Leveraging computer vision for predicting collision risks: a cross-sectional analysis of 2019-2021 fatal collisions in the USA.

OBJECTIVE: The USA has higher rates of fatal motor vehicle collisions than most high-income countries. Previous studies examining the role of the built environment were generally limited to small geographic areas or single cities. This study aims to quantify associations between built environment characteristics and traffic collisions in the USA. METHODS: Built environment characteristics were derived from Google Street View images and summarised at the census tract level. Fatal traffic collisions were obtained from the 2019-2021 Fatality Analysis Reporting System. Fatal and non-fatal traffic collisions in Washington DC were obtained from the District Department of Transportation. Adjusted Poisson regression models examined whether built environment characteristics are related to motor vehicle collisions in the USA, controlling for census tract sociodemographic characteristics. RESULTS: Census tracts in the highest tertile of sidewalks, single-lane roads, streetlights and street greenness had 70%, 50%, 30% and 26% fewer fatal vehicle collisions compared with those in the lowest tertile. Street greenness and single-lane roads were associated with 37% and 38% fewer pedestrian-involved and cyclist-involved fatal collisions. Analyses with fatal and non-fatal collisions in Washington DC found streetlights and stop signs were associated with fewer pedestrians and cyclists-involved vehicle collisions while road construction had an adverse association. CONCLUSION: This study demonstrates the utility of using data algorithms that can automatically analyse street segments to create indicators of the built environment to enhance understanding of large-scale patterns and inform interventions to decrease road traffic injuries and fatalities.

miR-92a promotes cervical cancer cell proliferation, invasion, and migration by directly targeting PIK3R1.

OBJECTIVE: To clarify the role of miR-92a in regulating the malignant progression of cervical cancer and its specific molecular mechanism. METHODS: qRT-PCR was used to detect the differential expression of miR-92a in cervical cancer and adjacent tissues. The effects of overexpression of miR-92a on the proliferation, migration, and invasion of HeLa and SiHa cells were tested. Luciferase assays and rescue experiments were used to investigate the regulatory mechanism of miR-92a on its downstream gene PIK3R1 and their interaction in the progression of cervical cancer. RESULTS: miR-92a was significantly up-regulated in cervical cancer tissues. Overexpression of miR-92a significantly increased the ability of cervical cancer cells to proliferate, migrate, and invade. PIK3R1 was identified as a downstream gene of miR-92a. In cervical cancer tissues, PIK3R1 was found to be down-regulated and negatively correlated with the level of miR-92a. Overexpression of PIK3R1 reversed the promotional effect of overexpressed miR-92a on the proliferation, migration, and invasion of cervical cancer. CONCLUSION: miR-92a is up-regulated in cervical cancer tissues. miR-92a promotes the malignant development of cervical cancer by negatively regulating PIK3R1.

Inactivation of Pseudomonas aeruginosa Biofilms by 405-Nanometer-Light-Emitting Diode Illumination.

Biofilm formation by Pseudomonas aeruginosa contributes to its survival on surfaces and represents a major clinical threat because of the increased tolerance of biofilms to disinfecting agents. This study aimed to investigate the efficacy of 405-nm light-emitting diode (LED) illumination in eliminating P. aeruginosa biofilms formed on stainless steel coupons under different temperatures. Time-dependent killing assays using planktonic and biofilm cells were used to determine the antimicrobial and antibiofilm activities of LED illumination. We also evaluated the effects of LED illumination on the disinfectant susceptibility, biofilm structure, extracellular polymeric substance (EPS) structure and composition, and biofilm-related gene expression of P. aeruginosa biofilm cells. Results showed that the abundance of planktonic P. aeruginosa cells was reduced by 0.88, 0.53, and 0.85 log CFU/ml following LED treatment for 2 h compared with untreated controls at 4, 10, and 25°C, respectively. For cells in biofilms, significant reductions (1.73, 1.59, and 1.68 log CFU/cm2) were observed following LED illumination for 2 h at 4, 10, and 25°C, respectively. Moreover, illuminated P. aeruginosa biofilm cells were more sensitive to benzalkonium chloride or chlorhexidine than untreated cells. Scanning electron microscopy and confocal laser scanning microscopic observation indicated that both the biofilm structure and EPS structure were disrupted by LED illumination. Further, reverse transcription-quantitative PCR revealed that LED illumination downregulated the transcription of several genes associated with biofilm formation. These findings suggest that LED illumination has the potential to be developed as an alternative method for prevention and control of P. aeruginosa biofilm contamination.IMPORTANCEPseudomonas aeruginosa can form biofilms on medical implants, industrial equipment, and domestic surfaces, contributing to high morbidity and mortality rates. This study examined the antibiofilm activity of 405-nm light-emitting diode (LED) illumination against mature biofilms formed on stainless steel coupons. We found that the disinfectant susceptibility, biofilm structure, and extracellular polymeric substance structure and composition were disrupted by LED illumination. We then investigated the transcription of several critical P. aeruginosa biofilm-related genes and analyzed the effect of illumination temperature on the above characteristics. Our results confirmed that LED illumination could be developed into an effective and safe method to counter P. aeruginosa biofilm contamination. Further research will be focused on the efficacy and application of LED illumination for elimination of complicated biofilms in the environment.

Clinical Efficacy of Combined Hysteroscopic and Laparoscopic Surgery and Reversible Ligation of the Uterine Artery for Excision and Repair of Uterine Scar in Patients with Type II and III Cesarean Scar Pregnancy.

BACKGROUND With the changes in China's family planning policy, the incidence of cesarean scar pregnancy (CSP) significantly increased in recent years. The present study aimed to investigate the clinical efficacy of combined hysteroscopic and laparoscopic surgery and reversible ligation of the uterine artery for cesarean scar excision and repair in patients with type II and III CSP. MATERIAL AND METHODS This was a retrospective study of 173 patients with type II and III CSP. They were assigned to the hysteroscopy and laparoscopy group (group A), hysteroscopy group (group B), and curettage group (group C) according to the surgery they underwent. The surgical indicators (intraoperative bleeding volume and hospital stay), postoperative recovery (time of serum ß-hCG returning to the normal, postoperative residual lesion, the thickness of the uterine scar, and recovery time of menstruation), and the postoperative complications were compared among the 3 groups. RESULTS In patients with type II and III CSP, significant differences (P<0.05) were observed between group A vs. groups B and C in terms of the time of serum ß-HCG returning to normal, postoperative residual lesions, the thickness of the uterine scar, and recovery time of menstruation, while there were no significant differences in intraoperative bleeding volume and postoperative hospital stay (P>0.05). CONCLUSIONS For patients with type II and III CSP, hysteroscopy and laparoscopy surgery and reversible ligation of the uterine artery achieved better clinical outcomes than hysteroscopy or curettage with respect to postoperative recovery. This could be suitable for patients with CSP and desire for fertility.

A Case of Psoas Muscle Endometriosis: A Distinct Approach to Diagnosis and Management.

Endometriosis is a common disease in women of childbearing age. Here, we report a case of psoas muscle endometriosis and our approach to treatment. A 28-year-old woman presented with an 8-month history of lower left abdominal and back pain. She was incorrectly diagnosed and treated for a psoas abscess at a previous hospital. Based on imaging results and previous history of severe dysmenorrhea, a diagnosis of psoas muscle endometriosis was considered. The patient underwent treatment with gonadotropin-releasing hormones and laparoscopic surgery and currently reports alleviation of symptoms. Psoas muscle endometriosis is rare, and the diagnosis can be difficult. It is important to recognize signs and symptoms to determine adequate treatment.

The Cellular Protein Complex Associated with a Transforming Region of E1A Contains c-MYC.

UNLABELLED: The cell-transforming activity of human adenovirus 5 (hAd5) E1A is mediated by the N-terminal half of E1A, which interacts with three different major cellular protein complexes, p300/CBP, TRRAP/p400, and pRb family members. Among these protein interactions, the interaction of pRb family proteins with conserved region 2 (CR2) of E1A is known to promote cell proliferation by deregulating the activities of E2F family transcription factors. The functional consequences of interaction with the other two protein complexes in regulating the transforming activity of E1A are not well defined. Here, we report that the E1A N-terminal region also interacted with the cellular proto-oncoprotein c-MYC and the homolog of enhancer of yellow 2 (ENY2). Our results suggested that these proteins interacted with an essential E1A transforming domain spanning amino acid residues 26 to 35 which also interacted with TRRAP and p400. Small interfering RNA (siRNA)-mediated depletion of TRRAP reduced c-MYC interaction with E1A, while p400 depletion did not. In contrast, depletion of TRRAP enhanced ENY2 interaction with E1A, suggesting that ENY2 and TRRAP may interact with E1A in a competitive manner. The same E1A region additionally interacted with the constituents of a deubiquitinase complex consisting of USP22, ATXN7, and ATXN7L3 via TRRAP. Acute short hairpin RNA (shRNA)-mediated depletion of c-MYC reduced the E1A transforming activity, while depletion of ENY2 and MAX did not. These results suggested that the association of c-MYC with E1A may, at least partially, play a role in the E1A transformation activity, independently of MAX. IMPORTANCE: The transforming region of adenovirus E1A consists of three short modules which complex with different cellular protein complexes. The mechanism by which one of the transforming modules, CR2, promotes cell proliferation, through inactivating the activities of the pRb family proteins, is better understood than the activities of the other domains. Our analysis of the E1A proteome revealed the presence of the proto-oncoprotein c-MYC and of ENY2. We mapped these interactions to a critical transforming module of E1A that was previously known to interact with the scaffolding molecule TRRAP and the E1A-binding protein p400. We showed that c-MYC interacted with E1A through TRRAP, while ENY2 interacted with it independently. The data reported here indicated that depletion of c-MYC in normal human cells reduced the transforming activity of E1A. Our result raises a novel paradigm in oncogenic transformation by a DNA viral oncogene, the E1A gene, that may exploit the activity of a cellular oncogene, the c-MYC gene, in addition to inactivation of the tumor suppressors, such as pRb.

[Clinical Value of Prophylactic Salpingectomy in Hysterectomy due to Uterine Benign Lesions].

OBJECTIVES: To explore the clinical value of resection of bilateral fallopian tubes in patients with benign uterine diseases who received (laparoscopic) hysterectomy or subhysterectomy through the postoperative pathologic analysis of resected fallopian tubes. METHODS: A retrospective analysis was conducted to review the histopathological examination results in 1 272 women who underwent (laparoscopic) total hysterectomy or subtotal hysterectomy and the removal of bilateral fallopian tube simultaneously due to uterine leiomyoma, adenomyosis and other benign lesions from December 2010 to December 2015. RESULTS: Of the 1 272 patients, laparoscopic resection was underwent in 1 005 patients (79.01%) and laparotomy in 267 patients (20.99%). In the attachment area, 334 patients (26.26%) had tenderness signs, and 401 patients (31.53%) had signs of thickening. Total 2 498 fallopian tubes were removed. There were 1 654 tubal with no obvious abnormal appearance (66.21%), 636 tubal with lumen part of the uplift (25.46%), 128 fallopian tube with congestion and swelling (5.12%), 80 fallopian tube atrophy adhesions (3.20%). Pathological. RESULTS: showed 2 386 (95.52%) fallopian tubes with chronic fallopian tube inflammation, 988 (39.55%) of fallopian tube cyst, 80 (3.20%) of normal fallopian tube, 78 (3.12%) of tubal effusion, 48 (1.92% ) of tubal hyperplasia, 4 (0.26%) of tubal benign tumor, 8 (0.32%) of tubal mucosa atypical hyperplasia change and 2(0.08%) of tubal cancer. In the 10 cases of fallopian tube cancer and atypical hyperplasia, 8 had obvious changes of chronic inflammation in the contralateral fallopian tube, including 7 cases of atypical hyperplasia and 1 case of fallopian tube cancer. CONCLUSION: Prophylactic salpingectomy can prevent the occurrence of tubal inflammation and removal cancer incentives.

Functional similarity between E6 proteins of cutaneous human papillomaviruses and the adenovirus E1A tumor-restraining module.

The adenovirus E1A C-terminal region restrains oncogenic transformation through interaction with three distinct cellular protein complexes that include the DYRK1A/1B/HAN11 complex. The E6 proteins of beta-human papillomaviruses (beta-HPVs) also interact with the DYRK1/HAN11 complex. A variant of HPV5 E6 frequently found in epidermodysplasia verruciformis skin lesions interacted less efficiently with DYRK1A/HAN11. The E6 variant and E7 of HPV5 efficiently coimmortalized primary epithelial cells, suggesting that naturally arising variants may contribute potential oncogenic activities of beta-HPV E6 proteins.

RNA-seq identifies differentially expressed genes involved in csal1 overexpression in granulosa cells of prehierarchical follicles in Chinese Dagu hens.

The transcription factor csal1 is an important molecule that plays a critical regulatory function in ovarian follicle development, as confirmed by our previous data. However, the candidate genes of csal1 and its regulatory mechanism remain poorly understood in the granulosa cells (GCs) of chicken prehierarchical follicles (PFs). Six transcriptomes of csal1 and empty vector were analyzed in Chinese Dagu hens by RNA sequencing. Six cDNA libraries were constructed, with more than 42 million clean reads and 16,779 unigenes. Of these 16,779 unigenes, 2,762 differentially expressed genes (DEGs) were found in GCs, including 1,605 upregulated and 1,157 downregulated unigenes. Fourteen genes, including BMP5, TACR2, AMH, PLAG1, MYOD1, BOP1, SIPA1, NOTCH1, BCL2L1, SOX9, ADGRA2, WNT5A, SLC7A11, and GATAD2B, were related to GC proliferation and differentiation, hormone production, ovarian follicular development, regulation of reproductive processes, and signaling pathways in the PFs. Further analysis demonstrated the DEGs in GCs of ovarian follicles were enriched in neuroactive ligand-receptor interaction, cell adhesion molecules, and pathways related to cytochrome P450, indicating a critical function for csal1 in the generation of egg-laying features by controlling ovarian follicle development. For the first time, the current study represents the transcriptome analysis with ectopic csal1 expression. These findings provide significant evidence for investigating the molecular mechanism by which csal1 controls PF development in the hen ovary.

Mechanisms underlying impaired spermatogenic function in orchitis induced by busulfan.

Busulfan is an alkylating agent commonly used in cancer chemotherapy. It is also an ideal agent for preparing transplant recipients of spermatogonial stem cells because of its high efficiency in destroying endogenous germ cells in the testis. However, its toxicity mechanism remains unclear, affecting its clinical use and applications. Based on reports of busulfan causing orchitis and a previous study by our team, this article summarizes the relationship between busulfan and orchitis, cytokines, the blood-testis barrier, and the cytoskeleton, unravels the regulatory pathways and mechanism behind busulfan-induced orchitis, and reveals the molecular mechanism underlying impaired spermatogenic function in orchitis, providing new ideas for the clinical application of busulfan while reducing its testicular toxicity.

Self-Supervised Medical Image Denoising Based on WISTA-Net for Human Healthcare in Metaverse.

Medical image processing plays an important role in the interaction of real world and metaverse for healthcare. Self-supervised denoising based on sparse coding methods, without any prerequisite on large-scale training samples, has been attracting extensive attention for medical image processing. Whereas, existing self-supervised methods suffer from poor performance and low efficiency. In this paper, to achieve state-of-the-art denoising performance on the one hand, we present a self-supervised sparse coding method, named the weighted iterative shrinkage thresholding algorithm (WISTA). It does not rely on noisy-clean ground-truth image pairs to learn from only a single noisy image. On the other hand, to further improve denoising efficiency, we unfold the WISTA to construct a deep neural network (DNN) structured WISTA, named WISTA-Net. Specifically, in WISTA, motivated by the merit of the lp-norm, WISTA-Net has better denoising performance than the classical orthogonal matching pursuit (OMP) algorithm and the ISTA. Moreover, leveraging the high-efficiency of DNN structure in parameter updating, WISTA-Net outperforms the compared methods in denoising efficiency. In detail, for a 256 by 256 noisy image, the running time of WISTA-Net is 4.72 s on the CPU, which is much faster than WISTA, OMP, and ISTA by 32.88 s, 13.06 s, and 6.17 s, respectively.

Deep Ladder-Suppression Network for Unsupervised Domain Adaptation.

