Homological percolation transitions in growing simplicial complexes.

Simplicial complex (SC) representation is an elegant mathematical framework for representing the effect of complexes or groups with higher-order interactions in a variety of complex systems ranging from brain networks to social relationships. Here, we explore the homological percolation transitions (HPTs) of growing SCs using empirical datasets and model studies. The HPTs are determined by the first and second Betti numbers, which indicate the appearance of one- and two-dimensional macroscopic-scale homological cycles and cavities, respectively. A minimal SC model with two essential factors, namely, growth and preferential attachment, is proposed to model social coauthorship relationships. This model successfully reproduces the HPTs and determines the transition types as an infinite-order Berezinskii-Kosterlitz-Thouless type but with different critical exponents. In contrast to the Kahle localization observed in static random SCs, the first Betti number continues to increase even after the second Betti number appears. This delocalization is found to stem from the two aforementioned factors and arises when the merging rate of two-dimensional simplexes is less than the birth rate of isolated simplexes. Our results can provide a topological insight into the maturing steps of complex networks such as social and biological networks.

RIP2/RICK-dependent cytokine production upon Yersinia enterocolitica infection in macrophages with TLR4 deficiency.

Receptor-interacting protein 2 (RIP2) is a caspase recruitment domain (CARD)-containing serine/threonine kinase that is activated by NOD1 or NOD2 recognition of their ligands and essential for the activation of NF-κB and mitogen-activated protein kinase (MAPK). RIP2 has been known to play an important role in innate immune responses against certain bacterial infection. However, the role and interplay of RIP2 with TLR signalling on cytokine production in macrophages against Yersinia enterocolitica infection remains poorly understood. In the present study, we examined whether RIP2 is essential for Yersinia-induced production of cytokines in macrophages. Our results showed that naïve RIP2-deficient macrophages produced similar level of IL-6, TNF-α and IL-10 upon Y. enterocolitica infection compared with wild-type macrophages. However, the production of IL-6, TNF-α and IL-10 by Y. enterocolitica was impaired in RIP2-deficient macrophages after lipopolysaccharide (LPS) pretreatment, a TLR4-tolerant condition. In addition, RIP2 inhibitors, SB203580, PP2, and gefitinib, reduced IL-6 production in TLR4-deficient macrophages in response to Y. enterocolitica, whereas they did not affect the cytokines production in WT cells. These results demonstrate that RIP2 may play an important role in proinflammatory cytokine production in macrophages at the absence of TLR signalling.

Morphological changes of injected calcium phosphate cement in osteoporotic compressed vertebral bodies.

SUMMARY: This study was undertaken to investigate the radiologic and clinical outcomes of vertebroplasty with calcium phosphate (CaP) cement in patients with osteoporotic vertebral compression fractures. The morphological changes of injected CaP cement in osteoporotic compressed vertebral bodies were variable and unpredictable. We suggest that the practice of vertebroplasty using CaP should be reconsidered. INTRODUCTION: Recently, CaP, an osteoconductive filler material, has been used in the treatment of osteoporotic compression fractures. However, the clinical results of CaP-cement-augmented vertebrae are still not well established. The purpose of this study is to assess the clinical results of vertebroplasty with CaP by evaluating the morphological changes of CaP cement in compressed vertebral bodies. METHODS: Fourteen patients have been followed for more than 2 years after vertebroplasty. The following parameters were reviewed: age, sex, T score, compliance with osteoporosis medications, visual analog scale score, compression ratio, subsequent compression fractures, and any morphological changes in the filler material. RESULTS: The morphological changes of injected CaP included reabsorption, condensation, bone formation (osteogenesis), fracture of the CaP solid hump, and heterotopic ossification. Out of 14 patients, 11 (78.6%) developed progression of the compression of the CaP-augmented vertebral bodies after vertebroplasty. CONCLUSIONS: The morphological changes of the injected CaP cement in the vertebral bodies were variable and unpredictable. The compression of the CaP-augmented vertebrae progressed continuously for 2 years or more. The findings of this study suggest that vertebroplasty using CaP cement should be reconsidered.

Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys.

