Global contribution of invertebrates to forest litter decomposition.

Forest litter decomposition is an essential component of global carbon and nutrient turnover. Invertebrates play important roles in litter decomposition, but the regional pattern of their effects is poorly understood. We examined 476 case studies across 93 sites and performed a meta-analysis to estimate regional effects of invertebrates on forest litter decomposition. We then assessed how invertebrate diversity, climate and soil pH drive regional variations in invertebrate-mediated decomposition. We found that (1) invertebrate contributions to litter decomposition are 1.4 times higher in tropical and subtropical forests than in forests elsewhere, with an overall contribution of 31% to global forest litter decomposition; and (2) termite diversity, together with warm, humid and acidic environments in the tropics and subtropics are positively associated with forest litter decomposition by invertebrates. Our results demonstrate the significant difference in invertebrate effects on mediating forest litter decomposition among regions. We demonstrate, also, the significance of termites in driving litter mass loss in the tropics and subtropics. These results are particularly pertinent in the tropics and subtropics where climate change and human disturbance threaten invertebrate biodiversity and the ecosystem services it provides.

The diversity of social complexity in termites.

Sociality underpins major evolutionary transitions and significantly influences the structure and function of complex ecosystems. Social insects, seen as the pinnacle of sociality, have traits like obligate sterility that are considered 'master traits', used as single phenotypic measures of this complexity. However, evidence is mounting that completely aligning both phenotypic and evolutionary social complexity, and having obligate sterility central to both, is erroneous. We hypothesize that obligate and functional sterility are insufficient in explaining the diversity of phenotypic social complexity in social insects. To test this, we explore the relative importance of these sterility traits in an understudied but diverse taxon: the termites. We compile the largest termite social complexity dataset to date, using specimen and literature data. We find that although functional and obligate sterility explain a significant proportion of variance, neither trait is an adequate singular proxy for the phenotypic social complexity of termites. Further, we show both traits have only a weak association with the other social complexity traits within termites. These findings have ramifications for our general comprehension of the frameworks of phenotypic and evolutionary social complexity, and their relationship with sterility.

Shifts in internal stem damage along a tropical precipitation gradient and implications for forest biomass estimation.

Woody biomass is a large carbon store in terrestrial ecosystems. In calculating biomass, tree stems are assumed to be solid structures. However, decomposer agents such as microbes and insects target stem heartwood, causing internal wood decay which is poorly quantified. We investigated internal stem damage across five sites in tropical Australia along a precipitation gradient. We estimated the amount of internal aboveground biomass damaged in living trees and measured four potential stem damage predictors: wood density, stem diameter, annual precipitation, and termite pressure (measured as termite damage in downed deadwood). Stem damage increased with increasing diameter, wood density, and termite pressure and decreased with increasing precipitation. High wood density stems sustained less damage in wet sites and more damage in dry sites, likely a result of shifting decomposer communities and their differing responses to changes in tree species and wood traits across sites. Incorporating stem damage reduced aboveground biomass estimates by > 30% in Australian savannas, compared to only 3% in rainforests. Accurate estimates of carbon storage across woody plant communities are critical for understanding the global carbon budget. Future biomass estimates should consider stem damage in concert with the effects of changes in decomposer communities and abiotic conditions.

The challenge of estimating global termite methane emissions.

Methane is a powerful greenhouse gas, more potent than carbon dioxide, and emitted from a variety of natural sources including wetlands, permafrost, mammalian guts and termites. As increases in global temperatures continue to break records, quantifying the magnitudes of key methane sources has never been more pertinent. Over the last 40 years, the contribution of termites to the global methane budget has been subject to much debate. The most recent estimates of termite emissions range between 9 and 15 Tg CH4 year-1, approximately 4% of emissions from natural sources (excluding wetlands). However, we argue that the current approach for estimating termite contributions to the global methane budget is flawed. Key parameters, namely termite methane emissions from soil, deadwood, living tree stems, epigeal mounds and arboreal nests, are largely ignored in global estimates. This omission occurs because data are lacking and research objectives, crucially, neglect variation in termite ecology. Furthermore, inconsistencies in data collection methods prohibit the pooling of data required to compute global estimates. Here, we summarise the advances made over the last 40 years and illustrate how different aspects of termite ecology can influence the termite contribution to global methane emissions. Additionally, we highlight technological advances that may help researchers investigate termite methane emissions on a larger scale. Finally, we consider dynamic feedback mechanisms of climate warming and land-use change on termite methane emissions. We conclude that ultimately the global contribution of termites to atmospheric methane remains unknown and thus present an alternative framework for estimating their emissions. To significantly improve estimates, we outline outstanding questions to guide future research efforts.

