Endocytosis efficiency and targeting ability by the cooperation of nanoparticles.

Cooperative wrapping of nanoparticles (NPs) with small sizes is an important pathway for the uptake of NPs by cell membranes. However, the cooperative wrapping efficiency and the effects of NPs' rigidity remain ambiguous. With the aid of computer simulations, we show that the complete wrapping mechanism of cooperative endocytosis is that the aggregation of NPs leads to greater wrapping forces than the single NP case, which triggers the increase of the wrapping degree and in turn further increases the wrapping forces until they are finally fully taken up. The effects of the NP size, initial distance, interaction strength, arrangement and stiffness on cooperative endocytosis were systematically studied. The cooperative wrapping efficiency increases as the NP radius increases. Hexagonal close packed NPs have the highest internalization efficiency. When the interactions are strong, softer NPs exhibit higher endocytosis efficiency. We further propose two strategies by combining NPs with different wrapping properties for targeting applications. By combining two NPs decorated with different types of ligands, the combination NPs can only be fully endocytosed by the cell membrane with two cognate types of receptors and adhere to the normal cell membrane with only one type of receptor. We also design composite NPs using a large NP non-covalently decorated with several small NPs. By harnessing the competition between the ligand-receptor interactions and the excluded volume interactions between the small NPs and the lipid membrane, the composite NPs have targeting ability towards the cancer cell membrane. The design concept of combining NPs with different wrapping properties for drug targeting applications may be very promising in biomedicine.

Prognostic value of lymph node ratio in patients with non-metastatic cervical cancer treated with radical hysterectomy: A population-based study.

BACKGROUND: The lymph node ratio (LNR) is an emerging prognostic biomarker in multiple malignancies. This study aimed to explore the prognostic role of LNR in patients with non-metastatic cervical cancer undergoing radical hysterectomy. METHODS: Data were extracted from the SEER 17 registry. Univariate and multivariate Cox analyses were performed to identify the prognostic factors associated with cancer-specific survival (CSS). A nomogram was constructed to predict the 5-year and 10-year CSS. Survival analyses stratified by the status of LNR and different adjuvant treatments were performed using the Kaplan-Meier method. RESULTS: A total of 8128 female patients with non-metastatic cervical cancer who underwent radical hysterectomy and regional node examination (≥8) were enrolled. Of these, 1269 (15.6%) were confirmed as lymph node-positive. Cox regression analyses showed that age, race, tumor size, tumor grade, histology, and LNR were significant factors affecting CSS. A nomogram was developed for predicting the 5-year and 10-year CSS, which showed good discrimination and calibration. Patients without lymph node involvement had inferior CSS with adjuvant treatments compared to those who did not receive further treatment. In patients with LNR ≤10%, only those receiving adjuvant radiotherapy had a trend of better CSS. In patients with an LNR between 10% and 30% and more than 30%, concurrent radiochemotherapy (CCRT) proved to be the best treatment. CONCLUSIONS: LNR is an independent prognostic factor in patients with non-metastatic cervical cancer undergoing radical hysterectomy. For patients with negative lymph nodes, no further treatment is recommended. Patients with positive lymph nodes could benefit more from CCRT.

An inulin-type fructan CP-A from Codonopsis pilosula alleviates TNBS-induced ulcerative colitis based on serum-untargeted metabolomics.

Ulcerative colitis (UC) is an inflammatory disease with abdominal pain, diarrhea, and bloody stool as the main symptoms. Several studies have confirmed that polysaccharides are effective against UC. It is commonly accepted that the traditional benefits of Radix Codonopsis can be attributed to its polysaccharide contents, and inulin-type fructan CP-A is the main active monomer in the polysaccharide components. Herein, we established a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC rat model and lipopolysaccharide (LPS)-induced colonic epithelial cell model (NCM460) to investigate the effect of CP-A on UC. Untargeted metabolomics studies were conducted to identify differential metabolites using ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS) and enrich metabolic pathways in rat serum. The in vivo assays demonstrated that CP-A reduces colonic macroscopic injury, disease activity index (DAI), histopathological score, interleukin (IL)-8, and tumor necrosis factor-α (TNF-α) levels, as well as the expression of intercellular adhesion molecules. On the other hand, CP-A increases IL-10 and transforming growth factor-ß (TGF-ß) levels. The in vitro experiments indicated that CP-A treatment could reduce nitric oxide (NO) and IL-1ß after LPS stimulation. The metabolomics results suggested that CP-A therapy for UC may be related to the mammalian target of rapamycin (mTOR) signaling pathway. The in vitro and in vivo validation of the pathway showed similar results, indicating that CP-A alleviates UC by preventing the activation of mTOR/p70S6K signaling pathway. These findings offer a fresh approach to treating UC and a theoretical foundation for the future advancement of CP-A.NEW & NOTEWORTHY We report that an inulin-type fructan from Codonopsis pilosula CP-A exhibits a therapeutic effect on experimental colitis. Its mechanism may be to alleviate intestinal inflammation by preventing the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling pathway. These findings offer a fresh approach to treating ulcerative colitis (UC) and a theoretical foundation for the future advancement of CP-A.

Exosomal miR-224-5p from Colorectal Cancer Cells Promotes Malignant Transformation of Human Normal Colon Epithelial Cells by Promoting Cell Proliferation through Downregulation of CMTM4.

Background: Interactions between malignant cells and neighboring normal cells are important for carcinogenesis. In addition, cancer cell-derived exosomes have been shown to promote the malignant transformation of recipient cells, but the mechanisms remain unclear. Methods: The level of miR-224-5p in CRC cell-derived exosomes was determined by RT-qPCR assay. In addition, PKH26 dye-labeled exosomes were used to assess the efficacy of the transfer of exosomes between SW620 and normal colon epithelial cell line CCD 841 CoN. Results: In this study, we found that overexpression of miR-224-5p significantly promoted the proliferation, migration, and invasion and inhibited the oxidative stress of SW620 cells. In addition, miR-224-5p can be transferred from SW620 cells to CCD 841 CoN cells via exosomes. SW620 cell-derived exosomal miR-224-5p markedly promoted proliferation, migration, and invasion of CCD 841 CoN cells. Meanwhile, SW620 cell-derived exosomal miR-224-5p notably decreased the expression of CMTM4 in CCD 841 CoN cells. Furthermore, SW620 cell-derived exosomal miR-224-5p significantly promoted tumor growth in a xenograft model in vivo. Conclusion: These findings suggested that SW620 cell-derived exosomal miR-224-5p could promote malignant transformation and tumorigenesis in vitro and in vivo via downregulation of CMTM4, suggesting that miR-224-5p might be a potential target for therapies in CRC.

Effect of the neuropathic pain receptor P2X3 on bladder function induced by intraperitoneal injection of cyclophosphamide (CYP) in interstitial cystitis rats.

Background: The role of purinergic receptor P2X3 in pathological bladder dysfunction and chronic pelvic pain remains unclear. We aim to investigate the effect of P2X3 on bladder function in interstitial cystitis (IC) through the IC rat model induced by cyclophosphamide (CYP). Methods: A total of 120 female Sprague-Dawley (SD) rats were randomly divided into 6 groups: control, CYP-4h, CYP-48h, CYP-10d, CYP-30d, and CYP-45d groups. The control group was injected with normal saline. The rats in the CYP-4h and CYP-48h groups were given a single high dose. The rats in the CYP-10d, CYP-30d, and CYP-45d groups were given a low dose of CYP repeatedly every three days. Bladder voiding function was measured using urodynamic techniques to observe the effect of the P2X3 receptor on bladder function in CYP-induced IC. Results: The rats in the CYP-4h group showed significant overactivity of the bladder compared with the control group, the bladder voiding interval was shortened (P<0.01), and the maximal voiding pressure was increased (P<0.01). At the same time, the degree of overactive bladder in the CYP-48h, CYP-10d, CYP-30d, and CYP-45d groups became increasingly serious, the interval of bladder micturition was shortened stepwise (P<0.01), and the maximal micturition pressure was increased stepwise (P<0.01). Compared with the control group, the CYP-48h group mainly showed a shorter bladder voiding interval (P<0.01), lower voiding volume, and higher activation of mast cells and inflammatory factors in the bladder. In the CYP-10d group, bladder mast cell activation and inflammatory factors increased significantly. Intrathecal injection (IT) of A-317491 significantly prolonged the bladder voiding intervals in CYP-4h, CYP-48h, CYP-10d, CYP-30d, and CYP-45d rats (P<0.01), and the maximal voiding pressure of the CYP-4h, CYP-48h, CYP-10d, CYP-30d, and CYP-45d groups was significantly decreased (P<0.05), while the maximal voiding pressure of the CYP-10d group was not significantly affected. Conclusions: P2X3 receptors in dorsal root ganglion (DRG) play an important role in bladder function induced by intraperitoneal injection of CYP in rats. IT of P2X3 inhibitors can significantly improve the grade of bladder voiding dysfunction and chronic pelvic pain.

