Restoration of invaded Cape Floristic Region riparian systems leads to a recovery in foliage-active arthropod alpha- and beta-diversity

The Cape Floristic Region of South Africa is a global biodiversity hotspot threatened by invasive alien plants (IAPs). We assessed the effect of plant invasions, and their subsequent clearing, on riparian arthropod diversity. Foliage-active arthropod communities were collected from two native and one invasive alien tree species. Alpha- and beta-diversity of their associated arthropod communities were compared between near pristine, Acacia-invaded and restored sites. Arthropod alpha-diversity at near pristine sites was higher than at restored sites, and was lowest at invaded sites. This was true for most arthropod taxonomic groups associated with all native tree species and suggests a general trend towards recovery in arthropod alpha-diversity after IAP removal. Overall, arthropod species turnover among sites was significantly influenced by plant invasions with communities at near pristine sites having higher turnover than those at restored and invaded sites. This pattern was not evident at the level of individual tree species. Although arthropod community composition was significantly influenced by plant invasions, only a few significant differences in arthropod community composition could be detected between restored and near pristine sites for all tree species and arthropod taxonomic groups. Assemblage composition on each tree species generally differed between sites with similar degrees of plant invasion indicating a strong turnover of arthropod communities across the landscape. Results further suggest that both arthropod alpha- and beta-diversity can recover after IAP removal, given sufficient time, but catchment signatures must be acknowledged when monitoring restoration recovery.     

Genetic diversity and population structure of invasive and native populations of Erigeron canadensis L.

小蓬草入侵地和原产地种群的遗传多样性和种群结构 外来入侵植物对全球生物多样性造成了危害。小蓬草(Erigeron canadensis L.)是危害最为严重的外来农业杂草之一,代表了洲际入侵的典型例子。本研究利用10个多态性SSR位点,分别对采自中国江苏和浙江省的入侵地和采自美国阿拉巴马州的原产地各5个种群、共计312个植株的基因型进行了遗传多样性和遗传结构分析。结果表明,江苏省和浙江省的入侵种群显示出与阿拉巴马州原产地种群相似的遗传多样性,表明入侵期间没有严重的遗传瓶颈。利用STRUCTURE对种群结构的分析结果显示,种群之间分化较低,在原产地和入侵范围内均只仅检测到两个基因群。在入侵种群中观察到的遗传多样性较高,表明在入侵初期可能存在多次引入或引入了遗传背景不同的繁殖体。上述研究为阐明小蓬草这一全球有害杂草在中国东部的入侵动态提供了新的证据。在防除实践中,应注意防范小蓬草入侵种群和本地种群之间的种子基因流传播,阻止除草剂抗性植株的引入和扩散。     

Inhibitor of Apoptosis Proteins Physically Interact with and Block Apoptosis Induced by Drosophila Proteins HID and GRIM

Reaper (RPR), HID, and GRIM activate apoptosis in cells programmed to die during Drosophila development. We have previously shown that transient overexpression of RPR in the lepidopteran SF-21 cell line induces apoptosis and that members of the inhibitor of apoptosis (IAP) family of antiapoptotic proteins can inhibit RPR-induced apoptosis and physically interact with RPR through their BIR motifs (D. Vucic, W. J. Kaiser, A. J. Harvey, and L. K. Miller, Proc. Natl. Acad. Sci. USA 94:10183–10188, 1997). In this study, we found that transient overexpression of HID and GRIM also induced apoptosis in the SF-21 cell line. Baculovirus and Drosophila IAPs blocked HID- and GRIM-induced apoptosis and also physically interacted with them through the BIR motifs of the IAPs. The region of sequence similarity shared by RPR, HID, and GRIM, the N-terminal 14 amino acids of each protein, was required for the induction of apoptosis by HID and its binding to IAPs. When stably overexpressed by fusion to an unrelated, nonapoptotic polypeptide, the N-terminal 37 amino acids of HID and GRIM were sufficient to induce apoptosis and confer IAP binding activity. However, GRIM was more complex than HID since the C-terminal 124 amino acids of GRIM retained apoptosis-inducing and IAP binding activity, suggesting the presence of two independent apoptotic motifs within GRIM. Coexpression of IAPs with HID stabilized HID levels and resulted in the accumulation of HID in punctate perinuclear locations which coincided with IAP localization. The physical interaction of IAPs with RPR, HID, and GRIM provides a common molecular mechanism for IAP inhibition of these Drosophila proapoptotic proteins.     

