIKE1 (IDL1) and its receptor HAESA-LIKE2 (HSL2), mediating such communication. Live imaging over several days characterized this process from initial fractures in LRC cell files to full separation of a layer. Enhanced expression of IDL1 in the separating root cap layers resulted in increased frequency of sloughing, balanced with generation of new layers in a HSL2-dependent manner. Transcriptome analyses linked IDL1-HSL2 signalling to the transcription factors BEARSKIN1/2 and genes associated with programmed cell death. Mutations in either IDL1 or HSL2 slowed down cell division, maturation and separation. Thus, IDL1-HSL2 signalling potentiates dynamic regulation of the homeostatic balance between stem cell division and sloughing activity

Analysis of differences and commonalities in wildlife hunting across the Africa-Europe South-North gradient

Hunting and its impacts on wildlife are typically studied regionally, with a particular focus on the Global South. Hunting can, however, also undermine rewilding efforts or threaten wildlife in the Global North. Little is known about how hunting manifests under varying socioeconomic and ecological contexts across the Global South and North. Herein, we examined differences and commonalities in hunting characteristics across an exemplary Global South-North gradient approximated by the Human Development Index (HDI) using face-to-face interviews with 114 protected area (PA) managers in 25 African and European countries. Generally, we observed that hunting ranges from the illegal, economically motivated, and unsustainable hunting of herbivores in the South to the legal, socially and ecologically motivated hunting of ungulates within parks and the illegal hunting of mainly predators outside parks in the North. Commonalities across this Africa-Europe South-North gradient included increased conflict-related killings in human-dominated landscapes and decreased illegal hunting with beneficial community conditions, such as mutual trust resulting from community involvement in PA management. Nevertheless, local conditions cannot outweigh the strong effect of the HDI on unsustainable hunting. Our findings highlight regional challenges that require collaborative, integrative efforts in wildlife conservation across actors, while identified commonalities may outline universal mechanisms for achieving this goal.publishedVersio

Peroxisomal alterations in Alzheimer’s disease

In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology