A biogeochemical framework for metal detoxification in sulfidic systems

We develop a comprehensive biogeochemical framework for understanding and quantitatively evaluating metals bio-protection in sulfidic microbial systems. We implement the biogeochemical framework in CCBATCH by expanding its chemical equilibrium and biological sub-models for surface complexation and the formation of soluble and solid products, respectively. We apply the expanded CCBATCH to understand the relative importance of the various key ligands of sulfidic systems in Zn detoxification. Our biogeochemical analysis emphasizes the relative importance of sulfide over other microbial products in Zn detoxification, because the sulfide yield is an order of magnitude higher than that of other microbial products, while its reactivity toward metals also is highest. In particular, metal-titration simulations using the expanded CCBATCH in a batch mode illustrate how sulfide detoxifies Zn, controlling its speciation as long as total sulfide is greater than added Zn. Only in the absence of sulfide does complexation of Zn to biogenic organic ligands play a role in detoxification. Our biogeochemical analysis conveys fundamental insight on the potential of the key ligands of sulfidic systems to effect Zn detoxification. Sulfide stands out for its reactivity and prevalence in sulfidic systems.     

Integrated network reconstruction,visualization and analysis using YANAsquare

Background  

Modeling of metabolic networks includes tasks such as network assembly, network overview, calculation of metabolic fluxes and testing the robustness of the network.     

Cell migration patterns and ongoing somatic mutations in the progression of follicular lymphoma

Follicular lymphoma (FL) constitutes the neoplastic equivalent of germinal center B-cells. Like its physiological counterpart, FL grows in (atypical) follicular structures, the formation of which is as yet poorly understood. Recent data indicate that in early tumour stages, neoplastic FL cells home to and colonise reactive germinal centers. Laser microdissection (LMD) and micromanipulation techniques now allow for the molecular genetic analysis of single cell mutation patterns in FL. The purpose of the present study was the analysis of the sequence and order of somatic mutations in FL, i.e. the influence of the germinal center microenvironment on the clonal evolution in different grades of FL. By generating phylogenetic trees as calculated from tumour cell sequences, the clonal evolution from a putative progenitor cell was elucidated and finally, the tumour cell migration pattern in disease progression was assessed by analyzing biopsies at different time points in relapsed tumours. Four patients suffering from FL were included in the study. A primary FL grade 1 showed clustering of genetically related subclones in distinct follicles. A moderate interfollicular exchange of tumour cells was detected. Three cases of FL grade 2 were found to show decreased subclonal clustering in follicles and an increase in the interfollicular migration. Accumulations of replacement mutations in antigen binding domains (CDR) and silent mutations in non-antigen binding domains (FR), respectively, indicating antigen influence on hypermutation were only found in the case of FL grade 1. Our conclusion is that the microenvironment in germinal centers exercises influence on clonal evolution and tumour cell distribution patterns in FL. With increasing histologic grade during disease progression, a reduced intraclonal diversity and selection of subclones also occurs outside the setting of transformation to high-grade lymphoma. Antigen-dependent hypermutations were only seen in FL grade 1, while in progressed FL, random mutation patterns and a decrease of clonal diversity were found.     

Evolution of sociality by natural selection on variances in reproductive fitness: evidence from a social bee

Background  

The Central Limit Theorem (CLT) is a statistical principle that states that as the number of repeated samples from any population increase, the variance among sample means will decrease and means will become more normally distributed. It has been conjectured that the CLT has the potential to provide benefits for group living in some animals via greater predictability in food acquisition, if the number of foraging bouts increases with group size. The potential existence of benefits for group living derived from a purely statistical principle is highly intriguing and it has implications for the origins of sociality.     