Invasion legacy effects versus sediment deposition as drivers of riparian vegetation

Riparian zones are formed by interactions between fluvio-geomorphological processes, such as sediment deposition, and biota, such as vegetation. Establishment of invasive alien plant (IAP) species along rivers may influence vegetation dynamics, evidenced as higher seasonal or inter-annual fluctuations in native plant diversity when IAP cover is high. This could impact the overall functioning of riparian ecosystems. Conversely, fine sediment deposited in riparian zones after floods may replenish propagule banks, thus supporting recruitment of native species. The interactive effects of invasion and fine sediment deposition have hitherto, however, been ignored. Vegetation surveys across rivers varying in flow regime were carried out over 2 years to assess changes in community composition and diversity. Artificial turf mats were used to quantify over-winter sediment deposition. The viable propagule bank in soil and freshly deposited sediment was then quantified by germination trials. Structural Equation Models were used to assess causal pathways between environmental variables, IAPs and native vegetation. Greater variation in flow increased the cover of IAPs along riverbanks. An increased in high flow events and sediment deposition were positively associated with the diversity of propagules deposited. However, greater diversity of propagules did not result in a more diverse plant community at invaded sites, as greater cover of IAPs in summer reduced native plant diversity. Seasonal turnover in the above-ground vegetation was also accentuated at previously invaded sites, suggesting that a legacy of increased competition in previous years, not recent sediment deposition, drives above-ground vegetation structure at invaded sites. The interaction between fluvial disturbance via sediment deposition and invasion pressure is of growing importance in the management of riparian habitats. Our results suggest that invasion can uncouple the processes that contribute to resilience in dynamic habitats making already invaded habitats vulnerable to further invasions.     

Effects of changes in the shape of the intracellular action potential on the peak-to-peak ratio of single muscle fibre potentials

In situ recording of the intracellular action potential (IAP) of human muscle fibres is not yet feasible, and consequently, knowledge about certain IAP characteristics of these IAPs is still limited. The ratio between the amplitudes of the second and first phases (the so-called peak-to-peak ratio, PPR) of a single fibre action potential (SFAP) is known to be closely related to the IAP profile. The PPR of experimentally recorded SFAPs has been found to be largely independent of changes in the fibre-to-electrode (radial) distance. The main goal of this paper is to analyze the effect of changes in different aspects of the IAP spike on the relationship between PPR and radial distance. Based on this analysis, we hypothesize about the characteristics of IAPs obtained experimentally. It was found that the sensitivity of the SFAP PPR to changes in radial distance is essentially governed by the duration of the IAP spike. Assuming that, for mammals, the duration of the IAP rising phase lies within the range 0.2-0.4 ms, we tentatively suggest that the duration of the IAP spike should be over approximately 0.75 ms, with the shape of the spike strongly asymmetric. These IAP characteristics broadly coincide with those observed in mammal IAPs.     

Identification and Phytotoxicity Assessment of Phenolic Compounds in Chrysanthemoides monilifera subsp. monilifera (Boneseed)