Functional compensation in a savanna scavenger community.

Functional redundancy, the potential for the functional role of one species to be fulfilled by another, is a key determinant of ecosystem viability. Scavenging transfers huge amount of energy through ecosystems and is, therefore, crucial for ecosystem viability and healthy ecosystem functioning. Despite this, relatively few studies have examined functional redundancy in scavenger communities. Moreover, the results of these studies are mixed and confined to a very limited range of habitat types and taxonomic groups. This study attempts to address this knowledge gap by conducting a field experiment in an undisturbed natural environment assessing functional roles and redundancy in vertebrate and invertebrate scavenging communities in a South African savanna. We used a large-scale field experiment to suppress ants in four 1 ha plots in a South African savanna and paired each with a control plot. We distributed three types of small food bait: carbohydrate, protein and seed, across the plots and excluded vertebrates from half the baits using cages. Using this combination of ant suppression and vertebrate exclusion, allowed us explore the contribution of non-ant invertebrates, ants and vertebrates in scavenging and also to determine whether either ants or vertebrates were able to compensate for the loss of one another. In this study, we found the invertebrate community carried out a larger proportion of overall scavenging services than vertebrates. Moreover, although scavenging was reduced when either invertebrates or vertebrates were absent, the presence of invertebrates better mitigated the functional loss of vertebrates than did the presence of vertebrates against the functional loss of invertebrates. There is a commonly held assumption that the functional role of vertebrate scavengers exceeds that of invertebrate scavengers; our results suggest that this is not true for small scavenging resources. Our study highlights the importance of invertebrates for securing healthy ecosystem functioning both now and into the future. We also build upon many previous studies which show that ants can have particularly large effects on ecosystem functioning. Importantly, our study suggests that scavenging in some ecosystems may be partly resilient to changes in the scavenging community, due to the potential for functional compensation by vertebrates and ants.

The Biologic IRL201805 Alters Immune Tolerance Leading to Prolonged Pharmacodynamics and Efficacy in Rheumatoid Arthritis Patients.

A homologue of binding immunoglobulin protein/BiP-IRL201805 alters the function of immune cells in pre-clinical in vivo and in vitro studies. The aim of the study was to select biomarkers that clearly delineate between RA patients who respond to IRL201805 and placebo patients and reveal the immunological mode of action of IRL201805 driving the extended pharmacodynamics observed in responding patients. Biomarkers that distinguished between responding patients and placebo patients included downregulation of serum interferon-γ and IL-1ß; upregulation of anti-inflammatory mediators, serum soluble CTLA-4, and intracellular monocyte expression of IDO; and sustained increased CD39 expression on CD3+CD4+CD25hi CD127lo regulatory T cells. In the responding patients, selected biomarkers verified that the therapeutic effect could be continuous for at least 12 weeks post-infusion. In secondary co-culture, pre-infusion PBMCs cultured 1:1 with autologous PBMCs, isolated at later time-points during the trial, showed significantly inhibited IL-6 and IL-1ß production upon anti-CD3/CD28 stimulation demonstrating IRL201805 alters the function of immune cells leading to prolonged pharmacodynamics confirmed by biomarker differences. IRL201805 may be the first of a new class of biologic drug providing long-term drug-free therapy in RA.

Endothelial Cell-Derived Soluble CD200 Determines the Ability of Immune Cells to Cross the Blood-Brain Barrier.

The infiltration of immune cells into the central nervous system mediates the development of autoimmune neuroinflammatory diseases. We previously showed that the loss of either Fabp5 or calnexin causes resistance to the induction of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis (MS). Here we show that brain endothelial cells lacking either Fabp5 or calnexin have an increased abundance of cell surface CD200 and soluble CD200 (sCD200) as well as decreased T-cell adhesion. In a tissue culture model of the blood-brain barrier, antagonizing the interaction of CD200 and sCD200 with T-cell CD200 receptor (CD200R1) via anti-CD200 blocking antibodies or the RNAi-mediated inhibition of CD200 production by endothelial cells increased T-cell adhesion and transmigration across monolayers of endothelial cells. Our findings demonstrate that sCD200 produced by brain endothelial cells regulates immune cell trafficking through the blood-brain barrier and is primarily responsible for preventing activated T-cells from entering the brain.

