The immunology and ecology of co‐infection

It's a wormy world. All natural vertebrate populations are subject to infection and re‐infection with helminth parasites (Stoll 1947). Even in humans, around one billion people in developing nations are infected by one or several of a range of helminth parasites (Lustigman et al. 2012). Infection by worms is therefore the norm and is reflected in vertebrate immune responses. Thus, there is probably little point in generating an inflammatory response to clear every last worm, with ensuing collateral damage to our own tissue, when rapid re‐infection from the environment by another worm is pretty much assured. Instead, the vertebrate immune system modifies its response to worms, controlling (but not always clearing) these infections and at the same time limiting damage to host tissue caused by inflammatory immune responses (Jackson et al. 2009). The immune system, however, has to fight battles on several fronts and, while fighting a prolonged war of attrition against helminth parasites, it also has to protect against periodic invasion by bacteria, where a rapid response to kill invading microbes before they spread is essential (Fig.  1 ). In this issue of Molecular Ecology, Friberg et al. (2013) ask what effect worm infections have on a host's ability to mount antimicrobial responses.

Figure 1 Open in figure viewer PowerPoint Helminths generally produce chronic infections that elicit immune responses characterized by both the activation of T helper type 2 (Th2) cells and the production of regulatory responses, such as the cytokines transforming growth factor beta (TGF‐β) and interleukin‐10 (IL‐10) and regulatory T helper cells (T_REG). In combination, this immunological phenotype is often called a ‘modified’ Th2 response. Bacterial infections are recognized by pattern recognition receptors such as the Toll‐like receptors (TLRs) that are able to detect bacterial molecules such as lipopolysaccharides (by TLR‐4), flagellins (by TLR‐5) and unmethylated CpG (by TLR‐9) and generate a rapid inflammatory response [characterized by tumour necrosis factor (TNF)‐α production], particularly at the site of infection. As indicated by the dashed line, these contrasting responses have the potential to interact, especially in animals that spend much of their life harbouring chronic helminth infections that may have systemic anti‐inflammatory effects.

Friberg et al. ( 2013 ) begin their study in laboratory mice, where the immunological reagents exist to make mechanistic insights into helminth/bacterial co‐infections in a controlled environment. They focus on Toll‐like receptors (TLRs), which provide a first line of immune defence by recognizing microbial infection, triggering a rapid inflammatory response at the site of infection and can also help develop subsequent, acquired responses (Medzhitov 2001 ). Infection with the nematode Heligmosomoides polygyrus modified these responses but in a counter‐intuitive fashion. One might expect worm infection to reduce TLR‐mediated responses, consistent with a role of chronic helminth infections in down‐regulating inflammatory responses to limit tissue damage. Instead, TLR‐2, TLR‐4 and TLR‐9‐mediated cytokine responses tended to be elevated in worm infections, including that of tumour necrosis factor (TNF)‐α, which is a potent pro‐inflammatory cytokine. Potential explanations are that helminth infection changes the bacterial community composition of the gut flora or that helminth infection damages the gut wall and forces the host to defend itself against gut bacteria. Examining systemic effects of infection for immune responses within a whole animal (as opposed to cell culture) is challenging because immune responses are dynamic and variable. Having given an infective dose of nematodes, both the number of worms and the immune responses to these worms change through time. Friberg et al. ( 2013 ) also find that the dynamics of TLR‐mediated responses differ somewhat depending on the mouse strain used and on whether worm infections are delivered as a single pulse or split across multiple small doses (a so‐called ‘trickle’ infection), which may be more representation of infection in the field (Paterson et al. 2008 ). Varying the mode of infection and the host genetic background is important because the approach taken by much of the immunological literature is to try to eliminate variation by infecting a single host genotype with a single infective dose, which makes it difficult to generalize immunological results to the field. If examining immune responses in laboratory animals is difficult, what are the prospects for examining immune responses in a natural population? From a mechanistic perspective, the prospects would seem hopeless. The (already complex) dynamics of an immune response through time will be compounded by immunological variation among hosts in their pathogen exposure, age, nutrition and so forth that are found in natural populations. However, from an ecological perspective, quantifying the magnitude of variation in TLR‐mediated responses and identifying associations between immune responses and measurable variables such as macroparasite burden help to define what groups of individuals are most vulnerable to bacterial infection (Pedersen & Babayan 2011 ). Friberg et al. ( 2013 ) therefore performed an immuno‐epidemiological study on a natural population of wood mice (Apodemus sylvaticus) and found significant associations between H. polygyrus and ectoparasites on TLR2‐mediated TNF‐α production. The result, however, is a complex one in that the direction of the effect switched sharply between the 2 years in which the population was sampled. The cause of this switch is unclear, but may reflect qualitatively or quantitatively different pathogen exposures between the 2 years. Certainly, these data highlight that immune responses in the field are context‐dependent, even if the nature of that context remains elusive. Friberg et al.'s ( 2013 ) results, and a small but growing body of similar studies (Abolins et al. 2011 ; Boysen et al. 2011 ; Jackson et al. 2011 ), show both the potential and the difficulty in analysing immunological responses in the natural environment. In an earlier review in Molecular Ecology, Pedersen & Babayan ( 2011 ) make a compelling case to study the ecological context of immune responses in the wild. Ultimately, immune responses should enhance individual fitness, but it is not necessarily clear what constitutes a ‘good’ immune response. In particular, individuals in the wild may not have the luxury of deciding whether to tolerate a chronic worm infection or to clear an acute bacterial infection; the prevalence of co‐infection means that often they have to do both, often under conditions of nutritional stress (Pedersen & Babayan 2011 ). We are now only starting to bridge the gap between laboratory immunology and the ecology of natural populations. The technical barriers are readily apparent, including a lack of immunological reagents for non‐model species and the difficulty of sampling individuals and of measuring pathogen infection. Probably, a greater barrier, however, is linguistic; immunologists and ecologists speak very different languages. There is a steep learning curve for any ecologist trying to pick out what immune parameters they should try to measure in their system and how to interpret these. Equally, immunologists are unused to dealing with variation among individuals as anything other than a nuisance. However, there are great rewards for both ecologists and immunologists in understanding the sources of immunological variation in the field. It is therefore to be hoped that a common language can be developed between laboratory immunology and field ecology and that Molecular Ecology will be at the forefront of bringing these two fields together.

