No evidence for globally coherent warm and cold periods over the preindustrial Common Era.

Earth's climate history is often understood by breaking it down into constituent climatic epochs1. Over the Common Era (the past 2,000 years) these epochs, such as the Little Ice Age2-4, have been characterized as having occurred at the same time across extensive spatial scales5. Although the rapid global warming seen in observations over the past 150 years does show nearly global coherence6, the spatiotemporal coherence of climate epochs earlier in the Common Era has yet to be robustly tested. Here we use global palaeoclimate reconstructions for the past 2,000 years, and find no evidence for preindustrial globally coherent cold and warm epochs. In particular, we find that the coldest epoch of the last millennium-the putative Little Ice Age-is most likely to have experienced the coldest temperatures during the fifteenth century in the central and eastern Pacific Ocean, during the seventeenth century in northwestern Europe and southeastern North America, and during the mid-nineteenth century over most of the remaining regions. Furthermore, the spatial coherence that does exist over the preindustrial Common Era is consistent with the spatial coherence of stochastic climatic variability. This lack of spatiotemporal coherence indicates that preindustrial forcing was not sufficient to produce globally synchronous extreme temperatures at multidecadal and centennial timescales. By contrast, we find that the warmest period of the past two millennia occurred during the twentieth century for more than 98 per cent of the globe. This provides strong evidence that anthropogenic global warming is not only unparalleled in terms of absolute temperatures5, but also unprecedented in spatial consistency within the context of the past 2,000 years.

Intrinsic nonlinear dynamics drive single-species systems.

The importance of oscillations and deterministic chaos in natural biological systems has been discussed for several decades and was originally based on discrete-time population growth models (May 1974). Recently, all types of nonlinear dynamics were shown for experimental communities where several species interact. Yet, there are no data exhibiting the whole range of nonlinear dynamics for single-species systems without trophic interactions. Up until now, ecological experiments and models ignored the intracellular dimension, which includes multiple nonlinear processes even within one cell type. Here, we show that dynamics of single-species systems of protists in continuous experimental chemostat systems and corresponding continuous-time models reveal typical characteristics of nonlinear dynamics and even deterministic chaos, a very rare discovery. An automatic cell registration enabled a continuous and undisturbed analysis of dynamic behavior with a high temporal resolution. Our simple and general model considering the cell cycle exhibits a remarkable spectrum of dynamic behavior. Chaos-like dynamics were shown in continuous single-species populations in experimental and modeling data on the level of a single type of cells without any external forcing. This study demonstrates how complex processes occurring in single cells influence dynamics on the population level. Nonlinearity should be considered as an important phenomenon in cell biology and single-species dynamics and also, for the maintenance of high biodiversity in nature, a prerequisite for nature conservation.

Flavin-induced charge separation in transmembrane model peptides.

Hydrophobic peptide models derived from the α-helical transmembrane segment of the epidermal growth factor receptor were synthetically modified with a flavin amino acid as a photo-inducible charge donor and decorated with tryptophans along the helix as charge acceptors. The helical conformation of the peptides was conserved despite the modifications, notably also in lipid vesicles and multibilayers. Their ability to facilitate photo-induced transmembrane charge transport was examined by means of steady-state and time-resolved optical spectroscopy. The first tryptophan next to the flavin donor plays a major role in initiating the charge transport near the N-terminus, while the other tryptophans might promote charge transport along the transmembrane helix. These artificially modified, but still naturally derived helical peptides are important models for studying transmembrane electron transfer and the principles of photosynthesis.

Nasal Breathing Assessment Using Computational Fluid Dynamics: An Update from the Rhinologic Perspective.

An objective assessment of nasal breathing is currently insufficiently achievable. The application of computational fluid dynamics for this purpose is increasingly gaining attention. However, the suggested specific frameworks can differ considerably. To the best of our knowledge, there is not yet a widely accepted clinical usage of computational fluid dynamics. In this article, selected aspects are addressed that might be crucial for future development and possible implementation of computational fluid dynamics in rhinology.

Visible-Light Activation of Diorganyl Bis(pyridylimino) Isoindolide Aluminum(III) Complexes and Their Organometallic Radical Reactivity.

We report on the synthesis and characterization of a series of (mostly) air-stable diorganyl bis(pyridylimino) isoindolide (BPI) aluminum complexes and their chemistry upon visible-light excitation. The redox non-innocent BPI pincer ligand allows for efficient charge transfer homolytic processes of the title compounds. This makes them a universal platform for the generation of carbon-centered radicals. The photo-induced homolytic cleavage of the Al-C bonds was investigated by means of stationary and transient UV/Vis spectroscopy, spin trapping experiments, as well as EPR and NMR spectroscopy. The experimental findings were supported by quantum chemical calculations. Reactivity studies enabled the utilization of the aluminum complexes as reactants in tin-free Giese-type reactions and carbonyl alkylations under ambient conditions, which both indicated radical-polar crossover behavior. A deeper understanding of the physical fundamentals and photochemical process was provided, furnishing in turn a new strategy to control the reactivity of bench-stable aluminum organometallics.