The therapeutic mavericks: Potent immunomodulating chaperones capable of treating human diseases.

Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti-inflammatory functions respectively. CRT induces pro-inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti-inflammatory cytokines, inhibits DC maturation and heightens T-regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat-me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long-term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease-relevant immune responses leading to a beneficial clinical outcome.

Endoplasmic reticulum stress-induced release and binding of calreticulin from human ovarian cancer cells.

BACKGROUND: Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone, but can appear surface bound on cancers cells, including ovarian cancers (OC). We investigated at what stage of cell viability, CRT appeared associated with surface of human OC cells. CRT on pre-apoptotic tumour cells is thought to initiate their eradication via a process termed immunogenic cell death (ICD). METHODS: We treated OC cells with the chemotherapeutic-doxorubicin (DX) known to induce translocation of CRT to some tumour cell surfaces, with and without the ER stressor-thapsigargin (TG)-and/or an ER stress inhibitor-TUDCA. We monitored translocation/release of CRT in pre-apoptotic cells by flow cytometry, immunoblotting and ELISA. We investigated the difference in binding of FITC-CRT to pre-apoptotic, apoptotic and necrotic cells and the ability of extracellular CRT to generate immature dendritic cells from THP-1 monocytes. RESULTS: Dx-treatment increased endogenously released CRT and extracellular FITC_CRT binding to human pre-apoptotic OC cells. DX and TG also promoted cell death in OC cells which also increased CRT release. These cellular responses were significantly inhibited by TUDCA, suggesting that ER stress is partially responsible for the changes in CRT cellular distribution. Extracellular CRT induces maturation of THP-1 towards a imDC phenotype, an important component of ICD. CONCLUSION: Collectively, these cellular responses suggest that ER stress is partially responsible for the changes in CRT cellular distribution. ER-stress regulates in part the release and binding of CRT to human OC cells where it may play a role in ICD.

Termites have wider thermal limits to cope with environmental conditions in savannas.

The most diverse and abundant family of termites, the Termitidae, evolved in African tropical forests. They have since colonised grassy biomes such as savannas. These open environments have more extreme conditions than tropical forests, notably wider extremes of temperature and lower precipitation levels and greater temporal fluctuations (of both annual and diurnal variation). These conditions are challenging for soft-bodied ectotherms, such as termites, to survive in, let alone become as ecologically dominant as termites have. Here, we quantified termite thermal limits to test the hypothesis that these physiological limits are wider in savanna termite species to facilitate their existence in savanna environments. We sampled termites directly from mound structures, across an environmental gradient in Ghana, ranging from wet tropical forest through to savanna. At each location, we quantified both the Critical Thermal Maxima (CTmax ) and the Critical Thermal Minima (CTmin ) of all the most abundant mound-building Termitidae species in the study areas. We modelled the thermal limits in two separate mixed-effects models against canopy cover at the mound, temperature and rainfall, as fixed effects, with sampling location as a random intercept. For both CTmax and CTmin , savanna species had significantly more extreme thermal limits than forest species. Between and within environments, areas with higher amounts of canopy cover were significantly associated with lower CTmax values of the termite colonies. CTmin was significantly positively correlated with rainfall. Temperature was retained in both models; however, it did not have a significant relationship in either. Sampling location explained a large proportion of the residual variation, suggesting there are other environmental factors that could influence termite thermal limits. Our results suggest that savanna termite species have wider thermal limits than forest species. These physiological differences, in conjunction with other behavioural adaptations, are likely to have enabled termites to cope with the more extreme environmental conditions found in savanna environments and facilitated their expansion into open tropical environments.

The impact of invertebrate decomposers on plants and soil.