Her-2/neu is a well-characterized tumor-associated antigen, the overexpression of which in human carcinomas correlates with a poor prognosis. Here, we evaluated Her-2/neu-specific humoral and cellular immune responses in immunized monkeys after immunization with nonreplicating adenovirus (AdHM) expressing the extracellular and transmembrane domain of human Her-2/neu (HM) and/or naked DNA vaccine (pHM-hGM-CSF) expressing human granulocyte-macrophage colony-stimulating factor together with HM. Priming of monkeys with AdHM generated Her-2/neu-specific long-lasting antibody production. Furthermore, these Her-2/neu-specific antibodies produced by AdHM immunization, some of which shared epitope specificity with Herceptin, were able to induce antibody-dependent cellular cytotoxicity against Her-2-expressing target cells. Cellular immune responses were elicited in all monkeys immunized with Her-2/neu-expressing vaccine; interferon-gamma was secreted when these splenocytes were restimulated with Her-2/neu-expressing autologous cells, and immunization with AdHM induced Her-2/neu-specific lymphoproliferative responses. Further, immunization with pHM-hGM-CSF before AdHM immunization noticeably enhanced cytotoxic T-lymphocyte activity. In addition, we observed no abnormalities that would indicate that the genetic vaccines had toxic effects in the immunized monkeys. Thus, we can conclude that our genetic vaccines efficiently elicited Her-2/neu-specific humoral and cellular immune responses without causing severe adverse effects in nonhuman primates and that as such they warrant further clinical investigation.

Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis.

Inflammatory bowel disease (IBD) is characterized by detrimental immune reactivity in the gut, and the imbalance between proinflammatory and anti-inflammatory reactivity. The aims of this study were to determine whether oral administration of glabridin, a functional component of liquorice, could ameliorate dextran sulphate sodium (DSS)-induced colitis, as well as to understand the possible underlying mechanisms. Acute experimental colitis was induced in BALB/c mice by treatment with 5% DSS for 7 days. Glabridin (10 or 50 mg/kg/day) was given for 7 days. Treatment with glabridin significantly attenuated mortality, loss of body weight, shortening of the colon and severe clinical symptoms. This was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity and the production of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG) E2, and proinflammatory cytokines. These results suggest that glabridin-mediated anti-inflammatory action on colorectal sites may be a useful therapeutic approach to IBD.

Processing diets containing corn distillers' dried grains with solubles in growing broiler chickens: effects on performance, pellet quality, ileal amino acids digestibility, and intestinal microbiota.

The present study investigated the effects of feed form and distillers' dried grains with solubles (DDGS) on growth performance, nutrient digestibility, and intestine microbiota in broilers. A total of 720 broilers (Ross 308; average BW 541 ± 6 g) was randomly allotted to 6 treatments on the basis of BW. There were 6 replicates in each treatment with 20 birds per replicate. Birds were fed 3 different feed forms (mash, simple pellet, and expanded pellet) and DDGS (0 or 20% of diet) in a 3 × 2 factorial arrangement. Simple pellet (SP) and expanded pellet (EP) fed birds showed an increase in BW gain (P < 0.05). The interaction between feed processing and DDGS level was observed on pellet hardness (P < 0.01). The lowest (P < 0.01) pellet durability index (PDI) and hardness were observed in the diet with DDGS. Values for PDI and hardness were higher for EP compared with SP (P < 0.01). Simple pellet decreased ileal digestibility of CP compared to mash feed. The inclusion of DDGS decreased the digestibility of CP, and tended to decrease digestibility of DM (P = 0.056) and gross energy (P = 0.069). Expanded pellet feeding decreased (P < 0.05) the ileal digestibility of isoleucine, lysine, methionine, phenylalanine, threonine, cysteine, and glutamine compared with mash diet. Processed feed increased (P < 0.01) pH in the gizzard and duodenum; however, processing decreased pH in ileum. The addition of DDGS to the diet reduced pH in the duodenum. The population of Lactobacillus spp. was lower in the duodenum of birds fed the EP diet compared to the mash diet. Processed feed increased the colonization of Clostridium spp. in the gizzard. These results indicated that SP and EP in broiler diet had a potential to improve BW gain, but EP compromised amino acid digestibility. In addition, DDGS supplementation (20%) decreased pellet quality and CP digestibility in broiler chickens; however, the growth performance and feed intake were not affected.

Detection and characterization of intracranial aneurysms with 16-channel multidetector row CT angiography: a prospective comparison of volume-rendered images and digital subtraction angiography.

