Interferon signatures in immune disorders and disease

The interferon (IFN) family and the type-I IFNs specifically have an important and well-characterized role in antiviral defence, immune modulation and cell-cycle control and are regularly applied in the clinical context. Advances in high-content technologies have facilitated an enhanced understanding of the global IFN response capable of being induced. Recent application of these technologies is improving our understanding of the specificity and subtleties associated with this response. This review considers our current understanding of the temporal gene profile induced through IFN stimulation across a diversity of disease conditions including autoimmune diseases, bacterial and viral infections. Understanding these signatures, the disease-specific differences and the biological effects induced has the potential to facilitate IFN-driven therapeutic development.     

Interferon therapy in neoplastic diseases

Three types of interferon preparation (alpha, beta and gamma) have been used in the treatment of tumours in vivo. At the time of writing no information is available on IFN-gamma treatment of tumour patients. Treatments with IFN-alpha and IFN-beta have been undertaken at many clinical centres. Both types of preparation can exert side effects. Both types have also been able to cause regression of certain tumours in individual patients. At our hospital, IFN-alpha has been given to tumour patients over the last decade. Antitumour effects have been registered on patients with juvenile laryngeal papillomatosis, Hodgkin's disease, myelomatosis, ovarian carcinoma, hypernephroma and glioblastoma. Further study is needed on how therapy with IFN should best be undertaken and also how such treatment compares with other treatments of various tumour diseases. IFN therapy should also be combined with other such treatments.     

Global dinucleotide signatures and analysis of genomic heterogeneity

Early biochemical experiments measuring nearest neighbor frequencies established that the set of dinucleotide relative abundance values (dinucleotide biases) is a remarkably stable property of the DNA of an organism. Analyses of currently available genomic sequence data have extended these earlier results, showing that the dinucleotide biases evaluated for successive 50 kb segments of a genome are significantly more similar to each other than to those of sequences from more distant organisms. From this perspective, the set of dinucleotide biases constitutes a 'genomic signature' that can discriminate sequences from different organisms. The dinucleotide biases appear to reflect species-specific properties of DNA stacking energies, modification, replication, and repair mechanisms. The genomic signature is useful for detecting pathogenicity islands in bacterial genomes.     

Large-scale climatic signatures in lakes across Europe: a meta-analysis

Recent studies have highlighted the impact of the winter North Atlantic Oscillation (NAO) on water temperature, ice conditions, and spring plankton phenology in specific lakes and regions in Europe. Here, we use meta-analysis techniques to test whether 18 lakes in northern, western, and central Europe respond coherently to winter climate forcing, and to assess the persistence of the winter climate signal in physical, chemical, and biological variables during the year. A meta-analysis approach was chosen because we wished to emphasize the overall coherence pattern rather than individual lake responses. A particular strength of our approach is that time-series from each of the 18 lakes were subjected to the same robust statistical analysis covering the same 23-year period. Although the strongest overall coherence in response to the winter NAO was exhibited by lake water temperatures, a strong, coherent response was also exhibited by concentrations of soluble reactive phosphorus and soluble reactive silicate, most likely as a result of the coherent response exhibited by the spring phytoplankton bloom. Lake nitrate concentrations showed significant coherence in winter. With the exception of the cyanobacterial biomass in summer, phytoplankton biomass in all seasons was unrelated to the winter NAO. A strong coherence in the abundance of daphnids during spring can most likely be attributed to coherence in daphnid phenology. A strong coherence in the summer abundance of the cyclopoid copepods may have been related to a coherent change in their emergence from resting stages. We discuss the complex nature of the potential mechanisms that drive the observed changes.     

Characterization of heterogeneity in nanodisc samples using Feret signatures

Nanodiscs have become a popular tool in structure determination of membrane proteins using cryogenic electron microscopy and single particle analysis. However, the structure determination of small membrane proteins remains challenging. When the embedded protein is in the same size range as the nanodisc, the nanodisc can significantly contribute to the alignment and classification during the structure determination process. In those cases, it is crucial to minimize the heterogeneity in the nanodisc preparations to assure maximum accuracy in the classification and alignment steps of single particle analysis. Here, we introduce a new in-silico method for the characterization of nanodisc samples that is based on analyzing the Feret diameter distribution of their particle projection as imaged in the electron microscope. We validated the method with comprehensive simulation studies and show that Feret signatures can detect subtle differences in nanodisc morphologies and composition that might otherwise go unnoticed. We used the method to identify a specific biochemical nanodisc preparation with low size variations, allowing us to obtain a structure of the 23-kDa single-span membrane protein Bcl-xL while embedded in a nanodisc. Feret signature analysis can steer experimental data collection strategies, allowing more efficient use of high-end data collection hardware, as well as image analysis investments in studies where nanodiscs significantly contribute to the total volume of the full molecular species.     

Disease signatures are robust across tissues and experiments

Meta‐analyses combining gene expression microarray experiments offer new insights into the molecular pathophysiology of disease not evident from individual experiments. Although the established technical reproducibility of microarrays serves as a basis for meta‐analysis, pathophysiological reproducibility across experiments is not well established. In this study, we carried out a large‐scale analysis of disease‐associated experiments obtained from NCBI GEO, and evaluated their concordance across a broad range of diseases and tissue types. On evaluating 429 experiments, representing 238 diseases and 122 tissues from 8435 microarrays, we find evidence for a general, pathophysiological concordance between experiments measuring the same disease condition. Furthermore, we find that the molecular signature of disease across tissues is overall more prominent than the signature of tissue expression across diseases. The results offer new insight into the quality of public microarray data using pathophysiological metrics, and support new directions in meta‐analysis that include characterization of the commonalities of disease irrespective of tissue, as well as the creation of multi‐tissue systems models of disease pathology using public data.     