Soil invertebrates make significant contributions to the recycling of dead plant material across the globe. However, studies focussed on the consequences of decomposition for plant communities largely ignore soil fauna across all ecosystems, because microbes are often considered the primary agents of decay. Here, we explore the role of invertebrates as not simply facilitators of microbial decomposition, but as true decomposers, able to break down dead organic matter with their own endogenic enzymes, with direct and indirect impacts on the soil environment and plants. We recommend a holistic view of decomposition, highlighting how invertebrates and microbes act in synergy to degrade organic matter, providing ecological services that underpin plant growth and survival.

Carbon flux and forest dynamics: Increased deadwood decomposition in tropical rainforest tree-fall canopy gaps.

Tree mortality rates are increasing within tropical rainforests as a result of global environmental change. When trees die, gaps are created in forest canopies and carbon is transferred from the living to deadwood pools. However, little is known about the effect of tree-fall canopy gaps on the activity of decomposer communities and the rate of deadwood decay in forests. This means that the accuracy of regional and global carbon budgets is uncertain, especially given ongoing changes to the structure of rainforest ecosystems. Therefore, to determine the effect of canopy openings on wood decay rates and regional carbon flux, we carried out the first assessment of deadwood mass loss within canopy gaps in old-growth rainforest. We used replicated canopy gaps paired with closed canopy sites in combination with macroinvertebrate accessible and inaccessible woodblocks to experimentally partition the relative contribution of microbes vs. termites to decomposition within contrasting understorey conditions. We show that over a 12 month period, wood mass loss increased by 63% in canopy gaps compared with closed canopy sites and that this increase was driven by termites. Using LiDAR data to quantify the proportion of canopy openings in the study region, we modelled the effect of observed changes in decomposition within gaps on regional carbon flux. Overall, we estimate that this accelerated decomposition increases regional wood decay rate by up to 18.2%, corresponding to a flux increase of 0.27 Mg C ha-1  year-1 that is not currently accounted for in regional carbon budgets. These results provide the first insights into how small-scale disturbances in rainforests can generate hotspots for decomposer activity and carbon fluxes. In doing so, we show that including canopy gap dynamics and their impacts on wood decomposition in forest ecosystems can help improve the predictive accuracy of the carbon cycle in land surface models.

The Fabp5/calnexin complex is a prerequisite for sensitization of mice to experimental autoimmune encephalomyelitis.

We previously showed that calnexin (Canx)-deficient mice are desensitized to experimental autoimmune encephalomyelitis (EAE) induction, a model that is frequently used to study inflammatory demyelinating diseases, due to increased resistance of the blood-brain barrier to immune cell transmigration. We also discovered that Fabp5, an abundant cytoplasmic lipid-binding protein found in brain endothelial cells, makes protein-protein contact with the cytoplasmic C-tail domain of Canx. Remarkably, both Canx-deficient and Fabp5-deficient mice commonly manifest resistance to EAE induction. Here, we evaluated the importance of Fabp5/Canx interactions on EAE pathogenesis and on the patency of a model blood-brain barrier to T-cell transcellular migration. The results demonstrate that formation of a complex comprised of Fabp5 and the C-tail domain of Canx dictates the permeability of the model blood-brain barrier to immune cells and is also a prerequisite for EAE pathogenesis.

Darker ants dominate the canopy: Testing macroecological hypotheses for patterns in colour along a microclimatic gradient.

Gradients in cuticle lightness of ectotherms have been demonstrated across latitudes and elevations. Three key hypotheses have been used to explain these macroecological patterns: the thermal melanism hypothesis (TMH), the melanism-desiccation hypothesis (MDH) and the photo-protection hypothesis (PPH). Yet the broad abiotic measures, such as temperature, humidity and UV-B radiation, typically used to detect these ecogeographical patterns, are a poor indication of the microenvironment experienced by small, cursorial ectotherms like ants. We tested whether these macroecological hypotheses explaining cuticle lightness held at habitat and microclimatic level by using a vertical gradient within a tropical rainforest. We sampled 222 ant species in lowland, tropical rainforest across four vertical strata: subterranean, ground, understory and canopy. We recorded cuticle lightness, abundance and estimated body size for each species and calculated an assemblage-weighted mean for cuticle lightness and body size for each vertical stratum. Abiotic variables (air temperature, vapour pressure deficit and UV-B radiation) were recorded for each vertical stratum. We found that cuticle lightness of ant assemblages was vertically stratified: ant assemblages in the canopy and understory were twice as dark as assemblages in ground and subterranean strata. Cuticle lightness was not correlated with body size, and there was no support for the TMH. Rather, we attribute this cline in cuticle lightness to a combination of the MDH and the PPH. Our findings indicate that broad macroecological patterns can be detected at much smaller spatial scales and that microclimatic gradients can shape trait variation, specifically the cuticle lightness of ants. These results suggest that any changes to microclimate that occur due to land-use change or climate warming could drive selection of ants based on cuticle colour, altering assemblage structure and potentially ecosystem functioning.