Towards the discovery of novel molecular clocks in Prokaryotes.

Diel cycle is of enormous biological importance as it imposes daily oscillation in environmental conditions, which temporally structures most ecosystems. Organisms developed biological time-keeping mechanisms - circadian clocks - that provide a significant fitness advantage over competitors by optimising the synchronisation of their biological activities. While circadian clocks are ubiquitous in Eukaryotes, they are so far only characterised in Cyanobacteria within Prokaryotes. However, growing evidence suggests that circadian clocks are widespread in the bacterial and archaeal domains. As Prokaryotes are at the heart of crucial environmental processes and are essential to human health, unravelling their time-keeping systems provides numerous applications in medical research, environmental sciences, and biotechnology. In this review, we elaborate on how novel circadian clocks in Prokaryotes offer research and development perspectives. We compare and contrast the different circadian systems in Cyanobacteria and discuss about their evolution and taxonomic distribution. We necessarily provide an updated phylogenetic analysis of bacterial and archaeal species that harbour homologs of the main cyanobacterial clock components. Finally, we elaborate on new potential clock-controlled microorganisms that represent opportunities of ecological and industrial relevance in prokaryotic groups such as anoxygenic photosynthetic bacteria, methanogenic archaea, methanotrophs or sulphate-reducing bacteria.

The Roles of Secreted Wnt Ligands in Cancer.

Wnt ligands are secreted signaling proteins that display a wide range of biological effects. They play key roles in stimulating Wnt signaling pathways to facilitate processes such as tissue homeostasis and regeneration. Dysregulation of Wnt signaling is a hallmark of many cancers and genetic alterations in various Wnt signaling components, which result in ligand-independent or ligand-dependent hyperactivation of the pathway that have been identified. Recently, research is focusing on the impact of Wnt signaling on the interaction between tumor cells and their micro-environment. This Wnt-mediated crosstalk can act either in a tumor promoting or suppressing fashion. In this review, we comprehensively outline the function of Wnt ligands in different tumor entities and their impact on key phenotypes, including cancer stemness, drug resistance, metastasis, and immune evasion. Lastly, we elaborate approaches to target Wnt ligands in cancer therapy.

Targeting euchromatic histone lysine methyltransferases sensitizes colorectal cancer to histone deacetylase inhibitors.

Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Cotargeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient-derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC.

Annotating unknown species of urban microorganisms on a global scale unveils novel functional diversity and local environment association.

In urban ecosystems, microbes play a key role in maintaining major ecological functions that directly support human health and city life. However, the knowledge about the species composition and functions involved in urban environments is still limited, which is largely due to the lack of reference genomes in metagenomic studies comprises more than half of unclassified reads. Here we uncovered 732 novel bacterial species from 4728 samples collected from various common surface with the matching materials in the mass transit system across 60 cities by the MetaSUB Consortium. The number of novel species is significantly and positively correlated with the city population, and more novel species can be identified in the skin-associated samples. The in-depth analysis of the new gene catalog showed that the functional terms have a significant geographical distinguishability. Moreover, we revealed that more biosynthetic gene clusters (BGCs) can be found in novel species. The co-occurrence relationship between BGCs and genera and the geographical specificity of BGCs can also provide us more information for the synthesis pathways of natural products. Expanded the known urban microbiome diversity and suggested additional mechanisms for taxonomic and functional characterization of the urban microbiome. Considering the great impact of urban microbiomes on human life, our study can also facilitate the microbial interaction analysis between human and urban environment.

Genomic and proteomic profiles of biofilms on microplastics are decoupled from artificial surface properties.

Microplastics in marine ecosystems are colonized by diverse prokaryotic and eukaryotic communities. How these communities and their functional profiles are shaped by the artificial surfaces remains broadly unknown. In order to close this knowledge gap, we set up an in situ experiment with pellets of the polyolefin polymer polyethylene (PE), the aromatic hydrocarbon polymer polystyrene (PS), and wooden beads along a coastal to estuarine gradient in the Baltic Sea, Germany. We used an integrated metagenomics/metaproteomics approach to evaluate the genomic potential as well as protein expression levels of aquatic plastic biofilms. Our results suggest that material properties had a minor influence on the plastic-associated assemblages, as genomic and proteomic profiles of communities associated with the structurally different polymers PE and PS were highly similar, hence polymer-unspecific. Instead, it seemed that these communities were shaped by biogeographic factors. Wood, on the other hand, induced the formation of substrate-specific biofilms and served as nutrient source itself. Our study indicates that, while PE and PS microplastics may be relevant in the photic zone as opportunistic colonization grounds for phototrophic microorganisms, they appear not to be subject to biodegradation or serve as vectors for pathogenic microorganisms in marine habitats.

