Multifactorial Induction of an Orphan PKS-NRPS Gene Cluster in Aspergillus terreus

SummaryMining the genome of the pathogenic fungus Aspergillus terreus revealed the presence of an orphan polyketide-nonribosomal-peptide synthetase (PKS-NRPS) gene cluster. Induced expression of the transcriptional activator gene adjacent to the PKS-NRPS gene was not sufficient for the activation of the silent pathway. Monitoring gene expression, metabolic profiling, and using a lacZ reporter strain allowed for the systematic investigation of physiological conditions that eventually led to the discovery of isoflavipucine and dihydroisoflavipucine. Phytotoxin formation is only activated in the presence of certain amino acids, stimulated at alkaline pH, but strictly repressed in the presence of glucose. Global carbon catabolite repression by CreA cannot be abolished by positive-acting factors such as PacC and overrides the pathway activator. Gene inactivation and stable isotope labeling experiments unveiled the molecular basis for flavipucine/fruit rot toxin biosynthesis

Terrein Biosynthesis in Aspergillus terreus and Its Impact on Phytotoxicity

Terrein is a fungal metabolite with ecological, antimicrobial, antiproliferative, and antioxidative activities. Although it is produced by Aspergillus terreus as one of its major secondary metabolites, not much is known about its biosynthetic pathway. Here, we describe an unexpected discovery of the terrein biosynthesis gene locus made while we were looking for a PKS gene involved in production of conidia coloration pigments common for Aspergilli. The gene, ATEG_00145, here named terA, is essential for terrein biosynthesis and heterologous production of TerA in Aspergillus niger revealed an unusual plasticity in the products formed, yielding a mixture of 4-hydroxy-6-methylpyranone, orsellinic acid, and 6,7-dihydroxymellein. Biochemical and molecular genetic analyses indicate a low extension cycle specificity of TerA. Furthermore, 6-hydroxymellein was identified as a key intermediate in terrein biosynthesis. We find that terrein production is highly induced on plant-derived media, that terrein has phytotoxic activity on plant growth, and induces lesions on fruit surfaces

The AI Neuropsychologist: Automatic scoring of memory deficits with deep learning

Memory deficits are a hallmark of many different neurological and psychiatric conditions. The Rey-Osterrieth complex figure (ROCF) is the state–of-the-art assessment tool for neuropsychologists across the globe to assess the degree of non-verbal visual memory deterioration. To obtain a score, a trained clinician inspects a patient’s ROCF drawing and quantifies deviations from the original figure. This manual procedure is time-consuming, slow and scores vary depending on the clinician’s experience, motivation and tiredness. Here, we leverage novel deep learning architectures to automatize the rating of memory deficits. For this, a multi-head convolutional neural network was trained on 20225 ROCF drawings. Unbiased ground truth ROCF scores were obtained from crowdsourced human intelligence. The neural network outperforms both online raters and clinicians. Our AI-powered scoring system provides healthcare institutions worldwide with a digital tool to assess objectively, reliably and time-efficiently the performance in the ROCF test from hand-drawn images

Transcranial Alternating Current Stimulation Enhances Individual Alpha Activity in Human EEG

Non-invasive electrical stimulation of the human cortex by means of transcranial direct current stimulation (tDCS) has been instrumental in a number of important discoveries in the field of human cortical function and has become a well-established method for evaluating brain function in healthy human participants. Recently, transcranial alternating current stimulation (tACS) has been introduced to directly modulate the ongoing rhythmic brain activity by the application of oscillatory currents on the human scalp. Until now the efficiency of tACS in modulating rhythmic brain activity has been indicated only by inference from perceptual and behavioural consequences of electrical stimulation. No direct electrophysiological evidence of tACS has been reported. We delivered tACS over the occipital cortex of 10 healthy participants to entrain the neuronal oscillatory activity in their individual alpha frequency range and compared results with those from a separate group of participants receiving sham stimulation. The tACS but not the sham stimulation elevated the endogenous alpha power in parieto-central electrodes of the electroencephalogram. Additionally, in a network of spiking neurons, we simulated how tACS can be affected even after the end of stimulation. The results show that spike-timing-dependent plasticity (STDP) selectively modulates synapses depending on the resonance frequencies of the neural circuits that they belong to. Thus, tACS influences STDP which in turn results in aftereffects upon neural activity

Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence

The present study demonstrates that tDCS can alter WM performance by modulating the underlying neural oscillations. This result can be considered an important step towards a better understanding of the mechanisms involved in tDCS-induced modulations of WM performance, which is of particular importance, given the proposal to use electrical brain stimulation for the therapeutic treatment of memory deficits in clinical settings

Three decades of simulated global terrestrial carbon fluxes from a data assimilation system confronted with different periods of observations

During the last decade, carbon cycle data assimilation systems (CCDAS) have focused on improving the simulation of seasonal and mean global carbon fluxes over a few years by simultaneous assimilation of multiple data streams. However, the ability of a CCDAS to predict longer-term trends and variability of the global carbon cycle and the constraint provided by the observations have not yet been assessed. Here, we evaluate two near-decade-long assimilation experiments of the Max Planck Institute-Carbon Cycle Data Assimilation System (MPI-CCDAS v1) using spaceborne estimates of the fraction of absorbed photosynthetic active radiation (FAPAR) and atmospheric CO2 concentrations from the global network of flask measurement sites from either 1982 to 1990 or 1990 to 2000. We contrast these simulations with independent observations from the period 1982-2010, as well as a third MPI-CCDAS assimilation run using data from the full 1982-2010 period, and an atmospheric inversion covering the same data and time. With 30 years of data, MPI-CCDAS is capable of representing land uptake to a sufficient degree to make it compatible with the atmospheric CO2 record. The long-term trend and seasonal amplitude of atmospheric CO2 concentrations at station level over the period 1982 to 2010 is considerably improved after assimilating only the first decade (1982-1990) of observations. After 15-19 years of prognostic simulation, the simulated CO2 mixing ratio in 2007-2010 diverges by only 2 +/- 1.3 ppm from the observations, the atmospheric inversion, and the MPI-CCDAS assimilation run using observations from the full period. The long-term trend, phenological seasonality, and interannual variability (IAV) of FAPAR in the Northern Hemisphere over the last 1 to 2 decades after the assimilation were also improved. Despite imperfections in the representation of the IAV in atmospheric CO2, model-data fusion for a decade of data can already contribute to the prognostic capacity of land carbon cycle models at relevant timescales.Peer reviewe

Effects of changes in CO2, climate, and land use on the carbon balance of the land biosphere during the 21st century

International audienc

Persistence versus escape: Aspergillus terreus and Aspergillus fumigatus employ different strategies during interactions with macrophages.

Invasive bronchopulmonary aspergillosis (IBPA) is a life-threatening disease in immunocompromised patients. Although Aspergillus terreus is frequently found in the environment, A. fumigatus is by far the main cause of IBPA. However, once A. terreus establishes infection in the host, disease is as fatal as A. fumigatus infections. Thus, we hypothesized that the initial steps of disease establishment might be fundamentally different between these two species. Since alveolar macrophages represent one of the first phagocytes facing inhaled conidia, we compared the interaction of A. terreus and A. fumigatus conidia with alveolar macrophages. A. terreus conidia were phagocytosed more rapidly than A. fumigatus conidia, possibly due to higher exposure of β-1,3-glucan and galactomannan on the surface. In agreement, blocking of dectin-1 and mannose receptors significantly reduced phagocytosis of A. terreus, but had only a moderate effect on phagocytosis of A. fumigatus. Once phagocytosed, and in contrast to A. fumigatus, A. terreus did not inhibit acidification of phagolysosomes, but remained viable without signs of germination both in vitro and in immunocompetent mice. The inability of A. terreus to germinate and pierce macrophages resulted in significantly lower cytotoxicity compared to A. fumigatus. Blocking phagolysosome acidification by the v-ATPase inhibitor bafilomycin increased A. terreus germination rates and cytotoxicity. Recombinant expression of the A. nidulans wA naphthopyrone synthase, a homologue of A. fumigatus PksP, inhibited phagolysosome acidification and resulted in increased germination, macrophage damage and virulence in corticosteroid-treated mice. In summary, we show that A. terreus and A. fumigatus have evolved significantly different strategies to survive the attack of host immune cells. While A. fumigatus prevents phagocytosis and phagolysosome acidification and escapes from macrophages by germination, A. terreus is rapidly phagocytosed, but conidia show long-term persistence in macrophages even in immunocompetent hosts