Second primary malignancy among malignant solid tumor survivors aged 85 years and older.

The cancer burden in the oldest old has increased rapidly. This study aimed to investigate the epidemiology of second primary malignancy (SPM) in malignant solid tumor survivors aged 85 years and older utilizing the Surveillance, Epidemiology, and End Results (SEER) database. A total of 128,466 malignant solid tumor patients had been identified between 2000 and 2011, including 6774 patients who developed a SPM. The overall crude incidence of developing a SPM was 5.3%. Considering death as a competing event, the 3, 5, and 10-year cumulative incidence was 1.9%, 3.2%, and 5.4%, respectively. Relative younger age, male gender, surgery history, local stage and first primary malignancy (FPM) site located in the urinary system were related to higher cumulative incidence. A median time interval of 24.0 months was found between diagnosis of FPM and SPM. The most common SPM site was digestive system, whereas the least common was oral cavity and pharynx. The median overall survival (OS) was 49.0 months, and the median survival after SPM was 13.0 months. Relative older age, male gender and black race were associated with worse OS and survival after SPM, as well as higher hazard ratios of death. In conclusions, this study performed a comprehensive analysis of SPM among malignant solid tumor survivors aged 85 years and older. Additional studies are needed to characterize the specific cancer type of interest.

Negative Correlation Between Circular RNA SMARC5 and MicroRNA 432, and Their Clinical Implications in Bladder Cancer Patients.

Objective: Our study aimed to evaluate the correlation of circular RNA SMARCA5 (circ-SMARCA5) and microRNA 432 (miR-432) with clinical characteristics and survival in bladder cancer patients. Methods: Preoperative clinicopathologic features and survival data of 156 bladder cancer patients were retrospectively reviewed. A total of 156 cases of tumor tissues, whereas 71 cases out of 156 available adjacent tissues were obtained from the Pathology Department for circ-SMARCA5 and miR-432 detections using real-time quantitative polymerase chain reaction. Results: Circ-SMARCA5 was upregulated but miR-432 was downregulated in tumor tissues compared with adjacent tissues; meanwhile, circ-SMARCA5 expression was negatively correlated with miR-432 in bladder cancer tissues. Circ-SMARCA5 high expression was correlated with larger tumor size, higher tumor stage, and lymph node (LYN) metastasis. However, miR-432 high expression was correlated with single multiplicity, smaller tumor size, lower tumor stage, less LYN metastasis in bladder cancer patients. Regarding survival, circ-SMARCA5 high expression was correlated with shorter disease-free survival (DFS) and overall survival (OS); whereas, miR-432 high expression was correlated with longer DFS and OS in bladder cancer patients. Further multivariate Cox's regression analysis displayed that circ-SMARCA5 high expression was an independent predictive factor for both worse DFS and OS in bladder cancer patients. Conclusion: Circ-SMARCA5 high expression but miR-432 low expression is correlated with advanced tumor features and poor survival of bladder cancer patients, which present as potential prognostic markers in bladder cancer.

Factors for incidence risk and prognosis in non-small-cell lung cancer patients with synchronous brain metastasis: a population-based study.