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma.

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1-3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.

Correlation of Structural and Magnetic Properties in a Set of Mononuclear Lanthanide Complexes.

The electronic and magnetic properties of a set of mononuclear terbium(III) and dysprosium(III) complexes with two tetradentate 1-hydroxy-pyridin-2-one (1,2-HOPO) ligands are reported. Two primary coordination geometries are observed, depending on the length of the linker between the 1,2-HOPO donor moieties and the resulting arrangements of the linker. Fine details of the magnetic circular dichroism (MCD) spectra of the dysprosium(III) complexes illustrate differences in the splitting of the J multiplets and allow for a thorough ligand field analysis. High frequency electron paramagnetic resonance (HF-EPR) studies of the terbium(III) complexes give insight into the composition of the ground states. Ab initio calculations are utilized to rationalize the experimental results and further illustrate the effect of the structural features on the electronic and magnetic properties of the different complexes.

Analysis of Yersinia ruckeri strains isolated from trout farms in northwest Germany.

Enteric redmouth disease (ERM), caused by Yersinia ruckeri, is among the most important infectious diseases in rainbow trout Oncorhynchus mykiss aquaculture in Europe. Our aim was to analyse the persistence of Y. ruckeri strains in trout farms in northwest Germany and their dissemination between farms based on a detailed molecular and phenotypical characterisation scheme. The data on identification and characterisation of Y. ruckeri strains and examining the distribution of these strains in the field could serve as a basis for preventive disease monitoring plans. During the observation period from June 2011 until June 2012, we collected 48 Y. ruckeri isolates from 12 different rainbow trout hatcheries. In total, 44 (91.7%) of the isolates were non-motile; in particular, all isolates recovered during the sampling period in winter and early spring were non-motile. In several trout farms, characteristic farm-specific Y. ruckeri isolates from particular typing groups were isolated throughout the year, while in other farms, which had a trading relationship between each other, ERM outbreaks were caused by Y. ruckeri from the same typing group. Our data indicate that in some farms, the causative Y. ruckeri strains persisted in the respective trout farm. The presence of Y. ruckeri from the same typing group in farms with a trading relationship indicates a dissemination of the infection between the farms.

The gill chamber epibiosis of deep-sea shrimp Rimicaris exoculata: an in-depth metagenomic investigation and discovery of Zetaproteobacteria.

The gill chamber of deep-sea hydrothermal vent shrimp Rimicaris exoculata hosts a dense community of epibiotic bacteria dominated by filamentous Epsilonproteobacteria and Gammaproteobacteria. Using metagenomics on shrimp from the Rainbow hydrothermal vent field, we showed that both epibiont groups have the potential to grow autotrophically and oxidize reduced sulfur compounds or hydrogen with oxygen or nitrate. For carbon fixation, the Epsilonproteobacteria use the reductive tricarboxylic acid cycle, whereas the Gammaproteobacteria use the Calvin-Benson-Bassham cycle. Only the epsilonproteobacterial epibionts had the genes necessary for producing ammonium. This ability likely minimizes direct competition between epibionts and also broadens the spectrum of environmental conditions that the shrimp may successfully inhabit. We identified genes likely to be involved in shrimp-epibiont interactions, as well as genes for nutritional and detoxification processes that might benefit the host. Shrimp epibionts at Rainbow are often coated with iron oxyhydroxides, whose origin is intensely debated. We identified 16S rRNA sequences and functional genes affiliated with iron-oxidizing Zetaproteobacteria, which indicates that biological iron oxidation might play a role in forming these deposits. Fluorescence in situ hybridizations confirmed the presence of active Zetaproteobacteria in the R. exoculata gill chamber, thus providing the first evidence for a Zetaproteobacteria-invertebrate association.

Halorhabdus tiamatea: proteogenomics and glycosidase activity measurements identify the first cultivated euryarchaeon from a deep-sea anoxic brine lake as potential polysaccharide degrader.

