Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes the growth, survival, differentiation and activation of normal myeloid cells and is essential for fully functional macrophage differentiation in vivo. To better understand the mechanisms by which growth factors control the balance between proliferation and self-renewal versus growth-suppression and differentiation we have used the bi-potent FDB1 myeloid cell line, which proliferates in IL-3 and differentiates to granulocytes and macrophages in response to GM-CSF. This provides a manipulable model in which to dissect the switch between growth and differentiation. We show that, in the context of signaling from an activating mutant of the GM-CSF receptor β subunit, a single intracellular tyrosine residue (Y577) mediates the granulocyte fate decision. Loss of granulocyte differentiation in a Y577F second-site mutant is accompanied by enhanced macrophage differentiation, accumulation of β-catenin together with activation of Tcf4 and other Wnt target genes. These include the known macrophage lineage inducer, Egr1. We show that forced expression of Tcf4 or a stabilised β-catenin mutant is sufficient to promote macrophage differentiation in response to GM-CSF and that GM-CSF can regulate β-catenin stability, most likely via GSK3β. Consistent with this pathway being active in primary cells we show that inhibition of GSK3β activity promotes the formation of macrophage colonies at the expense of granulocyte colonies in response to GM-CSF. This study therefore identifies a novel pathway through which growth factor receptor signalling can interact with transcriptional regulators to influence lineage choice during myeloid differentiation.
Myeloid; transcription-factor; β-catenin; Tcf4; signal-transduction
While the process of homo-oligomer formation and disassembly into subunits represents a common strategy to regulate protein activity, reports of proteins in which the subunit and homo-oligomer perform independent functions are scarce. Tumorigenesis induced by the adenovirus E4-ORF1 oncoprotein depends on its binding to a select group of cellular PDZ proteins, including MUPP1, MAGI-1, ZO-2 and Dlg1. We report here that in cells E4-ORF1 exists as both a monomer and trimer and that monomers specifically bind and sequester MUPP1, MAGI-1 and ZO-2 within insoluble complexes whereas trimers specifically bind Dlg1 and promote its translocation to the plasma membrane. This work exposes a novel strategy wherein the oligomerization state of a protein not only determines the capacity to bind separate related targets but also couples the interactions to different functional consequences.
adenovirus; E4-ORF1; monomer; PDZ; trimer
External apical root resorption (ARR) is a common iatrogenic consequence of orthodontic treatment. One of the aims of this article is to present a brief overview of the literature, including; diagnosis and etiology, with emphasis on orthodontic forces to facilitate an understand of the prevention or management of ARR in orthodontic patients. We also present a long-term follow-up observation of severe ARR, including the last obtained cone beam computed tomography (CBCT) records, to demonstrate the effect of orthodontic forces on ARR.
Root resorption; orthodontic treatment; orthodontic forces; follow- up case
The purpose of this study is to determine whether the surgical outcomes achieved with computer-aided surgical simulation (CASS) are better than those achieved with traditional methods.
Material and Methods
Twelve consecutive patients with craniomaxillofacial deformities (CMF) deformities were enrolled. Following our CASS clinical protocol, a 3D computer composite skull model for each patient was generated and reoriented to the neutral head posture. These models underwent 2 virtual surgeries: one was based on CASS (experimental group) and the other was based on traditional methods a year later (control group). Once both virtual surgeries were completed, 2 experienced oral-maxillofacial surgeons at 2 different settings evaluated both surgical outcomes. They were blinded to the planning method used on the virtual models, and each other’s evaluation results. The primary outcome was overall CMF skeletal harmony. The secondary outcomes were individual maxillary, mandibular and chin harmonies. Finally, statistical analyses were performed.
Overall CMF skeletal harmony achieved with CASS was statistically significantly better than that achieved with traditional methods. In addition, the maxillary and mandibular surgical outcomes achieved with CASS method were also significantly better. Furthermore, although not included in the statistical model, the chin symmetry achieved by CASS tended to be better. Finally, a regression model was established between the mandibular symmetry and the overall CMF skeletal harmony.
The surgical outcomes achieved with CASS are significantly better than those achieved with traditional planning methods. In addition, CASS enables the surgeon to better correct maxillary yaw deformity, better place proximal/distal segment, and better restore mandibular symmetry. Finally, the critical step in achieving better overall CMF skeletal harmony is to restore mandibular symmetry.
The aim of this study was to investigate the initial effects of maxillary expansion therapy with Hyrax appliance and to evaluate the related changes in maxillary sinus volume.
Materials and Methods
Thirty patients (20 females, 10 males; 13.8 years) requiring maxillary expansion therapy, as part of their comprehensive orthodontic treatment, were examined. Each patient had cone-beam computed tomography (CBCT) images taken before (T1) and after (T2) maxillary expansion therapy with a banded Hyrax appliance. Multiplanar slices were used to measure linear dimensions and palatal vault angle. Volumetric analysis was used to measure maxillary sinus volumes. Student t tests were used to compare the pre- and post-treatment measurements. Additionally, differences between two age groups were compared with Mann-Whitney U test. The level of significance was set at p=0.05.
Comparison of pre-treatment to post-treatment variables revealed significant changes in the transverse dimension related to both maxillary skeletal and dental structures and palatal vault angle, resulting in a widened palatal vault (p<0.05). Hard palate showed no significant movement in the vertical and anteroposterior planes. Nasal cavity width increased on a mean value of 0.93mm(SD=0.23, p<0.05). Maxillary sinus volume remained virtually stable. No significant age differences were observed in the sample.
Hyrax expansion therapy did not have a significant impact on maxillary sinus volume.
Palatal Expansion Technique; Maxillary Sinus; Cone-Beam Computed Tomography
We report the discovery of the GATA2 gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS/AML in three families, and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS/AML family. The mutations reside within the second zinc finger of GATA2 which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutants on transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counselling, selection of related bone marrow transplant donors, and development of therapies.
The purpose of this study was to evaluate the clinical feasibility of a new method to orient three-dimensional (3D) computed tomography (CT) models to the natural head position (NHP). This method utilizes a small and inexpensive digital orientation device to record NHP in 3D. This device consists of a digital orientation sensor attached to the patient via a facebow and an individualized bite jig. The study was designed to answer two questions: 1) whether the weight of the new device can negatively influence the NHP; and 2) wether the new method is as accurate as the gold standard.
Materials and Methods
Fifteen patients with craniomaxillofacial deformities were included in the study. Each patient’s NHP is recorded 3 times. The 1st NHP was recorded using a laser scanning method without the presence of the digital orientation device. The 2nd NHP was recorded using the digital orientation device. Simultaneously, the 3rd NHP wa also recorded using the laser scanning method. Each recorded NHP measurement was then transferred to the patient’s 3D CT facial model, resulting in 3 different orientations for each patient. They include: the orientation generated using the laser scanning method without the presence of the digital orientation sensor and facebow (Orientation 1); the orientation generated using the laser scanning method with the presence of the digital orientation sensor and facebow (Orientation 2); and the orientation generated using the digital orientation device (Orientation 3). The comparisons are then made between Orientations 1 and 2, and Orientations 2 and 3, respectively. Statistical analyses are performed.
The results show that in each pair, the delta between the 2 measurements is not statistically significantly different from 0 degrees. In addition, in the 1st pair, Bland and Altman’s lower and upper limits of the delta between the 2 measurements are within 1.5° in pitch and sub-degree in roll and yaw. In the 2nd pair, the limits of the delta in all three dimensions are within 0.5°.
Our technique can accurately record NHP in three dimensions and precisely transfer it to a 3D model. In addition, the extra weight of the digital orientation sensor and facebow has minimal influence on the self-balanced NHP establishment.
Natural head position; self-balanced; three-dimensional; recording; transferring; computed tomography; computer modeling
p53 is critical in the normal response to a variety of cellular stresses including DNA damage and loss of p53 function is a common feature of many cancers. In hematological malignancies, p53 deletion is less common than in solid malignancies but is associated with poor prognosis and resistance to chemotherapy. Compared to their wild-type (WT) counterparts, hematopoietic progenitor cells lacking p53 have a greater propensity to survive cytokine loss, in part, due to the failure to transcribe Puma, a proapoptotic Bcl-2 family member. Using expression arrays, we have further characterized the differences that distinguish p53−/− cells from WT myeloid cells in the presence of Interleukin-3 (IL-3) to determine if such differences contribute to the increased clonogenicity and survival responses observed in p53−/− cells. We show that p53−/− cells have a deregulated intracellular signaling environment and display a more rapid and sustained response to IL-3. This was accompanied by an increase in active ERK1/2 and a dependence on an intact MAP kinase signaling pathway. Contrastingly, we find that p53−/− cells are independent on AKT for their survival. Thus, loss of p53 in myeloid cells results in an altered transcriptional and kinase signaling environment that favors enhanced cytokine signaling.
Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.
HIF2α; surviving; neural progenitor cells; apoptosis
The purpose was to determine whether or not a novel device used in conjunction with orthodontic treatment produced root resorption shown on 3D images generated from a new cone beam computerized tomography.
Subjects were actively recruited and those who received braces for the first time were invited to participate. Patients were assigned to receive a functioning device and used the devices for 20 min daily for a six month study period. CBCT images were taken of the dentition at the start of treatment and at the end of the study period.
14 subjects out of a possible 17 subjects completed using the device during the study period. The mean age of the subjects was 20.3 years. Measurements of all teeth present were made from the mesial buccal roots of the first molar on one side of the dental arch to the mesial buccal roots of the first molar on the opposing side of the same arch. These measurements were recorded as linear lengths in mm. A paired t-test was used to determine if significant differences occurred for root lengths at the end of treatment compared to the start of treatment for each of the individual tooth groups. No statistical differences were noted for root length changes above 0.5 mm and 1 mm.
No statistically significant findings were noted for root length change at the end of treatment compared to the start of treatment when using this novel robotic device. No significant differences were noted between roots of anterior and posterior teeth. No clinically significant changes between root lengths were noted above 0.5 mm.
In agreement with the results of animal studies, the plasma osteocalcin level is positively associated with improved glucose tolerance and insulin secretion and sensitivity. In addition, the plasma osteocalcin level is inversely associated with the development of diabetes; however, the plasma adiponectin level may not be involved in osteocalcin-mediated energy metabolism in humans.
Recent animal studies have suggested crosstalk between bone and energy metabolism through osteocalcin. The aims of this study were to determine whether or not osteocalcin is associated with the improved glucose tolerance and insulin secretion and sensitivity, and whether or not the association is dependent on the plasma adiponectin level in humans.
Four hundred twenty-five subjects, 19–82 years of age (mean age, 53 years), were enrolled. An oral glucose tolerance test (OGTT) and OGTT-based methods that were validated against the euglycemic clamp were determined. Total osteocalcin, leptin, and total adiponectin levels were measured.
The plasma levels of total osteocalcin were significantly different between the normal glucose tolerance, pre-diabetes, and diabetes groups. The glucose levels and homeostasis model assessment insulin resistance values varied inversely with the osteocalcin tertiles, and OGTT-based insulin secretion (HOMA-B%, disposition index) and insulin sensitivity indices (Stumvoll’s and OGIS indices) were increased with the tertiles. Although the plasma adiponectin level was positively correlated with the osteocalcin level, no changes in the association were noted between the plasma osteocalcin level and the glucose tolerance or insulin secretion and sensitivity indices after adjustment for the plasma adiponectin level. Based on multiple logistic regression analysis, the plasma osteocalcin level was inversely associated with the development of type 2 diabetes mellitus independent of age, gender, body mass index, and fasting plasma glucose and plasma adiponectin levels.
Circulating osteocalcin level is associated with improved glucose tolerance and insulin secretion and sensitivity independent of the plasma adiponectin level in humans.
Adiponectin; Insulin resistance; Insulin secretion; Osteocalcin
This NICE technology appraisal guidance considers the clinical and cost effectiveness of the use of alteplase for acute ischaemic stroke
In this study, we correlated array-comparative genomic hybridization-defined abnormalities with survival in two different cohorts of patients treated with therapy based on high-dose melphalan with autologous stem-cell transplantation (64 from the Mayo Clinic and 67 from the University of Arkansas Medical School) and identified that several regions of genomic gains and losses were significantly associated with poorer survival. Three noncontiguous survival relevant regions covering 1p31-33 and two noncontiguous regions covering 20p12.3-12.1 were common between the two datasets. The prognostic relevance of these hotspots was validated in an independent cohort using fluorescent in situ hybridization, which showed that 1p31-32 loss is significantly associated with shorter survival (24.5 months versus 40 months, log-rank P-value=0.01), whereas 20p12 loss has a trend toward shorter survival (26.3 months versus 40 months, log-rank P-value=0.06). On multivariate analysis, 1p31-32 loss is an independent prognostic factor. On further analysis, the prognostic impact of 1p31-32 loss is due to shortening of post-relapse survival as there is no impact on complete response rates and progression-free survival.
prognosis; array-comparative genomic hybridization; chromosome 1p
The Genomics Education Partnership offers an inclusive model for undergraduate research experiences incorporated into the academic year science curriculum, with students pooling their work to contribute to international data bases.
The authors examined the associations between placental vascular findings and preterm delivery in 1,053 subcohort women (239 preterm, 814 term) from a Michigan pregnancy cohort study (1998–2004). Twenty-nine placental vascular variables from microscopic examinations were grouped into 5 constructs: 3 maternal constructs—obstructive lesions (MV-O), bleeding/vessel integrity (MV-I), and lack of physiologic conversion of maternal spiral arteries (MV-D)—and 2 fetal constructs—obstructive lesions (FV-O) and bleeding/vessel integrity (FV-I). Construct-specific scores were created by adding the number of positive findings and deriving a dichotomous variable to approximate the top quintile (“high”) and bottom 4 quintiles (“not high”) within each construct. In multivariate polytomous logistic regression models, medically indicated preterm delivery at <35 weeks was significantly associated with high scores for each of the vascular constructs; adjusted odds ratios ranged from 2.4 to 5.4. Spontaneous preterm delivery at 35–36 weeks was significantly associated with a high score on any 1 of 3 constructs: MV-I, MV-D, and FV-I. Spontaneous preterm delivery at <35 weeks was significantly associated with a high score on 2 or more of 3 constructs: MV-I, MV-D, and FV-I; adjusted odds ratios ranged from 4.1 to 7.4. These results support a role for various placental vascular lesions in medically indicated and spontaneous preterm delivery.
blood vessels; placenta; premature birth
Structural changes in water molecules are related to physiological, anatomical and pathological properties of tissues. Near infrared (NIR) optical absorption methods are sensitive to water, however detailed characterization of water in thick tissues is difficult to achieve because subtle spectral shifts can be obscured by multiple light scattering. In the NIR, a water absorption peak is observed around 975nm. The precise NIR peak shape and position is highly sensitive to water molecular disposition. We introduce a Bound Water Index (BWI) that quantifies shifts observed in tissue water absorption spectra measured by broadband Diffuse Optical Spectroscopy (DOS). DOS quantitatively measures light absorption and scattering spectra and therefore reveals bound-water spectral shifts. BWI as a water state index was validated by comparing broadband DOS to Magnetic Resonance Spectroscopy, diffusion-weighted MRI and conductivity in bound water tissue phantoms. Non-invasive DOS measurements of malignant and normal breast tissues performed in 18 subjects showed a significantly higher fraction of free water in malignant tissues (p<0.0001) compared to normal tissues. BWI of breast cancer tissues inversely correlated with Nottingham-Bloom-Richardson histopathology scores. These results highlight broadband DOS sensitivity to molecular disposition of water, and demonstrate the potential of BWI as a non-invasive in-vivo index that correlates with tissue pathology.
Adefovir dipivoxil (ADV) is a potent nucleotide analogue against both the wild‐type and lamivudine (LMV) resistant hepatitis B virus (HBV). The cumulative incidence of ADV resistant mutations in the nucleoside/‐tide treatment naïve chronic hepatitis B patient (CHB) at weeks 48, 96, and 144 was 0, 0.8–3%, and ∼5.9%, respectively.
The aim of this study was to characterise the genotypic and phenotypic mutation profiles to ADV in 67 LMV resistant CHB patients who were treated with ADV.
Serum HBV DNA was quantified by real time polymerase chain reaction. The ADV mutant was detected using matrix assisted laser desorption/ionisation time of flight mass spectrometry based genotyping assays, termed restriction fragment mass polymorphism (RFMP).
RFMP analysis revealed that a total of 11 amino acid substitutions developed in the rt domain of the HBV polymerase in nine patients. The cumulative incidence of genotypic ADV resistance at months 12 and 24 was 6.4% and 25.4%, respectively. The rtA181V, rtN236T, and rtA181T mutations were detected in five, four, and two of the 67 patients at treatment months 12–17, 3–19, and 7–20, respectively. Serial quantification of serum HBV DNA revealed that two patients with the rtA181V mutation, with or without the rtN236T mutation, and one patient with the rtA181T mutation displayed HBV DNA rebound.
Emergence of the ADV mutation in LMV resistant patients who are treated with ADV appeared to present earlier and more frequently than was reported in previous studies on nucleoside/‐tide treatment naïve patients.
drug resistance; adefovir dipivoxil; lamivudine; hepatitis B virus
The purpose of this study was to evaluate the usefulness of a particular magnetic resonance imaging technique known as primary diffusion weighted imaging (DWI) for patients with lacunar syndrome in the emergency department (ED).
Patients with one of five classic lacunar syndromes underwent DWI as primary imaging modality. The DWI findings were classified into groups: (a) having a lesion with high signal intensity, (b) having a lesion with mixed signal intensity, and (c) unremarkable. The final clinical diagnoses were extracted from the patients' medical records, and used as a reference standard.
Of 151 DWI images, 120 (79%) were interpreted as high signal lesions, 21 (14%) as mixed signal lesions, and 10 (7%) as unremarkable. All patients with high signal lesions or unremarkable findings were diagnosed with ischaemic stroke. The patients with mixed signal lesions were diagnosed with haemorrhagic stroke with an exception of one ischaemic stroke.
Primary DWI is a feasible and useful neuroimaging tool for patients with lacunar syndrome in the ED.
Diffusion magnetic resonance imaging; cerebrovascular accident
The present study was conducted to evaluate the efficacy and safety of a combination regimen of docetaxel plus oxaliplatin in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous docetaxel 65 mg m−2 plus oxaliplatin 120 mg m−2 on day 1 based on a 3-week cycle. Forty-two patients were enrolled in the current study, among whom 39 were assessable for efficacy and all assessable for toxicity. One complete response and 18 partial responses were confirmed, giving an overall response rate of 45.2% (95% confidence interval (CI); 31.7–59.7%). At a median follow-up of 7.7 months, the median time to progression and median overall survival was 5.7 (95% CI; 4.3–7.2) months and 9.9 (95% CI; 7.8–12.0) months, respectively. Grade 3/4 neutropenia occurred in 11 patients (26.1%) and febrile neutropenia was observed in four patients (9.5%). The common non-haematologic toxicity was fatigue (grade 1/2, 61.9%) and nausea (grade 1/2, 47.7%). The combination of docetaxel and oxaliplatin was found to be well tolerated and effective in patients with advanced gastric cancer.