References

• Abolins S , Pocock M , Hafalla J , Riley EM , Viney ME (2011 ) The immune function of wild mice, Mus musculus . Molecular Ecology, 20 , 881 – 892 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Boysen P , Eide DM , Storset AK (2011 ) Natural killer cells in free‐living Mus musculus have a primed phenotype . Molecular Ecology, 20 , 5103 – 5110 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Friberg IM , Little S , Ralli C et al. (2013 ) Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic anti‐microbial pattern recognition responses . Molecular Ecology, 22 , 2810 – 2826 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Jackson JA , Friberg IM , Little S , Bradley JE (2009 ) Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies? Immunology, 126 , 18 – 27 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Jackson JA , Begon M , Birtles R et al. (2011 ) The analysis of immunological profiles in wild animals: a case study on immunodynamics in the field vole, Microtus agrestis . Molecular Ecology, 20 , 893 – 909 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Lustigman S , Prichard RK , Gazzinelli A et al. (2012 ) A research agenda for helminth diseases of humans: the problem of helminthiases . PLoS Neglected Tropical Diseases, 6 , e1582 . Crossref PubMed Web of Science® Google Scholar
• Medzhitov R (2001 ) Toll‐like receptors and innate immunity . Nature Reviews Immunology, 1 , 135 – 145 . Crossref CAS PubMed Web of Science® Google Scholar
• Paterson S , Wilkes C , Bleay C , Viney ME (2008 ) Immunological responses elicited by different infection regimes with Strongyloides ratti . PLoS ONE, 3 , e2509 . Crossref CAS PubMed Web of Science® Google Scholar
• Pedersen AB , Babayan SA (2011 ) Wild immunology . Molecular Ecology, 20 , 872 – 880 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Stoll NR (1947 ) This wormy world . The Journal of Parasitology, 33 , 1 – 18 . Crossref CAS PubMed Google Scholar

S.P. wrote this article. S.P.‘s research focuses on the causes and consequences of genetic diversity in host and parasite populations. He is a director of the Centre for Genomic Research at the University of Liverpool and applies high‐throughput sequencing and gene expression methods to laboratory, domesticated and natural populations of animals and their pathogens.