BACKGROUND AND PURPOSE: The aim of our study was to compare multidetector row CT angiography (MDCTA) with digital subtraction angiography (DSA) in the detection and characterization of intracranial aneurysms. MATERIALS AND METHODS: In our blinded prospective study, 85 patients with suspected intracranial aneurysm (47 women, 38 men; age range, 19-83 years) underwent both 16-channel MDCTA and DSA. The MDCT angiograms were interpreted for the presence, location, size, ratio of the neck to the dome (N/D ratio), and lobularity of the aneurysms and relationship of the aneurysm with the adjacent arterial branches, by using volume-rendering techniques. MDCTA and DSA images (reference standard) were interpreted by 2 independent readers, and the results were compared. RESULTS: A total of 93 aneurysms were detected at DSA in 71 patients, whereas no aneurysms were detected in 14 patients. Compared with DSA, the overall sensitivity, specificity, and accuracy of MDCTA on a per-aneurysm basis were 92.5%, 93.3%, and 92.6%, respectively, for both independent readers. For aneurysms of <3 mm, however, MDCTA had a sensitivity of 74.1% for reader 1 and 77.8% for reader 2. There was excellent agreement between readers in the detection of aneurysms (kappa = 0.822). In addition, MDCTA was also accurate in determining N/D ratio of aneurysms, aneurysm lobularity, and adjacent arterial branches. CONCLUSION: MDCTA is accurate in the detection and characterization of intracranial aneurysms and can be used as a reliable alternative imaging technique to DSA in selected cases.

Publisher's Note: Explosive percolation transitions in growing networks [Phys. Rev. E 93, 032316 (2016)].

This corrects the article DOI: 10.1103/PhysRevE.93.032316.

Explosive percolation transitions in growing networks.

Recent extensive studies of the explosive percolation (EP) model revealed that the EP transition is second order with an extremely small value of the critical exponent ß associated with the order parameter. This result was obtained from static networks, in which the number of nodes in the system remains constant during the evolution of the network. However, explosive percolating behavior of the order parameter can be observed in social networks, which are often growing networks, where the number of nodes in the system increases as dynamics proceeds. However, extensive studies of the EP transition in such growing networks are still missing. Here we study the nature of the EP transition in growing networks by extending an existing growing network model to a general case in which m node candidates are picked up in the Achiloptas process. When m = 2, this model reduces to the existing model, which undergoes an infinite-order transition. We show that when m ≥ 3, the transition becomes second order due to the suppression effect against the growth of large clusters. Using the rate-equation approach and performing numerical simulations, we also show that the exponent ß decreases algebraically with increasing m, whereas it does exponentially in a corresponding static random network model. Finally, we find that the hyperscaling relations hold but in different forms.

Repetitive Transcranial Magnetic Stimulation of the Primary Somatosensory Cortex Modulates Perception of the Tendon Vibration Illusion.

The effect of repetitive transcranial magnetic stimulation on kinesthetic perception, when applied to the somatosensory cortex, was examined. Further, the facilitatory and inhibitory effects of repetitive transcranial magnetic stimulation using different stimulation frequencies were tested. Six female (M age = 32.0 years, SD = 6.7) and nine male (M age = 32.9 years, SD = 6.6) participants were asked to perceive the tendon vibration illusion of the left wrist joint and to replicate the illusion with their right hand. When comparing changes in the corresponding movement amplitude and velocity after three different repetitive transcranial magnetic stimulation protocols (sham, 1 Hz inhibitory, and 5 Hz facilitatory repetitive transcranial magnetic stimulation), the movement amplitude was found to decrease with the inhibitory repetitive transcranial magnetic stimulation, while the movement velocity respectively increased and decreased with the facilitatory and inhibitory repetitive transcranial magnetic stimulation. These results confirmed the modulating effects of repetitive transcranial magnetic stimulation on kinesthetic perception in a single experimental paradigm.

Water-soluble lipopolymer as a gene carrier to corpus cavernosum.

Adenovirus or naked plasmid DNA (pDNA) has been used to deliver the therapeutic gene into corpus cavernosum. However, the potential risks of viral vector and inefficiency of naked pDNA have limited their clinical application. In this study, water-soluble lipopolymer (WSLP) was evaluated as a gene carrier to corpus cavernosum. The WSLP/pDNA complex was transfected to smooth muscle cells in vitro. WSLP had high transfection efficiency, which was comparable to poly(ethylenimine) (PEI). In addition, WSLP had much less cytotoxicity than PEI, suggesting that WSLP is a safer carrier than PEI. To evaluate the transfection efficiency to corpus cavernosum, the WSLP/pDNA complex was injected into the rat corpus cavernosum. As a result, the WSLP/pDNA complex showed higher transfection efficiency than naked pDNA. In addition, the gene expression was dependent upon the dose of the complex. The results suggest that WSLP may be useful for gene therapy of erectile dysfunction.