Unsupervised domain adaptation (UDA) aims at learning a classifier for an unlabeled target domain by transferring knowledge from a labeled source domain with a related but different distribution. Most existing approaches learn domain-invariant features by adapting the entire information of the images. However, forcing adaptation of domain-specific variations undermines the effectiveness of the learned features. To address this problem, we propose a novel, yet elegant module, called the deep ladder-suppression network (DLSN), which is designed to better learn the cross-domain shared content by suppressing domain-specific variations. Our proposed DLSN is an autoencoder with lateral connections from the encoder to the decoder. By this design, the domain-specific details, which are only necessary for reconstructing the unlabeled target data, are directly fed to the decoder to complete the reconstruction task, relieving the pressure of learning domain-specific variations at the later layers of the shared encoder. As a result, DLSN allows the shared encoder to focus on learning cross-domain shared content and ignores the domain-specific variations. Notably, the proposed DLSN can be used as a standard module to be integrated with various existing UDA frameworks to further boost performance. Without whistles and bells, extensive experimental results on four gold-standard domain adaptation datasets, for example: 1) Digits; 2) Office31; 3) Office-Home; and 4) VisDA-C, demonstrate that the proposed DLSN can consistently and significantly improve the performance of various popular UDA frameworks.

The Age-Accompanied and Diet-Associated Remodeling of the Phospholipid, Amino Acid, and SCFA Metabolism of Healthy Centenarians from a Chinese Longevous Region: A Window into Exceptional Longevity.

As centenarians provide a paradigm of healthy aging, investigating the comprehensive metabolic profiles of healthy centenarians is of utmost importance for the pursuit of health and longevity. However, relevant reports, especially studies considering the dietary influence on metabolism, are still limited, mostly lacking the guidance of a model of healthy aging. Therefore, exploring the signatures of the integrative metabolic profiles of the healthy centenarians from a famous longevous region, Bama County, China, should be an effective way. The global metabolome in urine and the short-chain fatty acids (SCFAs) in the feces of 30 healthy centenarians and 31 elderly people aged 60−70 from the longevous region were analyzed by non-targeted metabolomics combined with metabolic target analysis. The results showed that the characteristic metabolites related to longevity were mostly summarized into phosphatidylserine, lyso-phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, bile acids, and amino acids (p < 0.05). Six metabolic pathways were found significant relevant to longevity. Furthermore, acetic acid, propionic acid, butyric acid, valeric acid, and total SCFA were significantly increased in the centenarian group (p < 0.05) and were also positively associated with the dietary fiber intake (p < 0.01). It was age-accompanied and diet-associated remodeling of phospholipid, amino acid, and SCFA metabolism that expressed the unique metabolic signatures related to exceptional longevity. This metabolic remodeling is suggestive of cognitive benefits, better antioxidant capacity, the attenuation of local inflammation, and health-span-promoting processes, which play a critical and positive role in shaping healthy aging.

Adenovirus type 5 E1A and E6 proteins of low-risk cutaneous beta-human papillomaviruses suppress cell transformation through interaction with FOXK1/K2 transcription factors.

The adenovirus (Adv) oncoprotein E1A stimulates cell proliferation and inhibits differentiation. These activities are primarily linked to the N-terminal region (exon 1) of E1A, which interacts with multiple cellular protein complexes. The C terminus (exon 2) of E1A antagonizes these processes, mediated in part through interaction with C-terminal binding proteins 1 and 2 (CtBP1/2). To identify additional cellular E1A targets that are involved in the modulation of E1A C-terminus-mediated activities, we undertook tandem affinity purification of E1A-associated proteins. Through mass spectrometric analysis, we identified several known E1A-interacting proteins as well as novel E1A targets, such as the forkhead transcription factors, FOXK1/K2. We identified a Ser/Thr-containing sequence motif in E1A that mediated interaction with FOXK1/K2. We demonstrated that the E6 proteins of two beta-human papillomaviruses (HPV14 and HPV21) associated with epidermodysplasia verruciformis also interacted with FOXK1/K2 through a motif similar to that of E1A. The E1A mutants deficient in interaction with FOXK1/K2 induced enhanced cell proliferation and oncogenic transformation. The hypertransforming activity of the mutant E1A was suppressed by HPV21 E6. An E1A-E6 chimeric protein containing the Ser/Thr domain of the E6 protein in E1A interacted efficiently with FOXK1/K2 and inhibited cell transformation. Our results suggest that targeting FOXK1/K2 may be a common mechanism for certain beta-HPVs and Adv5. E1A exon 2 mutants deficient in interaction with the dual-specificity kinases DYRK1A/1B and their cofactor HAN11 also induced increased cell proliferation and transformation. Our results suggest that the E1A C-terminal region may suppress cell proliferation and oncogenic transformation through interaction with three different cellular protein complexes: FOXK1/K2, DYRK(1A/1B)/HAN11, and CtBP1/2.