Regional specificity of anuran larval skin during metamorphosis: dermal specificity in development and histolysis of recombined skin grafts

Summary Skins from back and tail were dissected from tadpoles of Rana japonica prior to resorption of the tail and separated into epidermis and dermis by treatment with neutral protease. Homotypically and heterotypically recombined skins were constructed from the separated epidermis and dermis and transplanted into the tail of the original tadpole. Skin grafts using dermis from tail region degenerated simultaneously with resorption of the tail. However, skin grafts containing dermis from back region survived on the posterior part of the juvenile frog beyond metamorphosis. Furthermore, all epidermis underlaid with dermis from back region formed secretory glands and became flattened epithelia characteristic of adult back skin, regardless of region from which the epidermis came. Even when epidermis isolated from tail skin was cultured inside a back skin graft, the tail epidermis survived forming an epithelial cyst and developed secretory glands. These results suggest that regional specificities of anuran larval skin, i.e., development of back skin and even histolysis of tail skin, are determined by regionally specific dermis. The results also suggest that some of epidermal cells of tail skin are able to differentiate into epithelial cells similar to back skin of the adult under the influence of back dermis.     

Interferon antibodies in patients with infectious diseases

Interferons (IFNs) are generally recognized as the most important therapeutic agent in some infectious diseases such as chronic hepatitis B and C. Since the early clinical trials it was documented that the therapeutic use of IFNs could be complicated by the development of antibodies able to neutralize or to bind to the IFN molecule. After several years of research it is now widely accepted that the presence of circulating anti-IFN antibodies may affect the response to IFN. Here we summarize what is currently know on the clinical significance of antibodies to IFN in IFN-treated viral diseases patients.     

Geographic signatures in species turnover: decoupling colonization and extinction across a latitudinal gradient

High latitude communities have low species richness and are rapidly warming with climate change. Thus, temporal changes in community composition are expected to be greatest at high latitudes. However, at the same time traits such as body size can also change with latitude, potentially offsetting or increasing changes to community composition over time. We tested how zooplankton communities (copepods and cladocerans) have changed over a 25–75 year time span by assessing colonization and extinction rates from lakes across an 1800 km latitudinal gradient, and further tested whether species traits predict rates of community change over time. Lake‐level dissimilarity, measured with Sorenson distance, decreased at higher latitudes. This decrease was due to higher colonization rates of cladocerans in lower latitude lakes and consistent extinction rates across the latitudinal gradient. At the species level, colonization increased with regional occupancy, and tended to be higher for smaller bodied, locally abundant, species. Local extinction rates were negatively correlated with local abundance and regional occupancy, but were not influenced by body size. None of these species‐specific characteristics changed predictably with latitude. Contrary to our expectations, low‐latitude zooplankton communities changed more rapidly than high‐latitude communities by becoming more species rich, not by losing species that were historically present. Moreover, colonization and extinction trends suggest that lakes have become increasingly dominated by species with smaller body sizes and that are already common locally and regionally. Together, these findings indicate that rates of species turnover in freshwater lakes across a latitudinal gradient are not predicted by rates of temperature change, but that turnover is nonetheless resulting in trait‐shifts that favour small, generalist species.     

The heterogeneity and acceptor specificity of human serum galactosyltransferase

Human serum was fractionated by high resolution agarose isoelectricfocusing and the galactosyltransferase activity profile was determined using the ovalbumin, mucin, glucose and N-acetylglucosamine acceptor assays. The four acceptors gave very similar activity profiles. There were minor quantitative differences in some of the 12 or more peaks of activity detected and the only qualitative difference between them was a minor peak at pH 3.90 (2% of the total activity) which reacted only with the mucin acceptor. This suggests that most of the isoenzymes of human serum galactosyltransferase have broad and similar acceptor specificities and that the heterogeneity seen in serum cannot be accounted for by acceptor-specific forms of the enzyme.     

Nucleotide specificity versus complex heterogeneity in exonuclease activity measurements

A recent publication reported on measurements of Exonuclease I activity using a real-time fluorescence method that measures the time required by molecules of Exonuclease I to hydrolyze single-stranded DNA that was synthesized to have two fluorescently labeled nucleotides. The observed fluorescence-intensity curves were interpreted as a sign of strong heterogeneity of the activity of Exonuclease I. Here, I propose a different model, which assumes that Exonuclease I activity is nucleotide-dependent, and that a fluorescent label bound to a nucleotide significantly slows its cleavage rate. The presented model fits the observed data equally well, but can be used to make specific predictions upon observable sequence dependence of measured fluorescence-intensity curves.     

scDART-seq reveals distinct m6A signatures and mRNA methylation heterogeneity in single cells

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Interferon therapy of infectious diseases: the state of the problem and prospects

The data contained in literature and obtained in our own investigations, aimed at the evaluation of the significance of interferon preparations for the correction of immunological disturbances are presented. A special place is given to the role of mild medicinal forms of interferon, the necessity of their use is grounded and good prospects for their inclusion into the complex therapy of infectious diseases are shown.