Citing Literature

Number of times cited according to CrossRef: 1

• M Orsucci, M Navajas, S Fellous, Genotype-specific interactions between parasitic arthropods, Heredity, 10.1038/hdy.2016.90, 118 , 3, (260-265), (2016). Crossref

Volume 22 , Issue 10 May 2013

Pages 2603-2604     

Butterfly genomics sheds light on the process of hybrid speciation

How common is hybridization between species and what effect does it have on the evolutionary process? Can hybridization generate new species and what indeed is a species? In this issue, Gompert et al. (2014) show how massive, genome‐scale data sets can be used to shed light on these questions. They focus on the Lycaeides butterflies, and in particular, several populations from the western USA, which have characteristics suggesting that they may contain hybrids of two or more different species (Gompert et al. 2006). They demonstrate that these populations do contain mosaic genomes made up of components from different parental species. However, this appears to have been largely driven by historical admixture, with more recent processes appearing to be isolating the populations from each other. Therefore, these populations are on their way to becoming distinct species (if they are not already) but have arisen following extensive hybridization between other distinct populations or species (Fig.  1 ).

Figure 1 Open in figure viewer PowerPoint There has been extensive historical admixture between Lycaeides species with some new species arising from hybrid populations. (Photo credits: Lauren Lucas, Chris Nice, and James Fordyce).

Their data set must be one of the largest outside of humans, with over one and half thousand butterflies genotyped at over 45 thousand variable nucleotide positions. It is this sheer amount of data that has allowed the researchers to distinguish between historical and more recent evolutionary and demographic processes. This is because it has allowed them to partition the data into common and rare genetic variants and perform separate analyses on these. Common genetic variants are likely to be older while rare variants are more likely to be due to recent mutations. Therefore, by splitting the genetic variation into these components, the researchers were able to show more admixture among common variants, while rare variants showed less admixture and clear separation of the populations. The extensive geographic sampling of individuals, including overlapping distributions of several of the putative species, also allowed the authors to rule out the possibility that the separation of the populations was simply due to geographical distance. The authors have developed a new programme for detecting population structure and admixture, which does the same job as STRUCTURE (Pritchard et al. 2000 ), identifying genetically distinct populations and admixture between these populations, but is designed to be used with next generation sequence data. They use the output of this model for another promising new method to distinguish between contemporary and historical admixtures. They fixed the number of source populations in the model at two and estimated the proportion of each individual's genome coming from these two populations. Therefore, an individual can either be purely population 1, or population 2 or some mixture of the two (they call this value q, the same parameter exists in STRUCTURE). They then compared this to the level of heterozygosity coming from the two source populations in the individual's genome. If an individual is an F1 hybrid of two source populations, then it would have a q of 0.5 and also be heterozygous at all loci that distinguish the parental populations. On the other hand, if it is a member of a stable hybrid lineage, it might also have a q of 0.5 but would not be expected to be heterozygous at these loci, because over time the population would become fixed for one or other of the source population states either by drift or selection (Fig.  2 ). This is indeed what they find in the hybrid populations. They tend to have intermediate q values, but the level of heterozygosity coming from the source populations (which they call Q₁₂) was consistently lower than expected.

Figure 2 Open in figure viewer PowerPoint The Q‐matrix analysis used by Gompert et al. ( 2014 ) to distinguish between contemporary (hybrid swarm) and historical (stable hybrid lineage) admixture.

Overall, the results support several of the populations as being stable hybrid lineages. Nevertheless, the strictest definitions of hybrid species specify that the process of hybridization between the parental species must be instrumental in driving the reproductive isolation of the new species from both parental populations (Abbott et al. 2013 ). This is extremely hard to demonstrate conclusively because it requires us to first of all identify the isolating mechanisms that operated in the early evolution of the species and then to show that these were caused by the hybridization event itself. One advantage of the Lycaeides system is that the species appear to be in the early stages of divergence, so barriers to gene flow that are operating currently are likely to be those that are driving the species divergence. While there is some evidence that hybridization gave rise to traits that allowed the new populations to colonize new environments (Gompert et al. 2006 ; Lucas et al. 2008 ), there is clearly further work to be carried out in this direction. One of the rare examples of homoploid hybrid speciation (hybrid speciation without a change in chromosome number) where the reproductive isolation criterion has been demonstrated, comes from the Heliconius butterflies. In this case, hybridization of two species has been shown to give rise to a new colour pattern that instantly becomes reproductively isolated from the parental species due to mate preference for that pattern (Mavárez et al. 2006 ). However, while this has become a widely accepted example (Abbott et al. 2013 ), the naturally occurring ‘hybrid species’ in fact has derived most of its genome from one of the parental species, with largely just the colour pattern controlling locus coming from the other parent, a process that has been termed ‘hybrid trait speciation’ (Salazar et al. 2010 ). This distinction is an important one in terms of our understanding of the organization of biological diversity. While hybrid trait speciation will still largely fit the model of a neatly branching evolutionary tree, with perhaps only the region surrounding the single introgressed gene deviating from this model, hybrid species that end up with mosaic genomes, like Lycaeides, will not fit this model when considering the genome as a whole. This distinction also more broadly applies when comparing the patterns of divergence between Heliconius and Lycaeides. These two butterfly genera have been driving forward our understanding of the prevalence and importance of hybridization at the genomic level, but they reveal different ways in which hybridization can influence the organization of biological diversity. Recent work in Heliconius has shown that admixture is extensive and has been ongoing over a large portion of the evolutionary history of species (Martin et al. 2013 ; Nadeau et al. 2013 ). Nevertheless, this has not obscured the clear and robust pattern of a bifurcating evolutionary tree when considering the genome as a whole (Nadeau et al. 2013 ). In contrast in Lycaeides, the genome‐wide phylogeny clearly does not fit a bifurcating tree, resembling more of a messy shrub, with hybrid taxa falling at intermediate positions on the phylogeny (Gompert et al. 2014 ). The extent to which we need to rethink the way we describe and organize biological diversity will depend on the relative prevalence of these different outcomes of hybridization. We are likely to see many more of these types of large sequence data sets for ecologically interesting organisms. Gompert et al. ( 2014 ) show that these data need not only be a quantitative advance, but can also qualitatively change our understanding of the evolutionary history of these organisms. In particular, analysing common and rare genetic variants separately may provide information that would otherwise be missed. The emerging field of ‘speciation genomics’ (Seehausen et al. 2014 ) should follow this lead in developing new ways of making the most of the flood of genomic data that is being generated, but also improve methods for integrating this with field observations and experiments to identify the sources and targets of selection and divergence.