LncRNA HOXA-AS2 Activates the Notch Pathway to Promote Cervical Cancer Cell Proliferation and Migration.

Long non-coding RNAs (lncRNAs) are crucial participants in cancer development. HOXA cluster antisense RNA 2 (HOXA-AS2) plays a tumor promoter role in bladder cancer. However, the functional role of HOXA-AS2 in cervical cancer remains unclear. Our study first found that HOXA-AS2 expression was up-regulated in cervical cancer cells. Then functional analysis including cell counting kit-8 (CCK-8), colony formation, transwell, and wound healing uncovered that reduction of HOXA-AS2 remarkably impeded cell proliferation and migration in cervical cancer. Additionally, luciferase reporter assays were performed to confirm that HOXA-AS2 activated Notch signaling pathway via the mediation of independent recombination signal binding protein for JK (RBP-JK) activity. As we know, Notch intracellular domain (NICD) is associated with RBP-JK in the nucleus to promote target genes in the Notch pathway. Through RNA immunoprecipitation (RIP), RNA pull down, and fluorescent in situ hybridization (FISH) assays, we observed that HOXA-AS2 combined with NICD. Moreover, the data from Co-IP assays indicated that HOXA-AS2 reduction weakened the interaction of NICD and RBP-JK. Collectively, HOXA-AS2 played a cancer-promoting role in cervical cancer development by modulating the Notch pathway, which might become a novel target for cervical cancer treatment.

Joint Clustering and Discriminative Feature Alignment for Unsupervised Domain Adaptation.

Unsupervised Domain Adaptation (UDA) aims to learn a classifier for the unlabeled target domain by leveraging knowledge from a labeled source domain with a different but related distribution. Many existing approaches typically learn a domain-invariant representation space by directly matching the marginal distributions of the two domains. However, they ignore exploring the underlying discriminative features of the target data and align the cross-domain discriminative features, which may lead to suboptimal performance. To tackle these two issues simultaneously, this paper presents a Joint Clustering and Discriminative Feature Alignment (JCDFA) approach for UDA, which is capable of naturally unifying the mining of discriminative features and the alignment of class-discriminative features into one single framework. Specifically, in order to mine the intrinsic discriminative information of the unlabeled target data, JCDFA jointly learns a shared encoding representation for two tasks: supervised classification of labeled source data, and discriminative clustering of unlabeled target data, where the classification of the source domain can guide the clustering learning of the target domain to locate the object category. We then conduct the cross-domain discriminative feature alignment by separately optimizing two new metrics: 1) an extended supervised contrastive learning, i.e., semi-supervised contrastive learning 2) an extended Maximum Mean Discrepancy (MMD), i.e., conditional MMD, explicitly minimizing the intra-class dispersion and maximizing the inter-class compactness. When these two procedures, i.e., discriminative features mining and alignment are integrated into one framework, they tend to benefit from each other to enhance the final performance from a cooperative learning perspective. Experiments are conducted on four real-world benchmarks (e.g., Office-31, ImageCLEF-DA, Office-Home and VisDA-C). All the results demonstrate that our JCDFA can obtain remarkable margins over state-of-the-art domain adaptation methods. Comprehensive ablation studies also verify the importance of each key component of our proposed algorithm and the effectiveness of combining two learning strategies into a framework.

Interaction of ZEB and histone deacetylase with the PLDLS-binding cleft region of monomeric C-terminal binding protein 2.

