Origin and evolution of the archaeo-eukaryotic primase superfamily and related palm-domain proteins: structural insights and new members

We report an in-depth computational study of the protein sequences and structures of the superfamily of archaeo-eukaryotic primases (AEPs). This analysis greatly expands the range of diversity of the AEPs and reveals the unique active site shared by all members of this superfamily. In particular, it is shown that eukaryotic nucleo-cytoplasmic large DNA viruses, including poxviruses, asfarviruses, iridoviruses, phycodnaviruses and the mimivirus, encode AEPs of a distinct family, which also includes the herpesvirus primases whose relationship to AEPs has not been recognized previously. Many eukaryotic genomes, including chordates and plants, encode previously uncharacterized homologs of these predicted viral primases, which might be involved in novel DNA repair pathways. At a deeper level of evolutionary connections, structural comparisons indicate that AEPs, the nucleases involved in the initiation of rolling circle replication in plasmids and viruses, and origin-binding domains of papilloma and polyoma viruses evolved from a common ancestral protein that might have been involved in a protein-priming mechanism of initiation of DNA replication. Contextual analysis of multidomain protein architectures and gene neighborhoods in prokaryotes and viruses reveals remarkable parallels between AEPs and the unrelated DnaG-type primases, in particular, tight associations with the same repertoire of helicases. These observations point to a functional equivalence of the two classes of primases, which seem to have repeatedly displaced each other in various extrachromosomal replicons

Microfacies analysis and varve-based chronology reveal a variable 14C reservoir effect in Lake Shira, northern Inner Asia, over the past 2500 years

Here, we present the first fully varve-based chronology for the deposits of the deep-water Lake Shira (Chulym-Yenisei Basin, South Siberia), derived from a new sediment core. The very well-preserved varves show typical properties of the clastic-biogenic and endogenic types that can be subdivided into four sublayers representing winter–early spring, late spring, early summer and late summer–autumn. The analysed sediment section of 147 cm length comprises 2491 varve years with a total counting error of 1.6 % (i.e. ±40 years), making the new sediment core from Lake Shira a unique high-resolution archive for multi-proxy studies of past climate/environmental change and human-environment interactions. Direct comparison of nine AMS radiocarbon (14C) dates based on sediment bulk organic fractions with an age-depth model based on varve counting made it possible to examine the 14C reservoir effect in the lake. The reservoir effect is a common issue when estimating the age of environmental proxies from lacustrine sedimentary archives in Inner Asia. Although a constant reservoir effect is commonly used to correct the 14C dates from a single core or lake basin, our results from Lake Shira demonstrate that it varies significantly over the last 2500 years, ranging from 240 ± 30 to 1045 ± 30 years. The spatiotemporal variability of the reservoir effect can considerably reduce the accuracy of age-depth models based solely on the bulk organic sediment fraction. Where varved sediment is unavailable, as is usually the case, lignin phenols, terrestrial plant remains and purified pollen concentrates should be considered as alternative dating materials.1. Introduction 2. Environmental setting 3. Material and methods 3.1. Sediment core 3.2. Thin sections, microfacies analysis and varve counting 3.3. Chemical element analysis 3.4. AMS 14C dating, reservoir age estimation and 137Cs measurements 4. Results and discussion 4.1. Varve properties 4.2. Varve chronology, 14C dating and 137Cs concentration 4.3. Reservoir effect 5. Conclusion

The earliest directly dated saddle for horse-riding from a mid-1st millennium BCE female burial in Northwest China

The invention of the saddle substantially improved horseback-riding, which not only revolutionized warfare, but also eased long-distance speedy movement across Eurasia. Here we present the first detailed construction analysis and absolute age determination of a well-preserved soft leather saddle recovered from the tomb of a female deceased at the Yanghai cemetery site in the Turfan Basin at the eastern end of the Tian Shan mountains. Compared with the oldest known saddle from the Scythian Pazyryk culture site Tuekta barrow no. 1 (430–420 BCE) in north-western Altai, the Yanghai specimen radiocarbon dated to 727–396 BCE (95.4% probability range) is contemporaneous or possibly older. The saddle features the basic elements of soft saddle construction that are still used today: two stuffed, wing-shaped hides sewn together along the outer edges and separated by a central gullet-like spacer and lens-shaped support elements, resembling knee and thigh rolls of modern saddles. Being a masterful piece of leather- and needlework, it is, however, less complex compared to Scythian saddles from the 5th–3rd centuries BCE. Another specimen from nearby Subeixi site, which is also described in detail for the first time in the present study, much closer resembles the Pazyryk saddles in shape, size and structure. In Yanghai, equestrian paraphernalia appear in the grave assemblages during the entire burial period (ca. 1300 BCE to 200 CE), although in higher numbers only from ca. 300 BCE. In the same way, the burial of horses was not common until then. Despite the generally very good preservation of leather, only two saddles were discovered in Yanghai which makes them an exception rather than the norm and raises the question of whether these saddles were acquired from more specialized horse breeders, riders, and saddlers in the North.1. Introduction 2. Material and methods 2.1. The leather saddle from the Yanghai archaeological site tomb IIM205 2.2. The leather saddle from Subeixi archaeological site tomb M10 3. Results and interpretations 3.1. Dating of the leather saddles 3.2. The saddle from Yanghai 3.2.1. Construction 3.2.2. Saddle panels 3.2.3. Gullet 3.2.4. Lens-shaped support elements 3.2.5. Type and preservation of leather 3.2.6. Saddle filling 3.2.7. Fastening of the saddle 3.3. The saddle from Subeixi 3.3.1. Construction 3.3.2. Saddle panels and gullet 3.3.3. Gussets and bone attachments 3.3.4. Girth 3.3.5. Crupper 3.3.6. Felt pad 3.3.7. Bridle 3.3.8. Leather type and saddle filling 4. Discussion 4.1. Comparison of the Yanghai and Subeixi saddles 4.2. Turfan in the evolution of saddlery in central and eastern Asia 4.3. Turfan in the early history of horse-riding in central and eastern Asia 5. Conclusion