References

• Abbott R , Albach D , Ansell S et al. (2013 ) Hybridization and speciation . Journal of Evolutionary Biology, 26 , 229 – 246 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Gompert Z , Fordyce JA , Forister ML , Shapiro AM , Nice CC (2006 ) Homoploid hybrid speciation in an extreme habitat . Science, 314 , 1923 – 1925 . Crossref CAS PubMed Web of Science® Google Scholar
• Gompert Z , Lucas LK , Buerkle CA et al. (2014 ) Admixture and the organization of genetic diversity in a butterfly species complex revealed through common and rare genetic variants . Molecular Ecology, 23 , 4555 – 4573 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Lucas LK , Fordyce JA , Nice CC (2008 ) Patterns of genitalic morphology around suture zones in North American Lycaeides (Lepidoptera: Lycaenidae): implications for taxonomy and historical biogeography . Annals of the Entomological Society of America, 101 , 172 – 180 . Crossref Web of Science® Google Scholar
• Martin SH , Dasmahapatra KK , Nadeau NJ et al. (2013 ) Genome‐wide evidence for speciation with gene flow in Heliconius butterflies . Genome Research, 23 , 1817 – 1828 . Crossref CAS PubMed Web of Science® Google Scholar
• Mavárez J , Salazar CA , Bermingham E et al. (2006 ) Speciation by hybridization in Heliconius butterflies . Nature, 441 , 868 – 871 . Crossref CAS PubMed Web of Science® Google Scholar
• Nadeau NJ , Martin SH , Kozak KM et al. (2013 ) Genome‐wide patterns of divergence and gene flow across a butterfly radiation . Molecular Ecology, 22 , 814 – 826 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Pritchard JK , Stephens M , Donnelly P (2000 ) Inference of population structure using multilocus genotype data . Genetics, 155 , 945 – 959 . Wiley Online Library CAS PubMed Web of Science® Google Scholar
• Salazar C , Baxter SW , Pardo‐Diaz C et al. (2010 ) Genetic evidence for hybrid trait speciation in Heliconius butterflies . PLoS Genetics, 6 , e1000930 . Crossref CAS PubMed Web of Science® Google Scholar
• Seehausen O , Butlin RK , Keller I et al. (2014 ) Genomics and the origin of species . Nature Reviews Genetics, 15 , 176 – 192 . Crossref CAS PubMed Web of Science® Google Scholar

This article was written and figures prepared by N.N. except as specified in the text (photo credits).

