Visual cues added to a virtual environment paradigm do not improve motor arrests in Parkinson's disease.

Objective. Elucidating how cueing alleviates freezing of gait (FOG) in Parkinson's disease (PD) would enable the development of more effective, personalized cueing strategies. Here, we aimed to validate a visual cueing virtual environment (VE) paradigm for future use in e.g. neuroimaging studies and behavioral studies on motor timing and scaling in PD patients with FOG.Approach. We included 20 PD patients with FOG and 16 age-matched healthy control subjects. Supine participants were confronted with a VE displaying either no cues, bars or staircases. They navigated forward using alternate suppression of foot pedals. Motor arrests (as proxy for FOG), and measures of motor timing and scaling were compared across the three VE conditions for both groups.Main results. VE cues (bars and staircases) did not reduce motor arrests in PD patients and healthy control subjects. The VE cues did reduce pedal amplitude in healthy control subjects, without effects on other motor parameters.Conclusion. We could not validate a visual cueing VE paradigm to study FOG. The VE cues possibly failed to convey the necessary spatial and temporal information to support motor timing and scaling. We discuss avenues for future research.

Validation of the Auditory Stroop Task to increase cognitive load in walking tasks in healthy elderly and persons with Parkinson's disease.

BACKGROUND: The development of treatments for freezing of gait (FOG) in Parkinson's disease (PD) requires experimental study set-ups in which FOG is likely to occur, and is amenable to therapeutic interventions. We explore whether the 'Auditory Stroop Task' (AST) can be used to increase cognitive load (and thereby elicit FOG), simultaneously with visual cues (as a therapeutic intervention for FOG). We additionally examined how these two contrasting effects might interact in affecting gait and FOG parameters. OBJECTIVES: We investigated whether: (1) the 'Auditory Stroop Task' (AST) influences gait in healthy elderly and persons with PD who experience FOG, and increases the frequency of FOG events among PD patients; (2) the AST and visual cues interact; and (3) different versions of the AST exert different cognitive loads. METHODS: In 'Experiment 1', 19 healthy elderly subjects performed a walking task while performing a high and low load version of the AST. Walking with a random numbers task, and walking without cognitive load served as control conditions. In 'Experiment 2', 20 PD patients with FOG and 18 healthy controls performed a walking task with the AST, and no additional cognitive load as control condition. Both experiments were performed with and without visual cues. Velocity, cadence, stride length, and stride time were measured in all subjects. FOG severity was measured in patients. RESULTS: Compared to the control conditions, the AST negatively affected all gait parameters in both patients and controls. The AST did not increase the occurrence of FOG in patients. Visual cues reduced the decline in stride length induced by cognitive load in both groups. Both versions of the AST exerted similar effects on gait parameters in controls. CONCLUSIONS: The AST is well-suited to simulate the effects of cognitive load on gait parameters, but not FOG severity, in gait experiments in persons with PD and FOG.

Blood flow velocity measured using the Retinal Function Imager predicts successful ranibizumab treatment in neovascular age-related macular degeneration: early prospective cohort study.

PURPOSE: Anti-VEGF treatment has a potent vasoconstrictive effect. Early changes of retinal blood flow velocity (RBFV) measured using the Retinal Function Imager (RFI) combined with indicators of vascular status may help in predicting the visual outcome 1 month post injection in patients with neovascular age-related macular degeneration (nvAMD) under ranibizumab treatment. To develop a simple prediction model based on the change in RBFV 3 days post injection and indicators of a patient's vascular status to assess the probability of a successful visual outcome 1 month post injection. METHODS: RBFV measured using RFI were prospectively collected pre-injection and 3 days post injection in 18 eyes of 15 patients. Indicators of vascular status (history of hypertension, diabetes mellitus without retinal affection, and smoking) were assessed by medical history. By univariate analyses, parameters associated with visual outcome were weighted (-1 to 6 points). A multivariate logistic regression model with the categorized visual outcome parameter (≥0 letters gained after 1 month) as the dependent variate and the sum score as the independent variate (continuous scale) was used to estimate the score value-specific probabilities of letters gained ≥0 1 month post injection. RESULTS: The indicators of vascular status negatively influenced the likelihood of a letter gain ≥0 whereas an increase in the arterial RBFV strongly increased it. The area under the receiver operating characteristics curve for these parameters investigated was 0.71 (95% CI: 0.43-1.00). CONCLUSION: Changes in the arterial RBFV following 3 days after ranibizumab injection combined with three indicators of the vascular status identified nvAMD patients with favorable visual outcome accurately.

[Effects of heat waves on mortality in Germany]. / Auswirkungen von Hitzewellen auf die Mortalität in Deutschland.

Heat waves present an increasing threat to population's health; there is increased activity in terms of research and preventive measures since the heat waves in 2003. This is the first narrative review of studies on heat wave-associated mortality in Germany. The review and critical evaluation includes 12 studies. Notable differences in the research methodology were observed. Scientific knowledge on heat wave-associated mortality in Germany is insufficient. So far, most studies have focused on large cities or states/provinces. However, risk assessments play an important role in deciding upon and planning of preventive measures.

