Early life thermal conditioning alters heat-shock protein expression in response to an adult thermal stressor.

Developmental environmental stressors can have instructive effects on an organism's phenotype. This developmental plasticity can prepare organisms for potentially stressful future environments, circumventing detrimental effects on fitness. However, the physiological mechanisms underlying such adaptive plasticity are understudied, especially in vertebrates. We hypothesized that captive male zebra finches (Taeniopygia castanotis) exposed to a mild heat conditioning during development would acquire a persisting thermotolerance, and exhibit increased heat-shock protein (HSP) levels associated with a decrease in oxidative damage when exposed to a high-intensity stressor in adulthood. To test this, we exposed male finches to a prolonged mild heat conditioning (38°C) or control (22°C) treatment as juveniles. Then in a 2 × 2 factorial manner, these finches were exposed to a high heat stressor (42°C) or control (22°C) treatment as adults. Following the adult treatment, we collected testes and liver tissue and measured HSP70, HSP90, and HSP60 protein levels. In the testes, finches exhibited lower levels of HSP90 and HSP60 when exposed to the high heat stressor in adulthood if they were exposed to the mild heat conditioning as juveniles. In the liver, finches exposed to the high heat stressor in adulthood had reduced HSP90 and HSP60 levels, regardless of whether they were conditioned as juveniles. In some cases, elevated testes HSP60 levels were associated with increased liver oxidative damage and diminishment of a condition-dependent trait, indicating potential stress-induced tradeoffs. Our results indicate that a mild conditioning during development can have persisting effects on HSP expression and acquired thermotolerance.

Modeling Population Growth under Climate Stressors Using Age-structured Matrix Models.

Climate resilience, a focus of many recent studies, has been examined from ecological, physiological, and evolutionary perspectives. However, sampling biases towards adults, males, and certain species have made establishing the link between environmental change and population-level change problematic. Here we used data from four laboratory studies, in which we administered pre- and post-natal stressors, such as suboptimal incubation temperature, heat stress, and food restriction, to zebra finches and quantified hatching success, post-hatch survival, and reproductive success, to parameterize age-structured population dynamics models with the goal of estimating the effect of the stressors on relative population growth rates. Using the same model structure, we tested the hypothesis that early life stages influence population growth rate more than later life stages. Our models suggested that stressful events during embryonic development, such as suboptimal incubation temperatures and reduced gas exchange for the embryos, have a greater total impact on population growth than post-hatch stressors, such as heat stress and food restriction. However, among life history traits, differences in hatching success and sex ratio of offspring in response to stressors changed population growth rates more than differences in any other demographic rate estimates. These results suggest that when predicting population resilience against climate change, it is critical to account for effects of climate change on all life stages, including early stages of life, and to incorporate individuals' physiology and stress tolerance that likely influence future stress responses, reproduction, and survival.

Tumor cell-induced macrophage senescence plays a pivotal role in tumor initiation followed by stable growth in immunocompetent condition.