docetaxel; oxaliplatin; chemotherapy; gastric cancer
Urine based gonadotropin assays provide a practical means of analyzing hormone secretion patterns. While research protocols have revealed pulsatile patterns of gonadotropins such as LH in the blood, these assays are of limited clinical use since daily venipuncture sampling is not feasible outside of a research environment. However, collection of several urine samples provides a method to achieve the same visualization of gonadotropin patterns in patients using a convenient and generally applicable technique based on analysis of the highly stable hLHβcf for monitoring LH and hCGβcf for monitoring pituitary hCG. We demonstrated that two different sampling techniques for analyzing these gonadotropin metabolites yielded the same information on their excretory patterns, either sampling of spot urines or collecting first morning void urines for several days. Next, we studied the core excretory patterns in several populations: menstruating and postmenopausal women from the general population, and two populations of women from a fertility center, one of which had polycystic ovaries (PCO). The PCO population was also subdivided into those with and without insulin resistance (IR). It was found that our hLHβcf assay did not measure the form of the LH core (v- hLHβcf) produced in subjects who were homozygous for a variant form of LH (v-LH). None of our patients tested were homozygous for the variant form of LH. It was also found that in most non-PCO (NPCO) patients, the hLHβcf peak lasted for 7–9 days while among the PCO patients this peak frequently lasted for less than 7 days and an erratic pattern tended to appear. The overall differences in patterns between the PCO and NPCO patients were confirmed by spectral statistical methods. The prevalence of certain characteristic hLHβcf patterns may be higher among women with PCO with a more severe clinical presentation. Use of urinary analysis of gonadotropin metabolites, especially hLHβcf, may supplement subjective ultrasound studies with more sensitive biochemical measurements.
Systemic chemotherapy for gastric cancer is often associated with treatment-related toxicity, which is particularly severe in patients with a poor performance status. In this paper, we describe the first study to evaluate S-1 monotherapy as an option for advanced gastric cancer patients who are not candidates for combination chemotherapy due to poor clinical condition. Fifty-two patients with Eastern Cooperative Oncology Group (ECOG) performance scale 2–3, whose general condition had made use of combination chemotherapy impossible, were enrolled. S-1 was administered to 30 patients as second- or third-line therapy. The initial dose of S-1 was 35 mg m−2, administered b.i.d for 14 days every 3 weeks. With a median follow-up period of 33 weeks, the median progression-free survival, and overall survival were 11 weeks (95% CI, 8–14) and 33 weeks (95% CI, 19–47), respectively. The overall 1-year survival rate was 29% by intent-to-treat analysis. The overall response rate was 12% (95% CI, 3–21), and the percentage of stable disease was 35%, resulting in the disease control rate of 47% (95% CI, 32–60). Significant drug-related toxicity included grade 3 diarrhoea (14%), anorexia (14%), fatigue (10%), neutropenia (10%), and leucopenia (6%). In conclusion, this study indicated the modest activity of S-1 in gastric cancer patients with poor performance status.
S-1; gastric adenocarcinoma; performance status
The Us5 gene of herpes simplex virus (HSV) encodes glycoprotein J (gJ). The only previously reported function of gJ was its ability to inhibit apoptosis. However, the mechanism by which gJ prevents apoptosis is not understood, and it is not known whether gJ mediates additional cellular effects. In this study, we evaluated the expression, localization, and cellular effects of Us5/gJ. Us5 was first expressed 4 h after infection. gJ was detectable at 6 h and was expressed in glycosylated and unglycosylated forms. Us5 was regulated as a late gene, with partial dependency on DNA replication for expression. Us5 expression was delayed in the absence of ICP22; furthermore, expression of Us5 in trans protected cells from apoptosis induced by an HSV mutant with deletion of ICP27, suggesting that the antiapoptotic effects of ICP22 and ICP27 are mediated in part through effects on gJ expression. Within HSV-infected or Us5-transfected cells, gJ was distributed widely, especially to the endoplasmic reticulum, trans-Golgi network, and early endosomes. gJ interacted with FoF1 ATP synthase subunit 6 by a yeast two-hybrid screen and had strong antiapoptotic effects, which were mediated by protein rather than mRNA. Antiapoptotic activity required the extracellular and transmembrane domains of gJ, but not the intracellular domain. Consistent with inhibition of FoF1 ATP synthase function, Us5 was required for HSV-induced reactive oxygen species (ROS) formation, and gJ was sufficient to induce ROS in Us5-transfected cells. Thus, HSV gJ is a multifunctional protein, modulating other cellular processes in addition to inhibition of apoptosis.