The Biophysical Interaction of the Danger-Associated Molecular Pattern (DAMP) Calreticulin with the Pattern-Associated Molecular Pattern (PAMP) Lipopolysaccharide.

The endoplasmic reticulum (ER) chaperone protein, calreticulin (CRT), is essential for proper glycoprotein folding and maintaining cellular calcium homeostasis. During ER stress, CRT is overexpressed as part of the unfolded protein response (UPR). In addition, CRT can be released as a damage-associated molecular pattern (DAMP) molecule that may interact with pathogen-associated molecular patterns (PAMPs) during the innate immune response. One such PAMP is lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall. In this report, we show that recombinant and native human placental CRT strongly interacts with LPS in solution, solid phase, and the surface of gram-negative and gram-positive bacteria. Furthermore, LPS induces oilgomerization of CRT with a disappearance of the monomeric form. The application of recombinant CRT (rCRT) to size exclusion and anion exchange chromatography shows an atypical heterogeneous elution profile, indicating that LPS affects the conformation and ionic charge of CRT. Interestingly, LPS bound to CRT is detected in sera of bronchiectasis patients with chronic bacterial infections. By ELISA, rCRT dose-dependently bound to solid phase LPS via the N- and C-domain globular head region of CRT and the C-domain alone. The specific interaction of CRT with LPS may be important in PAMP innate immunity.

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes.

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

Woody encroachment slows decomposition and termite activity in an African savanna.

Woody encroachment can lead to a complete switch from open habitats to dense thickets, and has the potential to greatly alter the biodiversity and ecological functioning of grassy ecosystems across the globe. Plant litter decomposition is a critical ecosystem process fundamental to nutrient cycling and global carbon dynamics, yet little is known about how woody encroachment might alter this process. We compared grass decay rates of heavily encroached areas with adjacent nonencroached open areas in a semi-arid South African savanna using litterbags that allowed or excluded invertebrates. We also assessed the effect of woody encroachment on the activity of termites- dominant decomposer organisms in savanna systems. We found a significant reduction in decomposition rates within encroached areas, with litter taking twice as long to decay compared with open savanna areas. Moreover, invertebrates were more influential on grass decomposition in open areas and termite activity was substantially lower in encroached areas, particularly during the dry season when activity levels were reduced to almost zero. Our results suggest that woody encroachment created an unfavourable environment for invertebrates, and termites in particular, leading to decreased decomposition rates in these areas. We provide the first quantification of woody encroachment altering the functioning of African savanna ecosystems through the slowing of aboveground plant decomposition. Woody encroachment is intensifying across the globe, and our results suggest that substantial changes to the carbon balance and biodiversity of grassy biomes could occur.

Ants are the major agents of resource removal from tropical rainforests.