BACKGROUND: The cancer stem cell theory proposes that tumor formation in vivo is driven only by specific tumor-initiating cells having stemness; however, clinical trials conducted to test drugs that target the tumor stemness provided unsatisfactory results thus far. Recent studies showed clear involvement of immunity in tumors; however, the requirements of tumor-initiation followed by stable growth in immunocompetent individuals remain largely unknown. METHODS: To clarify this, we used two similarly induced glioblastoma lines, 8B and 9G. They were both established by overexpression of an oncogenic H-RasL61 in p53-deficient neural stem cells. In immunocompromised animals in an orthotopic transplantation model using 1000 cells, both show tumor-forming potential. On the other hand, although in immunocompetent animals, 8B shows similar tumor-forming potential but that of 9G's are very poor. This suggests that 8B cells are tumor-initiating cells in immunocompetent animals. Therefore, we hypothesized that the differences in the interaction properties of 8B and 9G with immune cells could be used to identify the factors responsible for its tumor forming potential in immunocompetent animals and performed analysis. RESULTS: Different from 9G, 8B cells induced senescence-like state of macrophages around tumors. We investigated the senescence-inducing factor of macrophages by 8B cells and found that it was interleukin 6. Such senescence-like macrophages produced Arginase-1, an immunosuppressive molecule known to contribute to T-cell hyporesponsiveness. The senescence-like macrophages highly expressed CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase associated with NAD shortage in senescent cells. The addition of nicotinamide mononucleotide (NMN), an NAD precursor, in vitro inhibited to the induction of macrophage senescence-like phenotype and inhibited Arginase-1 expression resulting in retaining T-cell function. Moreover, exogenous in vivo administration of NMN after tumor inoculation inhibited tumor-initiation followed by stable growth in the immunocompetent mouse tumor model. CONCLUSIONS: We identified one of the requirements for tumor-initiating cells in immunocompetent animals. In addition, we have shown that tumor growth can be inhibited by externally administered NMN against macrophage senescence-like state that occurs in the very early stages of tumor-initiating cell development. This therapy targeting the immunosuppressive environment formed by macrophage senescence-like state is expected to be a novel promising cancer therapeutic strategy.

Mercury causes degradation of spatial cognition in a model songbird species.

Mercury is a widespread pollutant of increasing global concern that exhibits a broad range of deleterious effects on organisms, including birds. Because the developing brain is well-known to be particularly vulnerable to the neurotoxic insults of mercury, many studies have focused on developmental effects such as on the embryonic brain and resulting behavioral impairment in adults. It is not well understood how the timing of exposure, for example exclusively in ovo versus throughout life, influences the impact of mercury. Using dietary exposure to environmentally relevant methylmercury concentrations, we examined the role that timing and duration of exposure play on spatial learning and memory in a model songbird species, the domesticated zebra finch (Taeniopygia guttata castanotis). We hypothesized that developmental exposure was both necessary and sufficient to disrupt spatial memory in adult finches. We documented profound disruption of memory for locations of hidden food at two spatial scales, cage- and room-sized enclosures, but found that both developmental and ongoing adult exposure were required to exhibit this behavioral impairment. Methylmercury-exposed birds made more mistakes before mastering the spatial task, because they revisited unrewarded locations repeatedly even after discovering the rewarded location. Contrary to our prediction, hippocampal volume was not affected in birds exposed to methylmercury over their lifetimes. The disruption of spatial cognition that we detected is severe and would likely have implications for survival and reproduction in wild birds; however, it appears that individuals that disperse or migrate from a contaminated site might recover later in life if no longer exposed to the toxicant.

Heat-induced maternal effects shape avian eggshell traits and embryo development and phenotype at high incubation temperatures.

Phenotypic plasticity is an important avenue by which organisms may persist in the face of rapid environmental change. Environmental cues experienced by the mother can also influence the phenotype of offspring, a form of plasticity called maternal effects. Maternal effects can adaptively prepare offspring for the environmental conditions they will likely experience; however, their ability to buffer offspring against environmental stressors as embryos is understudied. Using captive zebra finches, we performed a maternal-offspring environmental match-mismatch experiment utilizing a 2 × 2 × 2 factorial design. Mothers were exposed to a mild heat conditioning (38°C) or control (22°C) treatment as juveniles, an acute high heat (42°C) or control (22°C) treatment as adults, then paired for breeding. The eggs produced by those females were incubated at a hyperthermic (38.5°C) or optimal temperature (37.2°C). We found that when mothers were exposed to a mild heat conditioning as juveniles, their embryos exhibited reduced water loss, longer development times, and produced hatchlings with heavier pectoralis muscles when incubated at high incubation temperatures, compared to embryos from control mothers. Mothers exposed to both the mild heat conditioning as juveniles and a high heat stressor as adults produced eggs with a higher density of shell pores and embryos with lower heart rates during development. However, there was a cost when there was a mismatch between maternal and embryo environment. Embryos from these conditioned and heat-stressed mothers had reduced survival at control incubation temperatures, indicating the importance of offspring environment when interpreting potential adaptive effects.