Th17 cells are more protective than Th1 cells against the intracellular parasite Trypanosoma cruzi

Th17 cells are a subset of CD4+ T cells known to play a central role in the pathogenesis of many autoimmune diseases, as well as in the defense against some extracellular bacteria and fungi. However, Th17 cells are not believed to have a significant function against intracellular infections. In contrast to this paradigm, we have discovered that Th17 cells provide robust protection against Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagas disease. Th17 cells confer significantly stronger protection against T. cruzi-related mortality than even Th1 cells, traditionally thought to be the CD4+ T cell subset most important for immunity to T. cruzi and other intracellular microorganisms. Mechanistically, Th17 cells can directly protect infected cells through the IL-17A-dependent induction of NADPH oxidase, involved in the phagocyte respiratory burst response, and provide indirect help through IL-21-dependent activation of CD8+ T cells. The discovery of these novel Th17 cell-mediated direct protective and indirect helper effects important for intracellular immunity highlights the diversity of Th17 cell roles, and increases understanding of protective T. cruzi immunity, aiding the development of therapeutics and vaccines for Chagas disease

Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor

Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve as common infection models. Here, we conducted global proteome profiling of rat CMV-infected cells and uncovered a pronounced loss of the transcription factor STAT2, which is crucial for antiviral interferon signalling. Via deletion mutagenesis, we found that the viral protein E27 is required for CMV-induced STAT2 depletion. Cellular and in vitro analyses showed that E27 exploits host-cell Cullin4-RING ubiquitin ligase (CRL4) complexes to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopy revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors called DCAFs (DDB1- and Cullin4-associated factors), thereby displacing them from the catalytic core of CRL4. Moreover, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, which partially overlaps with the IRF9 binding site. Structure-based mutations in M27, the murine CMV homologue of E27, impair the interferon-suppressing capacity and virus replication in mouse models, supporting the conserved importance of DCAF mimicry for CMV immune evasion

Toll-Like Receptor 4 Is Involved in Inflammatory and Joint Destructive Pathways in Collagen-Induced Arthritis in DBA1J Mice

In rheumatoid arthritis, a significant proportion of cytokine and chemokine synthesis is attributed to innate immune mechanisms. TLR4 is a prominent innate receptor since several endogenous ligands known to activate the innate immune system bind to it and may thereby promote joint inflammation. We generated TLR4 deficient DBA1J mice by backcrossing the TLR4 mutation present in C3H/HeJ strain onto the DBA1J strain and investigated the course of collagen-induced arthritis in TLR4 deficient mice in comparison to wild type littermates. The incidence of collagen- induced arthritis was significantly lower in TLR4 deficient compared to wild type mice (59 percent vs. 100 percent). The severity of arthritis was reduced in the TLR4 deficient mice compared to wild type littermates (mean maximum score 2,54 vs. 6,25). Mice deficient for TLR4 were virtually protected from cartilage destruction, and infiltration of inflammatory cells was reduced compared to wt mice. In parallel to the decreased clinical severity, lower anti-CCP antibody concentrations and lower IL-17 concentrations were found in the TLR4 deficient mice. The study further supports the role of TLR4 in the propagation of joint inflammation and destruction. Moreover, since deficiency in TLR4 led to decreased IL-17 and anti-CCP antibody production, the results indicate a link between TLR4 stimulation and the adaptive autoimmune response. This mechanism might be relevant in human rheumatoid arthritis, possibly in response to activating endogenous ligands in the affected joints

Ecological ReGional Ocean Model with vertically resolved sediments (ERGOM SED 1.0): coupling benthic and pelagic biogeochemistry of the south-western Baltic Sea

Sediments play an important role in organic matter mineralisation and nutrient recycling, especially in shallow marine systems. Marine ecosystem models, however, often only include a coarse representation of processes beneath the sea floor. While these parameterisations may give a reasonable description of the present ecosystem state, they lack predictive capacity for possible future changes, which can only be obtained from mechanistic modelling. This paper describes an integrated benthic–pelagic ecosystem model developed for the German Exclusive Economic Zone (EEZ) in the western Baltic Sea. The model is a hybrid of two existing models: the pelagic part of the marine ecosystem model ERGOM and an early diagenetic model by Reed et al. (2011). The latter one was extended to include the carbon cycle, a determination of precipitation and dissolution reactions which accounts for salinity differences, an explicit description of the adsorption of clay minerals, and an alternative pyrite formation pathway. We present a one-dimensional application of the model to seven sites with different sediment types. The model was calibrated with observed pore water profiles and validated with results of sediment composition, bioturbation rates and bentho-pelagic fluxes gathered by in situ incubations of sediments (benthic chambers). The model results generally give a reasonable fit to the observations, even if some deviations are observed, e.g. an overestimation of sulfide concentrations in the sandy sediments. We therefore consider it a good first step towards a three-dimensional representation of sedimentary processes in coupled pelagic–benthic ecosystem models of the Baltic Sea.</p