Porphyromonas gingivalis, Treponema denticola and toll-like receptor 2 are associated with hypertensive disorders in placental tissue: a case-control study.

AIM(S): To explore the associations between the presence of periodontal pathogens and the expression of toll-like receptors (TLR-2 and TLR-4) in the placental tissue of patients with hypertensive disorders compared to the placentas of healthy normotensive patients. MATERIAL AND METHODS: A case-control study was performed. From a cohort composed of 126 pregnant women, 33 normotensive healthy pregnant women were randomly selected, and 25 cases of patients with hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, were selected. Placental biopsy was obtained after aseptic placental collection at the time of delivery. All of the samples were processed and analysed for the detection of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Treponema denticola and Tannerella forsythia using the polymerase chain reaction (PCR) technique. Determination of the expressions of TLR-2 and TLR-4 was performed in samples of total purified protein isolated from placental tissues and analysed by ELISA. The data were assessed using descriptive statistics. The associations among variables were estimated through multiple logistic regression models and the Mann-Whitney test to evaluate the differences between the two groups. RESULTS: A significant increase was observed in the expression of TLR-2 in the placentas of patients with hypertensive disorders (p = 0.04). Additionally, the multiple logistic regression models demonstrated an association between the presence of T. denticola and P. gingivalis in placental tissues and hypertensive disorders (OR: 9.39, p = 0.001, CI 95% 2.39-36.88 and OR: 7.59, p = 0.019, CI 95% 1.39-41.51, respectively). CONCLUSIONS: In the present study, pregnant women with periodontal disease presented an association in the placental tissue between the presence of T. denticola and P. gingivalis and hypertensive disorders. Additionally, increased expression of TLR-2 was observed. However, further studies are required to determine the specific roles of periodontal pathogens and TLRs in the placental tissue of patients with pregnancy-related hypertensive disorders.

Heat-related mortality in Freiburg and Rostock in 2003 and 2005 - methodology and results.

In Freiburg and Rostock, heatwaves were compared to control periods for the years 2003/2005. In Freiburg, a long heatwave in 2003 cost 21 lives (equal to a significant excess mortality of 33 %). No or no significant excess mortalities were found for shorter heatwaves in Freiburg and for Rostock. The detection of heat-related mortality depends on the size of the cities (population) and the heatwave characteristics.

Co-detección de patógenos periodontales en pacientes chilenos con periodontitis crónica / Co-detection of periodontal pathogens in Chilean patients with chronic periodontitis

Las enfermedades periodontales asociadas a la placa dental son un importante problema de salud pública. La etiología de estas patologías es de origen multifactorial e involucra factores del hospedero, medio ambiente y de carácter infeccioso asociados a bacterias embebidas en la placa dental. Las principales bacterias asociadas a la periodontitis crónica son Porphyromonas gingivalis, Treponema denticola y Tannerella forsythia, mientras que Aggregatibacter actinomycetemcomitans se ha asociado principalmente a la periodontitis agresiva. Otro microorganismo clave en el desarrollo de la enfermedad es Fusobacterium nucleatum, el cual tiene la capacidad de co-agregarse con los patógenos periodontales y así facilitar su colonización. Para demostrar la prevalencia de estas bacterias, la co-detección y la asociación entre pacientes chilenos fumadores y no fumadores, se analizaron 67 muestras mediante PCR convencional. Los resultados mostraron que un 90 por ciento de las muestras fueron positivas para F. nucleatum, siendo la bacteria más detectada. Al analizar la co-detección entre las distintas bacterias se observa que F nucleatum está presente en más de un 80 por ciento de los casos cuando se detecta cualquiera de las cuatro bacterias restantes, mientas que A. actinomycetemcomitans se detecta en no más de un 20 por ciento al amplificar cualquiera de las bacterias restantes. Por otra parte, los resultados por género indican que existen diferencias significativas en la detección de T. forsythia, F. nucleatum y A. actinomycetemcomitans. Al considerar el factor de tabaquismo se observó que ninguna de las muestras de pacientes fumadores resultó ser positiva para A. actinomycetemcomitans.

Periodontal disease associated with dental plaque is a major public health problem. The etiology of these disorders is multifactorial involved seeing host factors, environmental factors and infectious nature associated with the presence of bacteria belonging to the plaque. The main bacteria associated with chronic periodontitis are Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, while Aggregatibacter actinomycetemcomitans is mainly associated with aggressive periodontitis. Another key organism in the development of the disease is Fusobacterium nucleatum, which has the ability to co-aggregate with other periodontal pathogen. To demonstrate the prevalence of these bacteria and the association between Chilean smokers and nonsmokers patients, 67 samples were analyzed by conventional PCR. The results showed that 90 percent of the samples were positive for F nucleatum being the most commonly detected bacteria. By analyzing the co-detection between different bacteria shows that F nucleatum is present in more than 80 percent of cases when it detects any of the four remaining bacteria, which lie A. actinomycetemcomitans was detected in no more than 20 percent by amplifying any remaining bacteria. Moreover the results by gender indicate that significant differences exist in the detection of T forsythia, F. nucleatum and A. actinomycetemcomitans. In considering the factor of smoking was observed that none of the samples from smokers was found to be positive for A. actinomycetemcomitans.