Ants are diverse and abundant, especially in tropical ecosystems. They are often cited as the agents of key ecological processes, but their precise contributions compared with other organisms have rarely been quantified. Through the removal of food resources from the forest floor and subsequent transport to nests, ants play an important role in the redistribution of nutrients in rainforests. This is an essential ecosystem process and a key energetic link between higher trophic levels, decomposers and primary producers. We used the removal of carbohydrate, protein and seed baits as a proxy to quantify the contribution that ants, other invertebrates and vertebrates make to the redistribution of nutrients around the forest floor, and determined to what extent there is functional redundancy across ants, other invertebrate and vertebrate groups. Using a large-scale, field-based manipulation experiment, we suppressed ants from c. 1 ha plots in a lowland tropical rainforest in Sabah, Malaysia. Using a combination of treatment and control plots, and cages to exclude vertebrates, we made food resources available to: (i) the whole foraging community, (ii) only invertebrates and (iii) only non-ant invertebrates. This allowed us to partition bait removal into that taken by vertebrates, non-ant invertebrates and ants. Additionally, we examined how the non-ant invertebrate community responded to ant exclusion. When the whole foraging community had access to food resources, we found that ants were responsible for 52% of total bait removal whilst vertebrates and non-ant invertebrates removed the remaining 48%. Where vertebrates were excluded, ants carried out 61% of invertebrate-mediated bait removal, with all other invertebrates removing the remaining 39%. Vertebrates were responsible for just 24% of bait removal and invertebrates (including ants) collectively removed the remaining 76%. There was no compensation in bait removal rate when ants and vertebrates were excluded, indicating low functional redundancy between these groups. This study is the first to quantify the contribution of ants to the removal of food resources from rainforest floors and thus nutrient redistribution. We demonstrate that ants are functionally unique in this role because no other organisms compensated to maintain bait removal rate in their absence. As such, we strengthen a growing body of evidence establishing ants as ecosystem engineers, and provide new insights into the role of ants in maintaining key ecosystem processes. In this way, we further our basic understanding of the functioning of tropical rainforest ecosystems.

Rab32 connects ER stress to mitochondrial defects in multiple sclerosis.

BACKGROUND: Endoplasmic reticulum (ER) stress is a hallmark of neurodegenerative diseases such as multiple sclerosis (MS). However, this physiological mechanism has multiple manifestations that range from impaired clearance of unfolded proteins to altered mitochondrial dynamics and apoptosis. While connections between the triggering of the unfolded protein response (UPR) and downstream mitochondrial dysfunction are poorly understood, the membranous contacts between the ER and mitochondria, called the mitochondria-associated membrane (MAM), could provide a functional link between these two mechanisms. Therefore, we investigated whether the guanosine triphosphatase (GTPase) Rab32, a known regulator of the MAM, mitochondrial dynamics, and apoptosis, could be associated with ER stress as well as mitochondrial dysfunction. METHODS: We assessed Rab32 expression in MS patient and experimental autoimmune encephalomyelitis (EAE) tissue, via observation of mitochondria in primary neurons and via monitoring of survival of neuronal cells upon increased Rab32 expression. RESULTS: We found that the induction of Rab32 and other MAM proteins correlates with ER stress proteins in MS brain, as well as in EAE, and occurs in multiple central nervous system (CNS) cell types. We identify Rab32, known to increase in response to acute brain inflammation, as a novel unfolded protein response (UPR) target. High Rab32 expression shortens neurite length, alters mitochondria morphology, and accelerates apoptosis/necroptosis of human primary neurons and cell lines. CONCLUSIONS: ER stress is strongly associated with Rab32 upregulation in the progression of MS, leading to mitochondrial dysfunction and neuronal death.

Symbiogenesis: Beyond the endosymbiosis theory?

Symbiogenesis, literally 'becoming by living together', refers to the crucial role of symbiosis in major evolutionary innovations. The term usually is reserved for the major transition to eukaryotes and to photosynthesising eukaryotic algae and plants by endosymbiosis. However, in some eukaryote lineages endosymbionts have been lost secondarily, showing that symbiosis can trigger a major evolutionary innovation, even if symbionts were lost secondarily. This leads to the intriguing possibility that symbiosis has played a role in other major evolutionary innovations as well, even if not all extant representatives of such groups still have the symbiotic association. We evaluate this hypothesis for two innovations in termites (Termitoidae, also known informally as "Isoptera"): i) the role of flagellate gut protist symbionts in the transition to eusociality from cockroach-like ancestors, and ii) the role of non-gut associated symbionts in the transition to 'higher' termites, characterized by the absence of flagellate gut protists. In both cases we identify a crucial role for symbionts, even though in both cases, subsequently, symbionts were lost again in some lineages. We also briefly discuss additional possible examples of symbiogenesis. We conclude that symbiogenesis is more broadly applicable than just for the endosymbiotic origin of eukaryotes and photosynthetic eukaryotes, and may be a useful concept to acknowledge the important role of symbiosis for evolutionary innovation. However, we do not accept Lynn Margulis's view that symbiogenesis will lead to a paradigm shift from neoDarwinism, as the role of symbiosis in evolutionary change can be integrated with existing theory perfectly.