Differences in binding behavior of (−)‐epigallocatechin gallate to β‐lactoglobulin heterodimers (AB) compared to homodimers (A) and (B)

The lipocalin β‐lactoglobulin (β‐LG) exists in different natural genetic variants—of which β‐LG A and B are predominant in bovine milk. At physiological conditions the protein dimerizes—building homodimers of β‐LG A and β‐LG B and heterodimers of β‐LG AB. Although β‐LG is one of the most intensely characterized lipocalins, the interaction behavior of ligands with hetero‐ and homodimers of β‐LG is largely unknown. The present findings revealed significant differences for hetero‐ and homodimers regarding ligand binding capacity as tested with a model ligand (i.e. surface binding (?)‐epigallocatechin gallate (EGCG)). These findings were confirmed using FT‐IR, where the addition of EGCG influenced the β‐sheet backbone of homodimer A and B with significantly higher intensity compared to heterodimer AB. Further, shape analysis by SAXS revealed oligomerization of both types of dimers upon addition of EGCG; however, homodimer A and B produced significantly larger aggregates compared to the heterodimer AB. In summary, the present study revealed that EGCG showed significantly different interaction reactivity (binding sites, aggregation size and conformational changes) to the hetero and homodimers of β‐LG in the order β‐LG A > B > AB. The results suggest that conformational differences between homodimers and heterodimers strongly influence the EGCG binding ability. This may also occur with other polyphenols and ligands of β‐LG and gives not only important information for β‐LG binding studies, but may also apply for polymorphisms of other self‐aggregating lipocalins. Copyright © 2015 John Wiley & Sons, Ltd.     

Contributions of Unique Intracellular Domains to Switchlike Biosensing by Toll-like Receptor 4

Toll-like receptors (TLRs) mediate immune recognition of both microbial infections and tissue damage. Aberrant TLR signaling promotes disease; thus, understanding the regulation of TLR signaling is of medical relevance. Although downstream mediators of TLR signaling have been identified, the detailed mechanism by which ligand binding-mediated dimerization induces downstream signaling remains poorly understood. Here, we investigate this question for TLR4, which mediates responsiveness to bacterial LPS and drives inflammatory disease. TLR4 exhibits structural and functional features that are unique among TLRs, including responsiveness to a wide variety of ligands. However, the connection between these structural features and the regulation of signaling is not clear. Here, we investigated how the unique intracellular structures of TLR4 contribute to receptor signaling. Key conclusions include the following. 1) The unique intracellular linker of TLR4 is important for achieving LPS-inducible signaling via Toll/IL-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF) but less so for signaling via myeloid differentiation primary response 88 (MyD88). 2) Membrane-bound TLR4 TIR domains were sufficient to induce signaling. However, introducing long, flexible intracellular linkers neither induced constitutive signaling nor ablated LPS-inducible signaling. Thus, the initiation of TLR4 signaling is regulated by a mechanism that does not require tight geometric constraints. Together, these observations necessitate refining the model of TLR4 signal initiation. We hypothesize that TLR4 may interact with an inhibitory partner in the absence of ligand, via both TIR and extracellular domains of TLR4. In this speculative model, ligand binding induces dissociation of the inhibitory partner, triggering spontaneous, switchlike TIR domain homodimerization to initiate downstream signaling.     

To be or not to be planktonic? Self‐inhibition of biofilm development

The transition between planktonic growth and biofilm formation represents a tightly regulated developmental shift that has substantial impact on cell fate. Here, we highlight different mechanisms through which bacteria limit their own biofilm development. The mechanisms involved in these self‐inhibition processes include: (i) regulation by secreted small molecules, which govern intricate signalling cascades that eventually decrease biofilm development, (ii) extracellular polysaccharides capable of modifying the physicochemical properties of the substratum and (iii) extracellular DNA that masks an adhesive structure. These mechanisms, which rely on substances produced by the bacterium and released into the extracellular milieu, suggest regulation at the communal level. In addition, we provide specific examples of environmental cues (e.g. blue light or glucose level) that trigger a cellular response reducing biofilm development. All together, we describe a diverse array of mechanisms underlying self‐inhibition of biofilm development in different bacteria and discuss possible advantages of these processes.