Chrysanthemoides monilifera subsp. monilifera (boneseed), a weed of national significance in Australia, threatens indigenous species and crop production through allelopathy. We aimed to identify phenolic compounds produced by boneseed and to assess their phytotoxicity on native species. Phenolic compounds in water and methanol extracts, and in decomposed litter-mediated soil leachate were identified using HPLC, and phytotoxicity of identified phenolics was assessed (repeatedly) through a standard germination bioassay on native Isotoma axillaris. The impact of boneseed litter on native Xerochrysum bracteatum was evaluated using field soil in a greenhouse. Collectively, we found the highest quantity of phenolic compounds in boneseed litter followed by leaf, root and stem. Quantity varied with extraction media. The rank of phenolics concentration in boneseed was in the order of ferulic acid > phloridzin > catechin > p-coumaric acid and they inhibited germination of I. axillaris with the rank of ferulic acid > catechin > phloridzin > p-coumaric acid. Synergistic effects were more severe compared to individual phenolics. The litter-mediated soil leachate (collected after15 days) exhibited strong phytotoxicity to I. axillaris despite the level of phenolic compounds in the decomposed leachate being decreased significantly compared with their initial level. This suggests the presence of other unidentified allelochemicals that individually or synergistically contributed to the phytotoxicity. Further, the dose response phytotoxic impacts exhibited by the boneseed litter-mediated soil to native X. bracteatum in a more naturalistic greenhouse experiment might ensure the potential allelopathy of other chemical compounds in the boneseed invasion. The reduction of leaf relative water content and chlorophyll level in X. bracteatum suggest possible mechanisms underpinning plant growth inhibition caused by boneseed litter allelopathy. The presence of a substantial quantity of free proline in the target species also suggests that the plant was in a stressed condition due to litter allelopathy. These findings are important for better understanding the invasive potential of boneseed and in devising control strategies.     

The Roles of IAPs with Ubiquitin Ligase Activity in the Occurrence and Development of Malignant Tumors

The inhibitors of apoptosis proteins (IAPs) are a family of highly conserved proteins involved in apoptosis. Recent studies indicate that IAPs with RING domains act as ubiquitin E3 ligases and play an important role in the occurrence and development of malignant tumors through inhibiting the caspases and regulating MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa-B) signaling. The mechanisms of IAPs in malignant tumors are complex and diverse, including resistance to cell death, inflammatory response, invasion and metastasis. IAPs inhibit apoptosis through both intrinsic and extrinsic pathways. They promote inflammatory response and regulate immune response. Besides, they both promote and inhibit tumor cell migration. Recent studies indicated that IAPs are positively correlated with poor prognosis in most malignant tumors, and negatively correlated with poor prognosis in some other few malignant tumors. The conclusions above show that it will be particularly necessary to further explore the relationship among IAPs, the occurrence and development of malignant tumors and the prognosis of patients. This review summarizes the latest research of IAPs that serve as E3s, in particular XIAP (X-chromosome linked IAP), c-IAP1 (cellular IAP1), c-IAP2 (cellular IAP2) and ML-IAP (melanoma IAP), covering the structures, functions in the malignant tumors, the signaling pathways and their correlation with the development and prognosis of malignant tumors, as well as the progress of anti-tumor drugs and therapies for IAPs. Furthermore, this review explores the problems and challenges in the current studies, which may provide new directions and strategies for future research.     

Nxf1 Natural Variant E610G Is a Semi-dominant Suppressor of IAP-Induced RNA Processing Defects

Endogenous retroviruses and retrotransposons contribute functional genetic variation in animal genomes. In mice, Intracisternal A Particles (IAPs) are a frequent source of both new mutations and polymorphism across laboratory strains. Intronic IAPs can induce alternative RNA processing choices, including alternative splicing. We previously showed IAP I∆1 subfamily insertional mutations are suppressed by a wild-derived allele of the major mRNA export factor, Nxf1. Here we show that a wider diversity of IAP insertions present in the mouse reference sequence induce insertion-dependent alternative processing that is suppressed by Nxf1^CAST alleles. These insertions typically show more modest gene expression changes than de novo mutations, suggesting selection or attenuation. Genome-wide splicing-sensitive microarrays and gene-focused assays confirm specificity of Nxf1 genetic modifier activity for IAP insertion alleles. Strikingly, CRISPR/Cas9-mediated genome editing demonstrates that a single amino acid substitution in Nxf1, E610G, is sufficient to recreate a quantitative genetic modifier in a co-isogenic background.     

Isolation and identification of an allelopathic substance in Pisum sativum

The residue of peas (Pisum sativum L.) has allelopathic activity and the putative compound causing this inhibitory effect was isolated from a methanol extract of pea shoots. Chemical structure of this compound was determined by high-resolution MS, IR and 1H NMR spectral data as pisatin. Pisatin inhibited growth of cress (Lepidium sativum L.) and lettuce (Lactuca sativa L.) seedlings at concentrations greater than 10 and 30 microM, respectively. The doses required for 50% growth inhibition of roots and hypocotyls of cress were 61 and 91 microM, respectively, and those of lettuce were 78 and 115 microM, respectively. The concentration of pisatin in the pea shoots was 32.7 nmol x g(-1) fresh weight. The effectiveness of pisatin on growth inhibition in cress and lettuce, and its occurrence in pea shoots suggest that it may contribute to the growth inhibitory effect of pea residue, and may play an important role in pea allelopathy.     