Citing Literature

Number of times cited according to CrossRef: 4

• V. Alex Sotola, David S. Ruppel, Timothy H. Bonner, Chris C. Nice, Noland H. Martin, Asymmetric introgression between fishes in the Red River basin of Texas is associated with variation in water quality, Ecology and Evolution, 10.1002/ece3.4901, 9 , 4, (2083-2095), (2019). Wiley Online Library
• Matej Bocek, Dominik Kusy, Michal Motyka, Ladislav Bocak, Persistence of multiple patterns and intraspecific polymorphism in multi-species Müllerian communities of net-winged beetles, Frontiers in Zoology, 10.1186/s12983-019-0335-8, 16 , 1, (2019). Crossref
• Nicola J. Nadeau, Takeshi Kawakami, Population Genomics of Speciation and Admixture, , 10.1007/13836_2018_24, (2018). Crossref
• Amanda Roe, Julian Dupuis, Felix Sperling, Molecular Dimensions of Insect Taxonomy in the Genomics Era, Insect Biodiversity, 10.1002/9781118945568, (547-573), (2017). Wiley Online Library

Volume 23 , Issue 18 September 2014

Pages 4441-4443     

Current developments in stepwise edman degradation of peptides and proteins

• 1.1. Since Edman's (1950, 1956) first publications about 30 years ago, the stepwise degradation of proteins and peptides is universally performed by protein chemists. We review the mechanism of the chemical reactions, and the different special problems encountered, during degradation and different manual methods of degradation.
• 2.2. We take one example of an alternative method using DABITC manually for the degradation of peptides in order to illustrate the evolution of manual degradation techniques (Chang, 1983).
• 3.3. Possibilities and limits of the liquid phase sequenator of Edman and Begg (1967), solid phase sequencer of Laursen (1975) and gas-liquid sequenator of Hewick et al. (1981) and those of Hunkapiller et al. (1983) are considered in detail.
• 4.4. We describe different procedures for identification of PTH-AA or DABTH-AA: thin layer chromatography, gas chromatography, high performance liquid chromatography, etc., in order to illustrate the evolution of the procedures of identification.
• 5.5. We conclude by taking two manual examples and two automatic procedures of degradation to underline the progress over the last decade.

     

Introducing quality measures in an academic research consortium: Lessons and recommendation from implementing an ad hoc quality management system for organ model research

Lessons from implementing quality control systems in an academic research consortium to improve Good Scientific Practice and reproducibility. Subject Categories: Microbiology, Virology & Host Pathogen Interaction, Science Policy & Publishing

Low reproducibility rates within biomedical research negatively impact productivity and translation. One promising approach to enhance the transfer of robust results from preclinical research into clinically relevant and transferable data is the systematic implementation of quality measures in daily laboratory routines.

Although many universities expect their scientists to adhere to GSPs, they often neither systematically support, nor monitor the quality of their research activities.

Today''s fast‐evolving research environment needs effective quality measures to ensure reproducibility and data integrity (Macleod et al, ²⁰¹⁴; Begley et al, ²⁰¹⁵; Begley & Ioannidis, ²⁰¹⁵; Baker, ²⁰¹⁶). Academic research institutions and laboratories may be as committed to good scientific practices (GSPs) as their counterparts in the biotech and pharmaceutical industry but operate largely without clearly defined standards (Bespalov et al, ²⁰²¹; Emmerich et al, ²⁰²¹). Although many universities expect their scientists to adhere to GSPs, they often neither systematically support, nor monitor the quality of their research activities. Peer review of publications is still regarded as the primary validation of quality control in academic research. However, reviewers only assess work after it has been performed—often over years—and interventions in the experimental process are thus no longer possible.The reasons for the lack of dedicated quality management (QM) implementations in academic laboratories include an anticipated overload of regulatory tasks that could negatively affect productivity, concerns about the loss of scientific freedom, and importantly, limited resources in academia and academic funding schemes.     

Ciliary/decarboxylase activities as indicators of PTZ,photoperiod and Ca-ionophore effect on Crassostrea virginica (gmelin)

• 1.1. Lateral ciliary activity and DOPA decarboxylase were measured in the ctenidium of Crassostrea virginica (Gmelin).
• 2.2. Activity of the lateral cilia is dependent upon branchial nerve (Paparo, 1985a,b) and on intracellular calcium homostasis (Baker, 1963; Rassmussen, 1970, 1971; Romero and Wittman, 1971; Blanstein et al., 1978).
• 3.3. PTZ induced lamella morphogenesis in eytosomes with subsequent release of calcium into the cytosol. This cilio-inhibition was enhanced in the presence of additional calcium in the perfusate.
• 4.4. Prolonged exposure to light also induces fully converted membranous eytosomes with subsequent production of a gradual lateral cilio-inhibition. Darkness produces the opposite effect, in that secondary membranous conversions of cytosomes are inhibited.
• 5.5. In the presence of A-23187 (a calcium releasing agent), inhibition of lateral activity is produced, independent of cytosomal conversion.
• 6.6. It is postulated that photic electrical and chemical stimulation of neuronal chromoproteins can lead to release of calcium from sequestered cytosomal stores which triggers a neuro-exocytosis of a neuroinhibitory transmitter, dopamine.