Euryarchaea from the genus Halorhabdus have been found in hypersaline habitats worldwide, yet are represented by only two isolates: Halorhabdus utahensis AX-2(T) from the shallow Great Salt Lake of Utah, and Halorhabdus tiamatea SARL4B(T) from the Shaban deep-sea hypersaline anoxic lake (DHAL) in the Red Sea. We sequenced the H. tiamatea genome to elucidate its niche adaptations. Among sequenced archaea, H. tiamatea features the highest number of glycoside hydrolases, the majority of which were expressed in proteome experiments. Annotations and glycosidase activity measurements suggested an adaptation towards recalcitrant algal and plant-derived hemicelluloses. Glycosidase activities were higher at 2% than at 0% or 5% oxygen, supporting a preference for low-oxygen conditions. Likewise, proteomics indicated quinone-mediated electron transport at 2% oxygen, but a notable stress response at 5% oxygen. Halorhabdus tiamatea furthermore encodes proteins characteristic for thermophiles and light-dependent enzymes (e.g. bacteriorhodopsin), suggesting that H. tiamatea evolution was mostly not governed by a cold, dark, anoxic deep-sea habitat. Using enrichment and metagenomics, we could demonstrate presence of similar glycoside hydrolase-rich Halorhabdus members in the Mediterranean DHAL Medee, which supports that Halorhabdus species can occupy a distinct niche as polysaccharide degraders in hypersaline environments.

Landscape of global urban environmental resistome and its association with local socioeconomic and medical status.

Antimicrobial resistance (AMR) poses a critical threat to global health and development, with environmental factors-particularly in urban areas-contributing significantly to the spread of antibiotic resistance genes (ARGs). However, most research to date has been conducted at a local level, leaving significant gaps in our understanding of the global status of antibiotic resistance in urban environments. To address this issue, we thoroughly analyzed a total of 86,213 ARGs detected within 4,728 metagenome samples, which were collected by the MetaSUB International Consortium involving diverse urban environments in 60 cities of 27 countries, utilizing a deep-learning based methodology. Our findings demonstrated the strong geographical specificity of urban environmental resistome, and their correlation with various local socioeconomic and medical conditions. We also identified distinctive evolutionary patterns of ARG-related biosynthetic gene clusters (BGCs) across different countries, and discovered that the urban environment represents a rich source of novel antibiotics. Our study provides a comprehensive overview of the global urban environmental resistome, and fills a significant gap in our knowledge of large-scale urban antibiotic resistome analysis.

The genome of the alga-associated marine flavobacterium Formosa agariphila KMM 3901T reveals a broad potential for degradation of algal polysaccharides.

In recent years, representatives of the Bacteroidetes have been increasingly recognized as specialists for the degradation of macromolecules. Formosa constitutes a Bacteroidetes genus within the class Flavobacteria, and the members of this genus have been found in marine habitats with high levels of organic matter, such as in association with algae, invertebrates, and fecal pellets. Here we report on the generation and analysis of the genome of the type strain of Formosa agariphila (KMM 3901(T)), an isolate from the green alga Acrosiphonia sonderi. F. agariphila is a facultative anaerobe with the capacity for mixed acid fermentation and denitrification. Its genome harbors 129 proteases and 88 glycoside hydrolases, indicating a pronounced specialization for the degradation of proteins, polysaccharides, and glycoproteins. Sixty-five of the glycoside hydrolases are organized in at least 13 distinct polysaccharide utilization loci, where they are clustered with TonB-dependent receptors, SusD-like proteins, sensors/transcription factors, transporters, and often sulfatases. These loci play a pivotal role in bacteroidetal polysaccharide biodegradation and in the case of F. agariphila revealed the capacity to degrade a wide range of algal polysaccharides from green, red, and brown algae and thus a strong specialization of toward an alga-associated lifestyle. This was corroborated by growth experiments, which confirmed usage particularly of those monosaccharides that constitute the building blocks of abundant algal polysaccharides, as well as distinct algal polysaccharides, such as laminarins, xylans, and κ-carrageenans.

The concept of rhinorespiratory homeostasis--a new approach to nasal breathing.

The suggested concept of rhinorespiratory homeostasis is a new theoretical model for the discussion of physiologic and physical principles of nasal breathing. This model is based on a comprehensive view of nasal functions that takes comparative animal physiology into account. Consequently, it has a universal cross-species character and emphasizes the central role of nasal secretion. In contrast to the established view, the focus is transferred from the inspired air to the nasal wall. This concept considers the parietal effect of airflow represented by wall shear stress with special regard to the epithelial lining fluid. It delivers one possible mechanism of an inherent triggering of the nasal cycle. Furthermore, the issue of biological fluid-structure interaction is introduced. This article presents a rethinking of nasal breathing that was inspired by clinical experience and results of flow field investigations through computational fluid dynamics.

An interactive three-dimensional nose model for rhinosurgery.

The motivation behind the development of a new interactive three-dimensional (3D) model of the cartilaginous and bony framework of the nose originated from the significant demand for sophisticated patient communication and for accurate documentation of the surgical steps in rhinoplasty. Basically, the model consists of three features--the viewer function, the freehand function, and default applications--enabling the surgeon to replicate fundamental compilations of findings and to graphically document operative measures easily. The user is able to save all graphics in two-dimensional format and allocate them to patient files. Because the application was designed to be sufficiently universal without being too complex, the 3D model provides a well-balanced mix between freehand and default functions, representing the consistent development of currently available tools.