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Bacterial cell division is coordinated by the Z-ring, a cytoskeletal structure of treadmilling filaments of FtsZ and their membrane anchors, FtsA and ZipA. For divisome maturation and initiation of constriction, the widely conserved actin-homolog FtsA plays a central role, as it links downstream cell division proteins in the membrane to the Z-ring in the cytoplasm. According to the current model, FtsA initiates cell constriction by switching from an inactive polymeric conformation to an active monomeric form, which then stabilizes the Z-ring and recruits downstream proteins such as FtsN. However, direct biochemical evidence for this mechanism is missing so far. Here, we used biochemical reconstitution experiments in combination with quantitative fluorescence microscopy to study the mechanism of divisome activation in vitro. By comparing the properties of wildtype FtsA and FtsA R286W, a gain-of-function mutant thought to mimic its active state, we found that active FtsA outperforms the wildtype protein in replicating FtsZ treadmilling dynamics, filament stabilization and FtsN recruitment. We could attribute these differences to a faster membrane exchange of FtsA R286W as well as its higher packing density below FtsZ filaments. Using FRET microscopy, we also show that binding of FtsN does not compete with, but promotes FtsA self-interaction. Together, our findings shed new light on the assembly and activation of the bacterial cell division machinery and the mechanism of how FtsA initiates cell constriction.

Experten aus Wissenschaft und Praxis gehen davon aus, dass wir noch in diesem Jahrzehnt die Automatisierung von Fahrzeugen erleben werden und sich somit die Art und Weise, wie wir uns fortbewegen, ganzlich verandern wird. Ein wesentlicher Treiber der Automatisierung ist die Steigerung der Sicherheit im Verkehr, bis hin zur „Vision Zero“. Hierbei soll erreicht werden, dass Unfalle im Strasenverkehr ganzlich vermieden werden und die Anzahl an Verkehrstoten und Schwerverletzten auf null gesenkt wird.

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in dsRNA. ADAR editing in pre-mRNAs recodes open reading frames and alters splicing, mRNA structure and interactions with miRNAs. Here, we review ADAR gene expression, splice forms, posttranslational modifications, subcellular localizations and functions of ADAR protein isoforms. ADAR1 edits cellular dsRNA to prevent aberrant activation of cytoplasmic antiviral dsRNA sensors; ADAR1 mutations lead to aberrant expression of interferon in Aicardi Goutières syndrome (AGS), a human congenital encephalopathy. We review related studies on mouse Adar1 mutant phenotypes, their rescues by preventing signaling from the antiviral RIG-I-like Sensors (RLRs), as well as Adar1 mechanisms in innate immune suppression and other roles of Adar1, including editing-independent effects. ADAR2, expressed primarily in CNS, edits glutamate receptor transcripts; regulation of ADAR2 activity in response to neuronal activity mediates homeostatic synaptic plasticity of vertebrate AMPA and kainite receptors. In Drosophila, synapses and synaptic proteins show dramatic decreases at night during sleep; Drosophila Adar, an orthologue of ADAR2, edits hundreds of mRNAs; the most conserved editing events occur in transcripts encoding synapse-associated proteins. Adar mutant flies exhibit locomotion defects associated with very increased sleep pressure resulting from a failure of homeostatic synaptic processes. A study on Adar2 mutant mice identifies a new role in circadian rhythms, acting indirectly through miRNAs such as let-7 to modulate levels of let-7 target mRNAs; ADAR1 also regulates let-7 miRNA processing. Drosophila ADAR, an orthologue of vertebrate ADAR2, also regulates let-7 miRNA levels and Adar mutant flies have a circadian mutant phenotype.

Die Mobilitatswelt befi ndet sich aktuell, ahnlich wie bereits vor 100 Jahren beim Umstieg von der Kutsche auf das Automobil, in einem disruptiven Wandel. Autonome Fahrzeuge und Flugtaxis, die per Smartphone bedarfsgerecht angefordert und uber eine App abgerechnet werden, Transportdrohnen, die Guter zustellen, etc. – mit solchen Bildern vermitteln einige Akteure aus dem Umfeld der Mobilitat den Konsumenten die schone neue Welt der urbanen Mobilitat der Zukunft . Allerdings ist der Wunsch nach einer derartigen, ganzheitlichen Mobilitat nicht neu – bereits 1939 wurden z. B. erste Visionen zum autonomen Fahren aufgezeigt.

We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutieres Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions.

Background Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. Methods We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed. Results Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse, latent tuberculosis, diabetes mellitus, atypical mycobacterial infections, vitamin D deficiency or metabolic bone disorders, anxiety disorders, and fractures; the incidence of pneumonia decreased significantly. Twenty-eight deaths occurred, yielding a standardized mortality rate 31.5 times that of the US population. Those who died were older, less likely to be receiving cART, and had lower CD4 cell counts and higher viral loads. Most deaths (86%) were due to HIV-related medical conditions. Conclusions Opportunistic infections and deaths are less common among HIV-infected youth in the US in the cART era, but the mortality rate remains elevated. Deaths were associated with poor HIV control and older age. Emerging complications, such as psychiatric, inflammatory, metabolic, and genital tract diseases, need to be addressed.