     

The breakthrough paradox: How focusing on one form of innovation jeopardizes the advancement of science

Research needs a balance of risk‐taking in “breakthrough projects” and gradual progress. For building a sustainable knowledge base, it is indispensable to provide support for both. Subject Categories: Careers, Economics, Law & Politics, Science Policy & Publishing

Science is about venturing into the unknown to find unexpected insights and establish new knowledge. Increasingly, academic institutions and funding agencies such as the European Research Council (ERC) explicitly encourage and support scientists to foster risky and hopefully ground‐breaking research. Such incentives are important and have been greatly appreciated by the scientific community. However, the success of the ERC has had its downsides, as other actors in the funding ecosystem have adopted the ERC’s focus on “breakthrough science” and respective notions of scientific excellence. We argue that these tendencies are concerning since disruptive breakthrough innovation is not the only form of innovation in research. While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science. This is problematic since, paradoxically, breakthrough potential in science builds on gradual innovation. If the value of gradual innovation is not better recognized, the potential for breakthrough innovation may well be stifled.

While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science.

Concerns that the hypercompetitive dynamics of the current scientific system may impede rather than spur innovative research have been voiced for many years (Alberts et al, 2014). As performance indicators continue to play a central role for promotions and grants, researchers are under pressure to publish extensively, quickly, and preferably in high‐ranking journals (Burrows, 2012). These dynamics increase the risk of mental health issues among scientists (Jaremka et al, 2020), dis‐incentivise relevant and important work (Benedictus et al, 2016), decrease the quality of scientific papers (Sarewitz, 2016) and induce conservative and short‐term thinking rather than risk‐taking and original thinking required for scientific innovation (Alberts et al, 2014; Fochler et al, 2016). Against this background, strong incentives for fostering innovative and daring research are indispensable.     

Preparation and characterization of biotinylated probes for the β-interferon receptor

• 1.1. Recently we described the isolation of the β-interferon receptor [Zhang et al. (1986) J. biol. Chem. 261, 8017–8021]. A highly purified product was obtained but in low quantities.
• 2.2. The use ofbiotinylated β-interferon as a ligand represents an alternate approach to receptor isolation.
• 3.3. We have prepared and characterized the derivatives N-(biotinyl)- and N-(biotinyl-ϵ-aminocaproyl)-recombinant human [Ser¹⁷-interferon β (B- and BC-recHulFNβ).
• 4.4. Biotin incorporation does not result in any loss of antiviral activity, demonstrating the recognition of the derivative by the cell receptor.
• 5.5. The biotinylated recHuIFNβ binds specifically and reversibly to succinoylavidin or guanidine thiocyanate-stripped succinoylavidin linked to a Sepharose matrix.
• 6.6. Comparison of the competition curves obtained with [¹⁴C]biotin and [³H]biotinyl recHuIFN, in the presence of increasing concentrations of biotin suggests that the IFN moiety of the derivative has little effect on the affinity of biotin for avidin.
• 7.7. Biotinylated recHuIFNβ derivatives represent useful probes for the β-IFN receptor.

     

Facilitating open science without sacrificing IP rights: A novel tool for improving replicability of published research

Conditional Access Agreements could improve replicability of research and enhance Open Science without jeopardizing intellectual property rights. Subject Categories: Economics, Law & Politics, Science Policy & Publishing

Replicability is a cornerstone of the scientific enterprise. Validating published scientific findings enhances their credibility and helps to build a self‐correcting cumulative knowledge base. It also increases public trust in science (Wingen et al  ²⁰²⁰). Unfortunately, the scientific community has been facing a considerable problem for at least two decades: the replication crisis (Ioannidis, ²⁰⁰⁵). Scientists in various disciplines have significant difficulties trying to verify published scientific findings (Baker, ²⁰¹⁶). One prominent factor accounting for non‐replicability is diminished access to research materials required for replication (replication materials).

Scientists in various disciplines have significant difficulties trying to verify published scientific findings.

This problem is particularly noticeable in computational studies: research that utilizes computational models, often with an immense amount of data. With the rise of powerful computers, machine learning and big data, computational studies are increasingly used in a variety of disciplines. This trend is evident in biology as well, including in systems biology, genomics, proteomics, and other areas (Markowetz, ²⁰¹⁷). A famous example that demonstrates the importance of computational biology is the Human Genome Project. Developments in computational biology are crucial in advancing promising research prospects in areas such as vaccine antigen design and structural bioinformatics.