A mechanism of IL-34-induced resistance against cytotoxic anti-cancer therapies such as radiation by X-ray and chemotherapy by Oxaliplatin.

Interleukin-34 (IL-34) has been known as a factor that is involved with tumor progression and therapeutic resistance. However, there are limitations to addressing the mechanism of how IL-34 induces therapeutic resistance. Here, we show a mechanism of IL-34-induced resistance against cytotoxic anti-cancer therapies such as radiotherapy using X-ray and chemotherapy by Oxaliplatin. This research demonstrates that IL-34 immunologically changes the tumor microenvironment after treatments with radiation or chemotherapeutic agents such as oxaliplatin. We identified the changes in immune cells using flow cytometry and immunofluorescent (IF) staining, which are up-regulated upon the existence of IL-34. Overall, these findings demonstrate the possibility of IL-34 blockade as a novel combination therapy for cancer.

5-Aminosalicylic acid alters the gut microbiota and altered microbiota transmitted vertically to offspring have protective effects against colitis.

Although many therapeutic options are available for inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA) is still the key medication, particularly for ulcerative colitis (UC). However, the mechanism of action of 5-ASA remains unclear. The intestinal microbiota plays an important role in the pathophysiology of IBD, and we hypothesized that 5-ASA alters the intestinal microbiota, which promotes the anti-inflammatory effect of 5-ASA. Because intestinal inflammation affects the gut microbiota and 5-ASA can change the severity of inflammation, assessing the impact of inflammation and 5-ASA on the gut microbiota is not feasible in a clinical study of patients with UC. Therefore, we undertook a translational study to demonstrate a causal link between 5-ASA administration and alterations of the intestinal microbiota. Furthermore, by rigorously controlling environmental confounders and excluding the effect of 5-ASA itself with a vertical transmission model, we observed that the gut microbiota altered by 5-ASA affected host mucosal immunity and decreased susceptibility to dextran sulfate sodium-induce colitis. Although the potential intergenerational transmission of epigenetic changes needs to be considered in this study, these findings suggested that alterations in the intestinal microbiota induced by 5-ASA directed the host immune system towards an anti-inflammatory state, which underlies the mechanism of 5-ASA efficacy.

Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells.

Among cancer immunotherapy, which has received great attention in recent years, cancer vaccines can potentially prevent recurrent tumors by using the exquisite power and specificity of the immune system. Specifically, whole tumor cell vaccines (WTCVs) based on surgically resected tumors have been considered to elicit robust anti-tumor immune responses by exposing various tumor-associated antigens to host immunity. However, most tumors have little immunogenicity because of immunoediting by continuous interactions with host immunity; thus, preparing WTCVs based on patient-derived non-modified tumors cannot prevent tumor onset. Hence, the immunogenicity of tumor cells must be improved for effective WTCVs. In this study, we indicate the importance of the interferon regulatory factor 7 (Irf7) axis, including Irf7 and its downstream factors, within tumor cells in regulating immunogenicity. Indeed, WTCVs that augmented the Irf7 axis have exerted remarkable recurrence-preventive effects when vaccinated after tumor inactivation by radiation. Most notably, vaccination with murine colon cancer cells that enhanced the Irf7 axis prevented the development of challenged tumors in all mice and resulted in a 100% survival rate during the observation period. Furthermore, the mechanism leading to vaccine effectiveness was mediated by interferon-gamma-producing B cells. This study provides novel insights into how to enhance tumor immunogenicity and use WTCVs as recurrence prophylaxis.

Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance.

In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation.

Induction of allograft tolerance by adoptive transfer of donor B cells: an immune regulatory strategy for transplantation using MHC-matched iPS cells.

For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor.

OBJECTIVE: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). METHODS: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. RESULTS: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. CONCLUSION: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

Temperature, size and developmental plasticity in birds.