The regulatory mechanism of phosphatidylinositol 3-kinase by insulin in 3T3 L1 fibroblasts: phosphorylation-independent activation of phosphatidylinositol 3-kinase.

Phosphatidylinositol (PI) 3-kinase plays an important role in transducing the signals of various growth factor receptors. However, the regulatory mechanism of PI3-kinase activity by these growth factor receptors is not completely understood. Therefore, we attempted to clarify the regulatory mechanism of PI3-kinase using insulin and 3T3 L1 fibroblasts. Our results showed that insulin stimulated PI3-kinase activity seven-fold and concomitantly phosphorylated a p85 subunit at the tyrosine residue. However, this tyrosine phosphorylation was not significant in the activation of PI3-kinase as the PI3-kinase pulled down by the overexpressed GST-p85 fusion protein showed as high an activity as the immunoprecipitated one. The p110 subunit was phosphorylated at both serine and tyrosine residues without insulin treatment. Since the phosphorylation state was not changed by insulin. The results suggested that phosphorylation of the p110 subunit does not control PI3-kinase activity. Finally, it was shown that the insulin receptor substrate-1 (IRS-1) binding to PI3-kinase was not sufficient for full activation because the amount of IRS-1 pulled down by the GST-p85 fusion protein reached almost maximum, after incubation with insulin-treated cell lysates for 20 min, whereas PI3-kinase activity reached its maximum only after incubation for 5 h. All results suggest that the phosphorylation of p85 subunit at tyrosine residues and phosphorylation of p110 subunit at tyrosine or serine residues are not functionally significant in the regulation of PI3-kinase activity. They also suggest that P13-kinase is needed to bind to other protein(s) as well as the insulin receptor substrate-1 for full activation.

Primers determine the sensitivity of PCR-mediated hepatitis B virus DNA detection and pretreatment of PCR mixture with 8-methoxypsoralen eliminates false-positive results.

Most methods for the diagnosis of hepatitis B virus (HBV) infection largely depend on viral DNA detection by polymerase chain reaction (PCR) or radioimmunological assay of viral antigens or antibodies. The quality assurance program recently established in Europe reported that PCR-mediated HBV DNA detection methods used in many laboratories produced a high rate of false-positive and false-negative results. Thus, we attempted to improve the conditions of current PCR methods for detection of HBV DNA. In the present study, we applied a recently developed method of releasing HBV DNA from virion by NaOH treatment of patient serum. Using four different primer sets specific to the HBV core region, we found that the sensitivity of first-round PCR can be improved by more than two orders of magnitude depending on the primers. The second round of PCR using nested primers was sensitive enough to detect up to 10(-6) pg of the HBV DNA, which is equivalent to approximately 3 copies of the HBV genome. Among the approximately 800 HBV-infected patient sera investigated in our laboratory, more than 60% of the tested samples gave positive results in the first-round PCR. The rate of positive results obtained using our experimental conditions is very high in comparison with other reports. The reamplification of the first-round PCR reaction mixture with the nested primers produced practically 100% positive results. For diagnosis of HBV infection, we routinely used 1 microliter of patient serum, which was found to be optimum in our laboratory. Surprisingly, from 20% of our positive results, even serum diluted to 1/100 (0.01 microliter) produced a stronger signal than 1 microliter. This observation suggests that direct PCR amplification of HBV DNA released from serum by NaOH treatment has to be compensated by other DNA detection methods for correct quantitation. In order to eliminate the false positive signal resulting from the carry-over due to massive screening of a large number of samples, PCR reaction mixture containing 8-methoxypsoralen was exposed to ultraviolet light prior to thermal cycle amplification. This exercise did not decrease the sensitivity of the detection method, but almost completely removed the false positive results caused by contaminated templates. We are in the process of improving PCR-mediated HBV DNA detection methods to attain more reliable and easily applicable methods.

Quantitative assessment of estrogenic activity in the water environment of Korea by the E-SCREEN assay.