The problem of diminished access to replication materials has been reported as a major stumbling block impeding the replicability of computational biology studies.

A scientific paper alone would not typically enable others to replicate the study described therein (Merali, ²⁰¹⁰). Replicating a computational study generally requires access to the code, software documentation, datasets, workflows, and other information regarding the methodology (Easterbrook, ²⁰¹⁴). In most cases, however, authors do not publicly share these elements, which renders such studies impossible to replicate (Merali, ²⁰¹⁰; Stodden et al, ²⁰¹⁸). The problem of diminished access to replication materials has been reported as a major stumbling block impeding the replicability of computational biology studies (Crook et al, ²⁰¹³; Miłkowski et al, ²⁰¹⁸).     

Stress-induced Changes in the S-palmitoylation and S-nitrosylation of Synaptic Proteins,

1. Download : Download high-res image (66KB)
2. Download : Download full-size image

Highlights

• •Using mass spectrometry-based proteomic approach, PANIMoni, we analyzed endogenous S-nitrosylation and S-palmitoylation of postsynaptic density proteins in mouse models of chronic stress.
• •We provided differential analysis of S-palmitoylation and S-nitrosylation at the level of exact sites of modifications.
• •We show that affected mechanism of S-palmitoylation and S-nitrosylation interplay of proteins involved in synaptic transmission, protein localization and regulation of synaptic plasticity is associated with chronic stress disorder.

     

Company news

• Daon
• Musicrypt
• EMI Music Canada
• Digital Broadband Networks
• FaceKey Corporation
• Eystar Media Inc (EMI)
• Temasya Wira
• Animated Electronic Industries
• BIO-key International
• Entryport Corporation

     

Alkylating spin labels for spin-labelling of DNA

• 1.1. Five alkylating spin labels, termed SL1, SL2, SL3, SL4 and SL5, have been synthesized and their suitability for spin-labelling of DNA was studied.
• 2.2. It was found that one of them (SL5) lost its free radical moiety under the conditions of spin-labelling, thus giving DNA with no EPR signal.
• 3.3. Two of the spin labels (SL2 and SL4) denatured DNA and therefore they were not appropriate for spin-labelling of double stranded DNA.
• 4.4. The spin labels SL1 and SL3 as well as the recently synthesi/ed HMSL [Raikova et al. (1982) Int. J. Biochem. 14, 41–46.] showed a low destabilizing effect on the DNA double helix and gave spin-labelled DNA with very immobilized EPR spectra (2Azz = 40G).
• 5.5. These three spin labels could be recommended as suitable for application in the EPR spectrometry of DNA.

     

Morphology and electrophysiological characteristics of caudodorsal cells of Lymnaea stagnalis in dissociated cell culture

• 1.1. The neuroendocrine caudodorsal cells (CDCs) of Lymnaea stagnalis are a network of about 100 electrotonically coupled neurones. The CDCs release multiple peptides, including an ovulation hormone, during a period of electrical activity, the CDC-discharge.
• 2.2. In isolated brains, a similar period of electrical activity (the afterdischarge) can be induced in all CDCs by a period of intracellular repetitive suprathreshold stimulation of one CDC.
• 3.3. In order to study the regulation of this electrical behaviour in the absence of electrical interactions and in a controlled environment, experiments were performed on CDCs in dissociated cell culture.
• 4.4. Methods for isolation and cell culture are described. Cell cultures had long-term viability and outgrowth of neurities occurred under serum-free conditions.
• 5.5. CDCs in cell culture maintained their capability of producing afterdischarges upon electrical stimulation. Cells in culture appeared more excitable than cells in the intact isolated brain.
• 6.6. The characteristic responses of CDCs in intact isolated brains to acetylcholine and FMRFamide were preserved in cultured CDCs. Both agents induced a transient hyperpolarization of the membrane, inexcitability and inhibition of an ongoing discharge.
• 7.7. In experiments where isolated CDCs were closely apposed, but physically separate, it was found that an afterdischarge in one CDC could induce a discharge in the other CDC.
• 8.8. These results confirm previous results which showed that an excitatory factor is released from the brain during the afterdischarge (Ter Maat et al., 1988, Brain Res., 43, 77–82), and demonstrate that this excitatory factor is released from the CDCs themselves.