BACKGROUND: Proteins of the C-terminal binding protein (CtBP) family, CtBP1 and CtBP2 are closely related transcriptional regulators that are coded by two different gene loci in the vertebrate genomes. They perform redundant and unique functions during animal development. CtBP proteins mediate their transcriptional function through interaction with various DNA-binding repressors that contain PLDLS-like motifs and chromatin modifying enzymes, such as class I histone deacetylases (HDAC) that do not contain such motifs. The N-terminal region of CtBP1/2 forms a hydrophobic cleft and is involved in interaction with both PLDLS-containing factors and non-PLDLS factors. CtBP proteins function as dimers to mediate transcriptional repression and dimerization is modulated by specific binding to NAD/NADH. RESULTS: In this study, we have investigated the role of dimerization of CtBP2 in recruitment of PLDLS-motif cofactors and non-PLDLS cofactors. Our results indicate that mutations in CtBP2 that interfere with dimerization abolish CtBP2 interaction with most cellular factors, except the PLDLS-motif factor zinc-finger E-box binding homeobox (ZEB) and the non-PLDLS factor HDAC2. Unlike most PLDLS-containing CtBP-binding proteins, ZEB contains three PLDLS-like motifs and all three contribute to the interaction with the CtBP2 monomer. Despite the ability to interact with ZEB and HDAC, the CtBP2 monomer fails to mediate ZEB-dependent transcriptional repression. The lack of repression activity of the CtBP2 monomer is correlated with the competition between ZEB and HDAC for interaction with the CtBP2 monomer. CONCLUSION: These results suggest a competition between the canonical PLDLS-motif factors such as E1A and non-PLDLS factor HDAC for interaction with CtBP. They also indicate that the affinity for the CtBP monomer may be determined by the number as well as amino acid sequence compositions of the PLDLS-like motifs. Our results are consistent with a model that the CtBP2 dimer may interact with a PLDLS-containing repressor through one monomer and recruit HDAC and other chromatin modifying enzymes through the second monomer in the CtBP2 dimer.

Interferon regulatory factor 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes.

Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. EBV latent membrane protein 1 (LMP-1) is required for EBV transformation processes. Interferon regulatory factor 4 (IRF-4) is a transcription factor and has oncogenic potential. We find that high levels of IRF-4 are associated with EBV transformation of human primary B cells in vitro and with EBV type III latency in which LMP-1 is expressed. We show that EBV LMP-1 stimulates IRF-4 expression in B lymphocytes. The stimulation of IRF-4 by LMP-1 requires signaling from LMP-1 and involves cellular NF-kappaB. The growth of EBV-transformed cells is inhibited when IRF-4 is specifically down-regulated. We further demonstrate that IRF-4 knockdown cells have lower proliferation but higher apoptotic rates than control cells. Finally, IRF-4 is expressed in significant numbers of specimens of primary central nervous system (CNS) lymphomas (12/27 [44.4%]), an EBV-associated malignancy. The association between the expression levels of LMP-1 and IRF-4 is statistically significant (P = 0.011) in these CNS lymphomas. Our data suggest that IRF-4 may be a critical factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia.

Programmed cell death factor 4 enhances the chemosensitivity of colorectal cancer cells to Taxol.

Drug resistance and disease relapse are still challenging problems in the chemotherapy of colorectal cancer (CRC). Programmed cell death factor 4 (PDCD4) has previously been reported to act as a tumor suppressor and was implicated in the chemosensitivity of numerous types of human malignancy. In this study, the effect of PDCD4 in the sensitivity of CRC to the chemotherapy drug Taxol was investigated. The results confirmed that lower PDCD4 expression was present in CRC tumor tissues, when compared with in normal adjacent tissues (p) and closely associated with the prognosis of patients with CRC. Upregulation of PDCD4 significantly enhanced the sensitivity of CRC cells to Taxol, by partially contributing to pro-apoptosis and anti-invasion pathways, both through upregulation of the apoptosis-associated protein Bax, and downregulation of the anti-apoptosis protein Bcl-2 and invasion-associated proteins MMP-9. These findings might present a novel strategy for sensitizing tumor cells to apoptosis and, thus, overcoming chemotherapy resistance in CRC.