Evidence of the niche expansion of crofton weed following invasion in China

Niche dynamics of invasive alien plants (IAPs) play pivotal roles in biological invasion. Ageratina adenophora—one of the most aggressive IAPs in China and some parts of the world—poses severe ecological and socioeconomic threats. However, the spatiotemporal niche dynamics of A. adenophora in China remain unknown, which we aimed to elucidate in the present study. China, Mexico; using a unifying framework, we reconstructed the climate niche dynamics of A. adenophora and applied the optimal MaxEnt model to predict its potential geographical distribution in China. Furthermore, we compared the heterogeneity of A. adenophora niche between Mexico (native) and China (invasive). We observed a low niche overlap between Mexico (native) and China (invasive). Specifically, the niche of A. adenophora in China has distinctly expanded compared to that in Mexico, enhancing the invasion risk of this IAP in the former country. In fact, the climatic niche of A. adenophora in Mexico is a subset of that in China. The potential geographical distribution of A. adenophora is concentrated in the tropical and subtropical zones of Southwest China, and its geographical distribution pattern in China is shaped by the combination of precipitation and temperature variables. The niche dynamics of A. adenophora follow the hypothesis of niche shift and conservatism. The present work provides a unifying framework for studies on the niche dynamics of other IAPs worldwide.     

Influence of Vacuum Cooling on Escherichia coli O157:H7 Infiltration in Fresh Leafy Greens via a Multiphoton-Imaging Approach

Microbial pathogen infiltration in fresh leafy greens is a significant food safety risk factor. In various postharvest operations, vacuum cooling is a critical process for maintaining the quality of fresh produce. The overall goal of this study was to evaluate the risk of vacuum cooling-induced infiltration of Escherichia coli O157:H7 into lettuce using multiphoton microscopy. Multiphoton imaging was chosen as the method to locate E. coli O157:H7 within an intact lettuce leaf due to its high spatial resolution, low background fluorescence, and near-infrared (NIR) excitation source compared to those of conventional confocal microscopy. The variables vacuum cooling, surface moisture, and leaf side were evaluated in a three-way factorial study with E. coli O157:H7 on lettuce. A total of 188 image stacks were collected. The images were analyzed for E. coli O157:H7 association with stomata and E. coli O157:H7 infiltration. The quantitative imaging data were statistically analyzed using analysis of variance (ANOVA). The results indicate that the low-moisture condition led to an increased risk of microbial association with stomata (P < 0.05). Additionally, the interaction between vacuum cooling levels and moisture levels led to an increased risk of infiltration (P < 0.05). This study also demonstrates the potential of multiphoton imaging for improving sensitivity and resolution of imaging-based measurements of microbial interactions with intact leaf structures, including infiltration.     

Context dependency of the allelopathic effects of Lonicera maackii on seed germination

Allelopathic effects of invasive plants on native flora may be mitigated by the abiotic and biotic environment into which the allelochemicals are released. Lonicera maackii (Amur honeysuckle), an invasive plant of the eastern deciduous forest, suppresses seed germination in laboratory assays. We investigated how L. maackii leachate interacts with abiotic conditions and with the soil microbial community. First, we tested the effects of leaf extract from L. maackii on germination of the native woodland herb, Blephilia hirsuta, under different light and soil conditions. We found that germination of Blephilia hirsuta was reduced by L. maackii extract, but abiotic conditions did not interact with this effect. We also tested the effects of leaf extract on germination of five native woodland species and L. maackii placed in sterile or live soil. There was an overall suppressive effect of L. maackii extract on itself and the other five native species tested. However, L. maackii extract interacted with live soil in ways that differed with the species being tested and, in some cases, changed over time. Our results indicate that allelopathic potential of L. maackii shows context dependency with respect to soil microorganisms and native species identity but not to light conditions or soil type. Our results imply that restoration of invaded areas may require active reintroduction of species sensitive to allelopathy in live soil. Further, laboratory assays of allelopathy should consider the interaction of allelochemicals with biotic and abiotic conditions to more accurately predict the impacts of allelopathy on plant communities.     

Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes

Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified—one tissue-nonspecific (TNAP) and three tissue-specific—named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes.     

Pathogenic and commensal Escherichia coli from irrigation water show potential in transmission of extended spectrum and AmpC β‐lactamases determinants to isolates from lettuce

There are few studies on the presence of extended-spectrum β-lactamases and AmpC β-lactamases (ESBL/AmpC) in bacteria that contaminate vegetables. The role of the production environment in ESBL/AmpC gene transmission is poorly understood. The occurrence of ESBL/AmpC in Escherichia coli (n = 46) from lettuce and irrigation water and the role of irrigation water in the transmission of resistant E. coli were studied. The presence of ESBL/AmpC, genetic similarity and phylogeny were typed using genotypic and phenotypic techniques. The frequency of β-lactamase gene transfer was studied in vitro. ESBLs/AmpC were detected in 35 isolates (76%). Fourteen isolates (30%) produced both ESBLs/AmpC. Prevalence was highest in E. coli from lettuce (90%). Twenty-two isolates (48%) were multi-resistant with between two and five ESBL/AmpC genes. The major ESBL determinant was the CTX-M type (34 isolates). DHA (33% of isolates) were the dominant AmpC β lactamases. There was a high conjugation efficiency among the isolates, ranging from 3.5 × 10⁻² to 1 × 10⁻² ± 1.4 × 10⁻¹ transconjugants per recipient. Water isolates showed a significantly higher conjugation frequency than those from lettuce. A high degree of genetic relatedness between E. coli from irrigation water and lettuce indicated possible common ancestry and pathway of transmission.     

The Activator of Apoptosis Smac-DIABLO Acts as a Tetramer in Solution

Smac-DIABLO in its mature form (20.8 kDa) binds to baculoviral IAP repeat (BIR) domains of inhibitor of apoptosis proteins (IAPs) releasing their inhibitory effects on caspases, thus promoting cell death. Despite its apparent molecular mass (∼100 kDa), Smac-DIABLO was held to be a dimer in solution, simultaneously targeting two distinct BIR domains. We report an extensive biophysical characterization of the protein alone and in complex with the X-linked IAP (XIAP)-BIR2-BIR3 domains. Our data show that Smac-DIABLO adopts a tetrameric assembly in solution and that the tetramer is able to bind two BIR2-BIR3 pairs of domains. Our small-angle x-ray scattering-based tetrameric model of Smac-DIABLO/BIR2-BIR3 highlights some conformational freedom of the complex that may be related to optimization of IAPs binding.     

Solution Structure of an Intramembrane Aspartyl Protease via Small Angle Neutron Scattering

Intramembrane aspartyl proteases (IAPs) comprise one of four families of integral membrane proteases that hydrolyze substrates within the hydrophobic lipid bilayer. IAPs include signal peptide peptidase, which processes remnant signal peptides from nascent polypeptides in the endoplasmic reticulum, and presenilin, the catalytic component of the γ-secretase complex that processes Notch and amyloid precursor protein. Despite their broad biomedical reach, basic structure-function relationships of IAPs remain active areas of research. Characterization of membrane-bound proteins is notoriously challenging due to their inherently hydrophobic character. For IAPs, oligomerization state in solution is one outstanding question, with previous proposals for monomer, dimer, tetramer, and octamer. Here we used small angle neutron scattering (SANS) to characterize n-dodecyl-β-D-maltopyranoside (DDM) detergent solutions containing and absent a microbial IAP ortholog. A unique feature of SANS is the ability to modulate the solvent composition to mask all but the enzyme of interest. The signal from the IAP was enhanced by deuteration and, uniquely, scattering from DDM and buffers were matched by the use of both tail-deuterated DDM and D₂O. The radius of gyration calculated for IAP and the corresponding ab initio consensus model are consistent with a monomer. The model is slightly smaller than the crystallographic IAP monomer, suggesting a more compact protein in solution compared with the crystal lattice. Our study provides direct insight into the oligomeric state of purified IAP in surfactant solution, and demonstrates the utility of fully contrast-matching the detergent in SANS to characterize other intramembrane proteases and their membrane-bound substrates.     