In this study, the E-SCREEN assay was optimized and validated for the sensitive quantitative determination of the total estrogenicity in river samples. River water and sediment samples were collected and analyzed with the E-SCREEN. River water (10 l) was extracted using combined solid-phase extraction in static adsorption mode with Soxhlet extraction. Estrogenic pollutants adsorbed to the XAD-4 resin were recovered with 98.24 +/- 5.90% efficiency by elution with ethyl acetate and dichloromethane (1:9). The detection limit by 17beta-estradiol equivalent concentration (EEQ) of the E-SCREEN assay was 8.03 pg EEQ/l. Among the water samples, the estrogenic activity was observed to be higher downstream of the Kumho river (7.43 ng EEQ/l) and upstream of Kum river (2.05 ng EEQ/l) than in other samples. More than 3 mg of equivalent sediment samples from the Kumho river, Kum river and Miho stream showed partial agonistic effects, and the Mankyung river showed a partial agonistic effect with only 1.5 mg of sediment. The highest value of RPE was 83.34 downstream of the Kumho river, and the lowest value of RPE was 6.52 downstream of the Miho stream. Full estrogen agonistic activities were observed downstream of the Kumho river and upstream of the Kum river. The partial agonistic activity was observed in upstream of the Kumho river, downstream of the Mankyung river, and upstream of the Miho stream, and no agonistic action was observed downstream of the Kum river or Miho stream, or upstream of the Mankyung river. The total estrogenic activity in the river water and sediment samples was between 0.50 pg/L and 7.4 ng/L, 3.39 pg/g and 10.70 pg/g.

Evaluation of an activated carbon felt passive sampler in monitoring organic vapors.

Using an activated carbon felt (ACF, KF-1600), the applicability of an ACF passive sampler in monitoring organic vapors was evaluated. The evaluated results of the ACF passive sampler were compared with those of a 3 M (Model 3500) passive sampler. At low-humidity condition (8 +/- 3% RH), the sampling rates of the ACF passive sampler for volatile organic vapors were within the range of +/-25% from the results of a charcoal tube, which was the reference method recommended by NIOSH. However, at high humidity condition (90 +/- 5% RH), even though the sampling rates for toluene, MIBK, and PCE were within the range of +/-25%, the sampling rates of ACF sampler for n-hexane and MEK decreased steeply with time after being high at the beginning of the exposure time. Under this condition, the sampling rate of the 3 M passive sampler for MEK was also high at the beginning of the exposure time. In case of the ACF passive sampler, the sampling rates of the relatively strong adsorbates such as toluene, MIBK, and PCE were much less affected by humidity than those of n-hexane and MEK which were weak adsorbates.

MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/ß-catenin signaling.

ß-Catenin has been widely implicated in the regulation of mammalian development and cellular homeostasis. However, the mechanisms by which Wnt/ß-catenin signaling components regulate physiological events during brain development remain undetermined. Inactivation of glycogen synthase kinase (GSK)-3ß leads to ß-catenin accumulation in the nucleus, where it couples with T-cell factor (TCF), an association that is disrupted by ICAT (inhibitor of ß-catenin and T cell factor). In this study, we sought to determine whether regulation of ICAT by members of the microRNA-29 family plays a role during neurogenesis and whether deregulation of ICAT results in defective neurogenesis due to impaired ß-catenin-mediated signaling. We found that miR-29b, but not miR-29a or 29c, is significantly upregulated in three-dimensionally cultured neural stem cells (NSCs), whereas ICAT is reduced as aged. Treatment with a miR-29b reduced the reporter activity of a luciferase-ICAT 3'-UTR construct whereas a control (scrambled) miRNA oligonucleotide did not, indicating that miR-29b directly targets the 3'-UTR of ICAT. We also found that treatment with miR-29b diminished NSC self-renewal and proliferation, and controlled their fate, directing their differentiation along certain cell lineages. Furthermore, our in vivo results showed that inhibition of miR-29b by in utero electroporation induced a profound defect in corticogenesis during mouse development. Taken together, our results demonstrate that miR-29b plays a pivotal role in fetal mouse neurogenesis by regulating ICAT-mediated Wnt/ß-catenin signaling.

Modified Ilizarov technique for the treatment of forearm deformities in multiple cartilaginous exostoses: case series and literature review.