Background: We aimed to investigate the epidemiology of synchronous brain metastasis (SBM) in non-small-cell lung cancer (NSCLC) patients. Methods: Logistic regression and Cox regression were used to identify the related factors of SBM incidence and cancer-specific survival (CSS). A nomogram for predicting CSS was developed and validated. Results: The incidence of SBM in NSCLC patients was 12.58%. The median CSS was 5 months. Patients with younger age, female gender, and adenocarcinoma had higher odd ratios for developing SBM. In addition, a nomogram was developed based on significant factors from Cox regression. The validation of the nomogram showed that it had good calibration and discrimination. Conclusions: SBM was highly prevalent in NSCLC patients, who also had poor survival.

Lay abstract Due to the high incidence and poor survival of non-small-cell lung cancer (NSCLC) patients with metastases in the brain (SBM), investigations on the epidemiology, risk factors of SBM incidence and biological indicators of prognosis are of high clinical importance. The data we used was from the Surveillance, Epidemiology, and End Results database, which is kept up to date by American oncologists. The results showed that the incidence of brain metastases in NSCLC patients was 12.58%. The median cancer-specific survival was 5 months. Patients with younger age and female gender had higher likelihood for developing SBM. In conclusion, SBM was highly prevalent in NSCLC patients, who also had poor survival.

Antimicrobial and antitumor activity of peptidomimetics synthesized from amino acids.

Thirteen cationic peptidomimetics derived from amino acids bearing an alkyl or ethynylphenyl moiety that mimic the structure of cationic antibacterial peptides were designed and synthesized using a simple coupling reaction of an amino acid with a substituted amine. Antibacterial activities of the resulting peptidomimetics against drug-sensitive bacteria, such as Gram-positive Staphylococcus aureus (S. aureus) and Bacillus subtilis, Gram-negative Escherichia coli (E. coli) and Salmonella enterica, and a drug-resistant bacterium, methicillin-resistant S. aureus (MRSA), were systematically evaluated. Most peptidomimetics show significant broad-spectrum antibacterial activity. A-L-Iso-C12 (isoleucine derivative bearing a dodecyl moiety) show MICs of 2.5 µg/mL against S. aureus and 4 µg/mL against MRSA and A-L-Val-C12 (valine derivative bearing a dodecyl moiety) show MICs of 1.67 µg/mL against E. coli and 8.3 µg/mL against MRSA. A-L-Val-C12 showed low cytotoxicity toward L929 cells in comparison with SGC 7901 cells, indicating tumor-directed killing by peptidomimetics while avoiding toxicity to normal cells. The influences of type of amino acid and substituent, length of substituent, and stereochemistry of amino acids on antibacterial activity and cytotoxicity of peptidomimetics were systematically investigated. The results indicate that this series of cationic peptidomimetics derived from amino acids display antitumor activity and may be useful for treatment of bacterial infections.

Multifunctional Polypropylene Separator via Cooperative Modification and Its Application in the Lithium-Sulfur Battery.

The continuous shuttling of dissolved polysulfides between the electrodes is the primary cause for the rapid decay of lithium-sulfur batteries. Modulation of the separator-electrolyte interface through separator modification is a promising strategy to inhibit polysulfide shuttling. In this work, we develop a graphene oxide and ferrocene comodified polypropylene separator with multifunctionality at the separator-electrolyte interface. The graphene oxide on the functionalized separator could physically adsorb the polysulfide while the ferrocene component could effectively facilitate the conversion of the adsorbed polysulfide. Due to the combination of these beneficial functionalities, the separator exhibits an excellent battery performance, with a high reversible capacity of 409 mAh g-1 after 500 cycles at 0.2 C. We anticipate that the combinatorial separator functionalization proposed herein is an effective approach for improving the performance of lithium-sulfur batteries.

A Bioinspired Functionalization of Polypropylene Separator for Lithium-Sulfur Battery.

Lithium-sulfur batteries have received intensive attention, due to their high specific capacity, but the shuttle effect of soluble polysulfide results in a decrease in capacity. In response to this issue, we develop a novel tannic acid and Au nanoparticle functionalized separator. The tannic acid and gold nanoparticles were modified onto commercial polypropylene separator through a two-step solution process. Due to a large number of phenolic hydroxyl groups contained in the modified layer and the strong polarity of the gold nanoparticles, the soluble polysulfide generated during battery cycling is well stabilized on the cathode side, slowing down the capacity fade brought by the shuttle effect. In addition, the modification effectively improves the electrolyte affinity of the separator. As a result of these benefits, the novel separator exhibits improved battery performance compared to the pristine polypropylene separator.