氮沉降对不同入侵程度加拿大一枝黄花化感作用的影响

为探究全球氮沉降影响外来植物入侵扩张的作用机制,该文通过受控模拟试验,以入侵植物加拿大一枝黄花(Solidago canadensis)为对象,研究了三种氮水平(N0、N5和N12)下五种不同入侵程度(种内及种间竞争)的加拿大一枝黄花凋落叶浸提液对本地植物莴苣(Lactuca sativa)种子萌发和幼苗生长化感作用的影响。结果表明:(1) N0、N5和N12处理下的不同入侵程度加拿大一枝黄花凋落叶浸提液均显著抑制莴苣的萌发和生长,其中N5土壤入侵初期(S1A3)处理浸提液的化感作用最显著,其发芽速度指数、发芽活力指数、根长、株高和叶长比对照分别降低了61%、79%、84%、68%和13%,此时凋落叶中的总酚和总黄酮含量最高,分别为0.48 mg·g^-1和1.50 mg·g^-1。(2)相同氮添加下,入侵程度对加拿大一枝黄花化感作用有显著影响,随着入侵程度的增加,加拿大一枝黄花化感作用显著减弱,入侵初期(S1A3)凋落叶化感作用显著高于入侵后期(S3A1)。(3)相同入侵程度下,氮添加对加拿大一枝黄花化感作用有显著影响,N5处理的加拿大一枝黄花...     

Uncoupling of the dynamics of host–pathogen interaction uncovers new mechanisms of viral interferon antagonism at the single-cell level

Antiviral defence in mammals is mediated through type-I interferons (IFNs). Viruses antagonise this process through expression of IFN antagonist proteins (IAPs). Understanding and modelling of viral escape mechanisms and the dynamics of IAP action has the potential to facilitate the development of specific and safe drugs. Here, we describe the dynamics of interference by selected viral IAPs, NS1 from Influenza A virus and NS3/4A from Hepatitis C virus. We used Tet-inducible IAP gene expression to uncouple this process from virus-driven dynamics. Stochastic activation of the IFN-β gene required the use of single-cell live imaging to define the efficacy of the inhibitors during the virus-induced signalling processes. We found significant correlation between the onset of IAP expression and halted IFN-β expression in cells where IFN-β induction had already occurred. These data indicate that IAPs not only prevent antiviral signalling prior to IFN-β induction, but can also stop the antiviral response even after it has been activated. We found reduced NF-κB activation to be the underlying mechanism by which activated IFN expression can be blocked. This work demonstrates a new mechanism by which viruses can antagonise the IFN response.     

Inhibitor of Apoptosis Proteins (IAPs) and Their Antagonists Regulate Spontaneous and Tumor Necrosis Factor (TNF)-induced Proinflammatory Cytokine and Chemokine Production

Inhibitor of apoptosis proteins (IAPs) play a major role in determining whether cells undergo apoptosis in response to TNF as well as other stimuli. However, TNF is also highly proinflammatory through its ability to trigger the secretion of multiple inflammatory cytokines and chemokines, which is arguably the most important role of TNF in vivo. Indeed, deregulated production of TNF-induced cytokines is a major driver of inflammation in several autoimmune conditions such as rheumatoid arthritis. Here, we show that IAPs are required for the production of multiple TNF-induced proinflammatory mediators. Ablation or antagonism of IAPs potently suppressed TNF- or RIPK1-induced proinflammatory cytokine and chemokine production. Surprisingly, IAP antagonism also led to spontaneous production of chemokines, particularly RANTES, in vitro and in vivo. Thus, IAPs play a major role in influencing the production of multiple inflammatory mediators, arguing that these proteins are important regulators of inflammation in addition to apoptosis. Furthermore, small molecule IAP antagonists can modulate spontaneous as well as TNF-induced inflammatory responses, which may have implications for use of these agents in therapeutic settings.