The aim of this study is to evaluate the results of gradual ulnar correction and lengthening using the modified Ilizarov technique for the treatment of forearm deformities in patients with multiple cartilaginous exostoses. We retrospectively reviewed 23 forearms in 16 patients. Three different types of operative procedures were performed: (1) corrective osteotomy and gradual lengthening of the ulna, (2) corrective osteotomy of the radius, and (3) excision of exostoses. We evaluated the radiographs; range of motion of the wrist, forearm, and elbow; and functional status using a questionnaire before and after operation. During the clinical interview, post-operative functional status was significantly improved than pre-operative functional status, 12 patients stated that they had no difficulty in performing daily activities, 11 patients stated that they had no pain, and 11 patients stated that the post-operative appearance of the operated forearm was satisfactory. At time of final follow-up, the mean range of motion of the wrist in ulnar/radial deviation, forearm pronation/supination was significantly improved. Also, the radiographic parameters including radial articular angle, carpal slip, radial bowing, and ulnar variance were significantly improved at time of final follow-up. In conclusion, we achieved successful clinical and radiological outcomes in our patients with forearm deformities after treatment with the modified Ilizarov method. However, there could be a recurrence of ulnar shortening and deformity during growth periods in skeletally immature patients.

Insulin concentration is critical in culturing human neural stem cells and neurons.

Cell culture of human-derived neural stem cells (NSCs) is a useful tool that contributes to our understanding of human brain development and allows for the development of therapies for intractable human brain disorders. Human NSC (hNSC) cultures, however, are not commonly used, mainly because of difficulty with consistently maintaining the cells in a healthy state. In this study, we show that hNSC cultures, unlike NSCs of rodent origins, are extremely sensitive to insulin, an indispensable culture supplement, and that the previously reported difficulty in culturing hNSCs is likely because of a lack of understanding of this relationship. Like other neural cell cultures, insulin is required for hNSC growth, as withdrawal of insulin supplementation results in massive cell death and delayed cell growth. However, severe apoptotic cell death was also detected in insulin concentrations optimized to rodent NSC cultures. Thus, healthy hNSC cultures were only produced in a narrow range of relatively low insulin concentrations. Insulin-mediated cell death manifested not only in all human NSCs tested, regardless of origin, but also in differentiated human neurons. The underlying cell death mechanism at high insulin concentrations was similar to insulin resistance, where cells became less responsive to insulin, resulting in a reduction in the activation of the PI3K/Akt pathway critical to cell survival signaling.

The radiological parameters correlated with the alignment of the femoral component after Oxford phase 3 unicompartmental knee replacement.

The purpose of this study was to measure the radiological parameters of femoral component alignment of the Oxford Phase 3 unicompartmental knee replacement (UKR), and evaluate their effect on clinical outcome. Multiple regression analysis was used to examine the relative contributions of the radiological assessment of femoral component alignment in 189 consecutive UKRs performed by a single surgeon. The American Knee Society scores were compared between groups, defined as being within or outside recommended tolerances of the position of the femoral component. For the flexion/extension position 21 UKRs (11.1%) lay outside the recommended limits, and for posterior overhang of the femoral component nine (4.8%) lay outside the range. The pre-operative hip/knee/ankle (HKA) angle, narrowest canal distance from the distal femoral entry point of the alignment jig and coronal entry-point position had significant effects on the flexion/extension position. Pre-operative HKA angle had a significant influence on posterior overhang of the femoral component. However, there was no significant difference in American Knee Society scores relative to the position of the femoral component.

Ebp1 sumoylation, regulated by TLS/FUS E3 ligase, is required for its anti-proliferative activity.

Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a putative tumor suppressor. Ebp1 translocates into the nucleus and functions as a transcription co-repressor for E2F-1. Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity. We find that translocation in liposarcoma (TLS)/FUS, an RNA-binding nuclear protein that is involved in pre-mRNA processing and nucleocytoplasmic shuttling, has Sumo1 E3 ligase activity for Ebp1 p42. Ebp1 directly binds TLS/FUS, which is regulated by genotoxic stress-triggered phosphorylation on Ebp1. Ebp1 sumoylation facilitates its nucleolar distribution and protein stability. Overexpression of TLS enhances Ebp1 sumoylation, whereas depletion of TLS abolishes Ebp1 sumoylation. Moreover, unsumoylated Ebp1 mutants fail to suppress E2F-1-regulated transcription, resulting in loss of its anti-proliferation activity. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.