[Clinical application of the free anterolateral thigh myocutaneous flap with the tensor fascia lata for one-stage repair of soft tissues defects at the dorsum of hands (feets)].

Objective: To explore the method and the therapeutic effect of the free anterolateral thigh myocutaneous flap with the tensor fascia lata for one-stage repair of soft tissues defects at the dorsum of hands (feets). Method: Between Jan.2010 and Dec.014,8 patients with finger (toe) extensor tendon and dorsal foot defect were treated with anterolateral thigh myocutaneous flap. The defect area ranged from 6 cm ×5cm to 18 cm× 10cm.All of the soft tissues defects at the dorsum of hands (feets) combined with tendon colobomam. The free anterolateral thigh myocutaneous flap (ranged from 8 cm × 7cm to 20 cm × 12cm) were applied for one-stage repair of the soft tissues defects. The anterolateral thigh flap was used to repair defect and fascia lata was used to bridge two ends of digitorum longus tendon. The defects at donor sites were sutured directly or repaired with the split-thickness skin graft.2-3 months after the surgery, tenolysis for tendon was performed, and fascia lata was split into tendon-like shape and the finger (toe) functional exercises were done. Results: All flaps survived completely after the first stage.Postoperative follow-up time was 6-12 months (average,8 months).Except 4 flaps with somewhat swelling, the other flaps had satisfactory appearance with soft texture. During the follow-up, part of the dorsiflexion function of hand recovered in 3 patients (5°-40°),and flexion function was normal;5 patients with soft tissues defects at the dorsum of foots could walk normally with no toe ptosis. Conclusions: Application of the free anterolateral thigh myocutaneous flap with the tensor fascia lata can repair soft tissues defects at the dorsum of hands (feets) combined with tendon colobomam. It can repair soft tissues defect combined with finger (toe) extensor tendon defects. Excellent clinical results can be achieved with short treatment time and less damage to the donor site.

Induction of autophagy contributes to the myocardial protection of valsartan against ischemia­reperfusion injury.

The mechanisms underlying the myocardial protection of valsartan against ischemia/reperfusion (I/R) injury are complicated and remain unclear. The aim of this study was to investigate whether autophagy machinery was involved in the protection against I/R injury that is induced by valsartan. In vivo rat hearts were subjected to ischemia by 30 min ligation of the left anterior descending coronary artery, followed by a 120 min reperfusion. 3­methyladenine (3­MA), a specific inhibitor on autophagic sequestration, was used to inhibit autophagy. The hemodynamics, infarct size of the ventricle and LC3B protein were measured. Western blot analysis was performed to investigate the mechanism by which autophagy was induced by valsartan. Valsartan preconditioning resulted in a significant decrease in infarct size and induced autophagy in the rat heart subjected to I/R injury. The hemodynamics assay showed that the valsartan­induced cardiac functional recovery was attenuated by 3­MA. By contrast, 3­MA decreased the improvement induced by valsartan on the histology and infarction of the rat heart subjected to I/R injury. Valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, independent of Beclin1. In conclusion, valsartan preconditioning induced autophagy via the AKT/mTOR/S6K pathway, which contributed to the myocardial protection against I/R injury.

TAT-Apoptin induces apoptosis in the human bladder cancer EJ cell line and regulates Bax, Bcl-2, caspase-3 and survivin expression.

In order to identify the antitumor effect of TAT-Apoptin on the human bladder cancer EJ cell line and study its impact on the expression of the apoptosis-related genes bax, bcl-2, caspase-3 and survivin, the MTT assay, real-time quantitative PCR and western blot analysis were used in this study. The results of the MTT assay indicated that TAT-Apoptin was able to inhibit the proliferation of EJ cells in a dose-dependent manner. The expression of Bax, Bcl-2, Caspase-3 and Survivin mRNA and protein following the treatment of the EJ cells with TAT-Apoptin (0.1, 0.5, 1, 10, 50 and 100 µg/ml) for 24, 48 and 72 h was analyzed. Cell proliferation was significantly different after treatment with the various concentrations of TAT-Apoptin and the durations of treatment. The level of expression of Bcl-2 and Survivin in EJ cells decreased significantly, while that of Bax and Caspase-3 increased significantly at the mRNA and protein levels.

Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants.

The molecular mechanism by which mutations in the cytoskeleton-organizing protein PSTPIP1 cause the autoinflammatory PAPA syndrome is still elusive. Here, we demonstrate that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1. We provide evidence that pyrin is a cytosolic receptor for PSTPIP1. Pyrin exists as a homotrimer in an autoinhibited state due to intramolecular interactions between its pyrin domain (PYD) and B-box. Ligation by PSTPIP1, which is also a homotrimer, activates pyrin by unmasking its PYD, thereby allowing it to interact with ASC and facilitate ASC oligomerization into an active ASC pyroptosome. Because of their high binding affinity to pyrin's B-box, PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation. Therefore, constitutive ligation and activation of pyrin by mutant PSTPIP1 proteins explain the autoinflammatory phenotype seen in PAPA syndrome.

Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death.

In yeast, Tim50 along with Tim23 regulate translocation of presequence-containing proteins across the mitochondrial inner membrane. Here, we describe the identification and characterization of a novel human mitochondrial inner membrane protein homologous to the yeast Tim50. We demonstrate that human Tim50 possesses phosphatase activity and is present in a complex with human Tim23. Down-regulation of human Tim50 expression by RNA interference increases the sensitivity of human cell lines to death stimuli by accelerating the release of cytochrome c from the mitochondria. Furthermore, injection of Tim50-specific morpholino antisense oligonucleotides during early zebrafish embryonic development causes neurodegeneration, dysmorphic hearts, and reduced motility as a result of increased cell death. These observations indicate that loss of Tim50 in vertebrates causes mitochondrial membrane permeabilization and dysfunction followed by cytoplasmic release of cytochrome c along with other mitochondrial inducers of cell death. Thus Tim50 is important for both mitochondrial function and early neuronal development.

The polypeptide chain-releasing factor GSPT1/eRF3 is proteolytically processed into an IAP-binding protein.

Smac/Diablo and HtrA2/Omi are inhibitors of apoptosis (IAP)-binding proteins released from the mitochondria of human cells during apoptosis and regulate apoptosis by liberating caspases from IAP inhibition. Here we describe the identification of a proteolytically processed isoform of the polypeptide chain-releasing factor GSPT1/eRF3 protein, which functions in translation, as a new IAP-binding protein. In common with other IAP-binding proteins, the processed GSPT1 protein harbors a conserved N-terminal IAP-binding motif (AKPF). Additionally, processed GSPT1 interacts biochemically with IAPs and could promote caspase activation, IAP ubiquitination and apoptosis. The IAP-binding motif of the processed GSPT1 is absolutely required for these activities. Our findings are consistent with a model whereby processing of GSPT1 into the IAP-binding isoform could potentiate apoptosis by liberating caspases from IAP inhibition, or target IAPs and the processed GSPT1 for proteasome-mediated degradation.

sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein.

Inhibitors of apoptosis proteins (IAPs) interact with caspases and inhibit their protease activity, whereas the IAP-inhibitory proteins Smac/DIABLO in mammals and Reaper, Hid, and Grim in flies relieve IAP-mediated inhibition to induce cell death. Here we describe the functional characterization of the novel Drosophila cell death protein Sickle (Skl), which binds to IAPs and neutralizes their apoptotic inhibitory activity. Skl exhibits no sequence homology to Reaper, Hid, Grim, or Smac/DIABLO, except within the 4 residue N-terminal IAP binding motif. Skl interacts with Drosophila and mammalian IAPs and can promote caspase activation in the presence of IAPs. Consistent with these findings, expression of Skl in Drosophila and mammalian cell lines or in Drosophila embryos induces apoptosis. Skl can also synergize with Grim to induce cell death in the Drosophila eye imaginal disc. Based on biochemical and structural data, the N terminus of Skl, like that of the mammalian Smac/DIABLO, is absolutely required for its apoptotic and caspase-promoting activities and its ability to interact with IAPs. These findings point to conservation in the structure and function of the IAP-inhibitory proteins across species and suggest the existence of other family members.