As temperatures increase, there is growing evidence that species across much of the tree of life are getting smaller. These climate change-driven size reductions are often interpreted as a temporal analogue of the observation that individuals within a species tend to be smaller in the warmer parts of the species' range. For ectotherms, there has been a broad effort to understand the role of developmental plasticity in temperature-size relationships, but in endotherms, this mechanism has received relatively little attention in favour of selection-based explanations. We review the evidence for a role of developmental plasticity in warming-driven size reductions in birds and highlight insulin-like growth factors as a potential mechanism underlying plastic responses to temperature in endotherms. We find that, as with ectotherms, changes in temperature during development can result in shifts in body size in birds, with size reductions associated with warmer temperatures being the most frequent association. This suggests developmental plasticity may be an important, but largely overlooked, mechanism underlying warming-driven size reductions in endotherms. Plasticity and natural selection have very different constraining forces, thus understanding the mechanism linking temperature and body size in endotherms has broad implications for predicting future impacts of climate change on biodiversity.

Postnatal expression of IGF2 is the norm in amniote vertebrates.

The insulin and insulin-like signalling (IIS) network plays an important role in mediating several life-history traits, including growth, reproduction and senescence. Although insulin-like growth factors (IGFs) 1 and 2 are both key hormones in the vertebrate IIS network, research on IGF2 in juveniles and adults has been largely neglected because early biomedical research on rodents found negligible IGF2 postnatal expression. Here, we challenge this assumption and ask to what degree IGF2 is expressed during postnatal life across amniotes by quantifying the relative gene expression of IGF1 and IGF2 using publicly available RNAseq data for 82 amniote species and quantitative polymerase chain reaction on liver cDNA at embryonic, juvenile and adult stages for two lizard, bird and mouse species. We found that (i) IGF2 is expressed postnatally across amniote species and life stages-often at a higher relative expression than IGF1, contradicting rodent models; (ii) the lack of rodent postnatal IGF2 expression is due to phylogenetic placement, not inbreeding or artificial selection; and (iii) adult IGF2 expression is sex-biased in some species. Our results demonstrate that IGF2 expression is typical for amniotes throughout life, suggesting that a comprehensive understanding of the mechanisms mediating variation in life-history traits will require studies that measure both IGFs.

Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model.

BACKGROUND: Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated. METHODS: Three transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed. RESULTS: In the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation. CONCLUSIONS: The findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed.

Erratum: Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade.

[This corrects the article DOI: 10.1016/j.isci.2020.101584.].

Resolving the Rules of Robustness and Resilience in Biology Across Scales.

Why do some biological systems and communities persist while others fail? Robustness, a system's stability, and resilience, the ability to return to a stable state, are key concepts that span multiple disciplines within and outside the biological sciences. Discovering and applying common rules that govern the robustness and resilience of biological systems is a critical step toward creating solutions for species survival in the face of climate change, as well as the for the ever-increasing need for food, health, and energy for human populations. We propose that network theory provides a framework for universal scalable mathematical models to describe robustness and resilience and the relationship between them, and hypothesize that resilience at lower organization levels contribute to robust systems. Insightful models of biological systems can be generated by quantifying the mechanisms of redundancy, diversity, and connectivity of networks, from biochemical processes to ecosystems. These models provide pathways towards understanding how evolvability can both contribute to and result from robustness and resilience under dynamic conditions. We now have an abundance of data from model and non-model systems and the technological and computational advances for studying complex systems. Several conceptual and policy advances will allow the research community to elucidate the rules of robustness and resilience. Conceptually, a common language and data structure that can be applied across levels of biological organization needs to be developed. Policy advances such as cross-disciplinary funding mechanisms, access to affordable computational capacity, and the integration of network theory and computer science within the standard biological science curriculum will provide the needed research environments. This new understanding of biological systems will allow us to derive ever more useful forecasts of biological behaviors and revolutionize the engineering of biological systems that can survive changing environments or disease, navigate the deepest oceans, or sustain life throughout the solar system.

Experimental Exposure to Noise Alters Gut Microbiota in a Captive Songbird.