     

Soluble cyclic amp-dependent protein kinases from chick liver: Effects of NaCl and heat-stable modulator

• 1.1. Two cyclic AMP-dependent protein kinases—Fraction I and II—have been isolated from chick liver soluble preparation on DEAE-cellulose.
• 2.2. Both fractions have an apparent K_m for ATP of 2 × 10⁻⁶M, are stimulated maximally by 5 × 10⁻⁸ M cyclic AMP and phosphorylate mainly basic proteins—histone and protamine.
• 3.3. They exhibit various pH values for optimal activity and show differences with respect to both sensitivity to NaCl and substrate specificity.
• 4.4. The heat-stable protein modulator inhibits the cyclic AMP-dependent protein kinase activity of both fractions, but with cyclic GMP one kinase is stimulated and the other inhibited.
• 5.5. Slight differences in histone triggered holoenzyme dissociation as well as the lack of difference between their ability for subunit reassociation do not allow to classify these isozymes as protein kinases of Type I and II, according to Corbin et al. (1975).

     

Company news

Including information on:

• ScanSoft
• SpeechWorks International
• Viisage Technology
• Firstec
• BIO-key International
• HP
• ZN Vision Technologies
• Unisys
• US Government’s
• Communication Intelligence Corporation
• Infinity Technologies

     

Cost and availability of novel cell and gene therapies: Can we avoid a catastrophic second valley of death?

Advanced gene and cellular therapies risk a second “valley of death” due to their high costs and low patient population. As these are life‐saving therapies, measures are urgently needed to prevent their withdrawal from the market. Subject Categories: Economics, Law & Politics, Genetics, Gene Therapy & Genetic Disease, Pharmacology & Drug Discovery

During the past years, several advanced gene and cell therapies to target rare genetic diseases have demonstrated long‐lasting efficacy: essentially “curing” severe and previously incurable diseases and returning patients to a normal life. These therapies are classified as advanced therapy medicinal products (ATMPs); a few of these have received marketing authorization in Europe and the USA, and more will conceivably follow in the near future (De Luca et al, ²⁰¹⁹). Their success represents a milestone in medicine that 1 day might be compared with the discovery of antibiotics or the development of vaccines.

… once a therapy is successfully out of this first, biomedical “valley of death” and approved for use, it frequently encounters a second, economic “valley of death” that prevents its use in patients.

As “advanced” implies, the development of these therapies from the research laboratory to clinical trials is a long and very expensive ordeal. Bringing an ATMP to the market takes years, often decades, and still has a high failure rate (Cossu et al, ²⁰¹⁸). However, once a therapy is successfully out of this first, biomedical “valley of death” and approved for use, it frequently encounters a second, economic “valley of death” that prevents its use in patients. This problem needs a solution for medical, ethical and economic reasons; readers are also refereed to recent articles dealing with the same problem for haematopoietic diseases (Aiuti et al, ²⁰²²; Halley et al, ²⁰²²) or genodermatoses (Palamenghi et al, ²⁰²²).     

Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT

In “Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT” by Lyu et al (2021), the authors depict the inhibitor MMV007839 in its hemiketal form in Fig 3A and F, Fig 4C, and Appendix Figs S10A, B and S13. We note that Golldack et al (2017) reported that the linear vinylogous acid tautomer of MMV007839 constitutes the binding and inhibitory entity of PfFNT. The authors are currently obtaining higher resolution cryo‐EM structural data of MMV007839‐bound PfFNT to ascertain which of the interconvertible isoforms is bound and the paper will be updated accordingly.     

Through an ecological lens: An ecosystem‐based approach to zoonotic risk assessment

Public health strategies to mitigate the emergence of novel pathogenic viruses should implement longitudinal metagenomic surveillance of ecosystems experiencing biodiversity changes to identify generalist viruses. Subject Categories: Evolution & Ecology, Microbiology, Virology & Host Pathogen Interaction

The emergence and pandemic spread of SARS‐CoV‐2 in late 2019 was a humbling reminder that novel infectious diseases continue to thwart our efforts to prevent another global pandemic. There is now strong evidence that SARS‐CoV‐2 is a zoonotic virus that likely spilled over from bats into humans via another mammalian host (Holmes et al, ²⁰²¹). Such zoonoses—pathogens that are able to transmit from animals to humans—are the main source of emerging disease and are estimated to have caused at least 60% of infectious disease outbreaks in humans since the 1940s (Jones et al, ²⁰⁰⁸). Alarmingly, the frequency of zoonotic events is projected to increase owing to climate change and other anthropogenic factors such as humans encroaching onto pristine forests and other ecosystems (Holmes, ^{2022a, 2022b}).