Noise pollution is an unprecedented evolutionary pressure on wild animals that can lead to alteration of stress hormone levels and changes in foraging behavior. Both corticosterone and feeding behavior can have direct effects on gut bacteria, as well as indirect effects through changes in gut physiology. Therefore, we hypothesized that exposure to noise will alter gut microbial communities via indirect effects on glucocorticoids and foraging behaviors. We exposed captive white-crowned sparrows to city-like noise and measured each individuals' corticosterone level, food intake, and gut microbial diversity at the end of four treatments (acclimation, noise, recovery, and control) using a balanced repeated measures design. We found evidence that noise acts to increase corticosterone and decrease food intake, adding to a growing body of research indicating noise exposure affects stress hormone levels and foraging behaviors. We also found evidence to support our prediction for a causal, positive relationship between noise exposure and gut microbial diversity, such that birds had higher measures of alpha diversity during noise exposure. These results help to explain previous findings that urban, free-living white-crowned sparrows have higher bacterial richness than rural sparrows. However, noise appeared to act directly on the gut microbiome or, more likely, through an unmeasured variable, rather than through indirect effects via corticosterone and food intake. Altogether, our study indicates that noise affects plasma corticosterone, feeding behavior, and the gut microbiome in a songbird and raises new questions as to the mechanism linking noise exposure to gut microbial diversity.

IL-34, the rationale for its expression in physiological and pathological conditions.

IL-34 is a cytokine that shares one of its receptors with CSF-1. It has long been thought that CSF-1 receptor (CSF-1R) receives signals only from CSF-1, but the identification of IL-34 reversed this stereotype. Regardless of low structural homology, IL-34 and CSF-1 emanate similar downstream signaling through binding to CSF-1R and provoke similar but different physiological events afterward. In addition to CSF-1R, protein-tyrosine phosphatase (PTP)-ζ and Syndecan-1 were also identified as IL-34 receptors and shown to be at play. Although IL-34 expression is limited to particular tissues in physiological conditions, previous studies have revealed that it is upregulated in several diseases. In cancer, IL-34 is produced by several types of tumor cells and contributes to therapy resistance and disease progression. A recent study has demonstrated that tumor cell-derived IL-34 abrogates immunotherapy efficacy through myeloid cell remodeling. On the other hand, IL-34 expression is downregulated in some brain and dermal disorders. Despite accumulating insights, our understanding of IL-34 may not be even close to its nature. This review aims to comprehensively describe the physiological and pathological roles of IL-34 based on its similarity and differences to CSF-1 and discuss the rationale for its disease-dependent expression pattern.

Detrimental or beneficial? Untangling the literature on developmental stress studies in birds.

Developing animals display a tremendous ability to change the course of their developmental path in response to the environment they experience, a concept referred to as developmental plasticity. This change in behavior, physiology or cellular processes is primarily thought to allow animals to better accommodate themselves to the surrounding environment. However, existing data on developmental stress and whether it brings about beneficial or detrimental outcomes show conflicting results. There are several well-referred hypotheses related to developmental stress in the current literature, such as the environmental matching, silver spoon and thrifty phenotype hypotheses. These hypotheses speculate that the early-life environment defines the capacity of the physiological functions and behavioral tendencies and that this change is permanent and impacts the fitness of the individual. These hypotheses also postulate there is a trade-off among organ systems and physiological functions when resources are insufficient. Published data on avian taxa show that some effects of developmental nutritional and thermal stressors are long lasting, such as the effects on body mass and birdsong. Although hypotheses on developmental stress are based on fitness components, data on reproduction and survival are scarce, making it difficult to determine which hypothesis these data support. Furthermore, most physiological and performance measures are collected only once; thus, the physiological mechanisms remain undertested. Here, we offer potential avenues of research to identify reasons behind the contrasting results in developmental stress research and possible ways to determine whether developmental programming due to stressors is beneficial or detrimental, including quantifying reproduction and survival in multiple environments, measuring temporal changes in physiological variables and testing for stress resistance later in life.