In vitro assessment of AhR-mediated activities of TCDD in mixture with humic substances.

Humic substances (HS) are ubiquitous natural products of decomposition of dead organic matter. HS is present in most freshwaters at concentrations ranging from 0.5 to 50mg L(-1). Organic carbon can represent 20% dry weight of sediments. Recently, the interaction of dissolved HS with the aryl hydrocarbon receptor (AhR) has been demonstrated. The AhR is a cytosolic receptor to which persistent organic pollutants (POPs) can bind and many of their toxic effects are mediated through interactions with this receptor. We describe in vitro effects (using H4IIE-luc cells) of binary mixtures of various HS with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), since in contaminated environments these compounds occur simultaneously. Six out of 12 HS samples activated AhR even at environmentally relevant concentrations (17 mg L(-1)), but did not reach the full AhR-activation even at excessive concentration. In simultaneous exposure of H4IIE-luc to HS (17 mg L(-1)) and TCDD (1.2 pM) without any preincubation prior to exposure, either significant additive or facilitative effects were observed. No negative interactions, due to possible sorption of TCDD to HS was observed. Nevertheless, if the HS-TCDD binary mixture was preincubated for 6 days prior to the exposure on H4IIE-luc cells, the additive and facilitative effects were less due to possible sorption of TCDD onto HS. Similar results were obtained from analogous experiments with greater concentrations of both TCDD and HS.

Changes of AhR-mediated activity of humic substances after irradiation.

Humic substances (HS) and natural organic matter (NOM) are natural organic compounds ubiquitous in the environment. However, some studies indicate that both HS and NOM can act as xenobiotics, e.g. induce hormone-like effects in fish, amphibians and invertebrates. Molecules of these substances contain a number of aromatic rings and conjugated double bonds--the so called chromophores. Irradiation of dissolved HS and NOM can lead to a series of photochemical reactions which can act on these substances itself, or on other substances present in aquatic environment along with HS and NOM such as e.g. xenobiotics. In our previous study, we have found significant interactions of five humic acids (HA) with cytosolic aryl hydrocarbon receptor (AhR) in an in vitro bioassay based on H4IIE-luc cells. In the present study, we have studied the changes in AhR-mediated activities both of HS and NOM after irradiation that simulated natural solar light. Nine different HS and two NOM samples were irradiated in Pyrex tubes with a medium-pressure mercury lamp for a duration of 0 to 52 h (which corresponds to 0-52 d natural solar radiation). Original concentrations of the samples were 50 mg L(-1), and the greatest concentration of HS and NOM photoproducts subsequently tested in the bioassay was 17 mg L(-1), which is an environmentally relevant concentration. After irradiation the absorbances of all the samples were less than the original materials. The AhR-mediated activity of the HA-Fluka and HA Sodium Salt were partially decreased by irradiation. The activities of other HS and NOM, that were either AhR-active or -inactive were not changed by irradiation. The results of the study demonstrate that AhR-mediated activities of two active HA is caused by both photo-stable and photo-labile AhR activators, while the other three active HA contain only photo-stable AhR activators. Potential mechanisms of the observed irradiation-induced changes in AhR-mediated activities are discussed.

AhR-mediated and antiestrogenic activity of humic substances.

Humic substances (HS) were for decades regarded as inert in the ecosystems with respect to their possible toxicity. However, HS have been recently shown to elicit various adverse effects generally attributed to xenobiotics. In our study, we used MVLN and H4IIE-luc cell lines stably transfected with luciferase gene under control of estrogen receptor (ER) and Ah receptor (AhR; receptor connected with so-called dioxin-like toxicity) for assessment of anti/estrogenic and AhR-mediated effects of 12 commercially available humic substances. Out of those, five humic acids were shown to induce AhR-mediated activity with relative potencies related to TCDD 2.6 x 10(-8)-7.4 x 10(-8). Organic extracts of HS solutions also elicited high activities what means that lipophilic molecules are responsible for a great part of effect. However, relatively high activity remaining in extracted solution suggests also presence of polar AhR-agonists. Contribution of persistent organic compounds to the observed effects was ruled out by H(2)SO(4) treatment. Eight out of twelve HS elicited significant antiestrogenic effects with IC(50) ranging from 40 to 164 mg l(-1). The possible explanations of the antiestrogenic effect include sorption of 17-beta-estradiol (E2) on HS, changes in membrane permeability for E2 or another specific mechanism.

Chromosomal aberrations and gene expression profiles in non-small cell lung cancer.

Alterations in genomic content and changes in gene expression levels are central characteristics of tumors and pivotal to the tumorigenic process. We analyzed 23 non-small cell lung cancer (NSCLC) tumors by array comparative genomic hybridization (array CGH). Aberrant regions identified included well-characterized chromosomal aberrations such as amplifications of 3q and 8q and deletions of 3p21.31. Less frequently identified aberrations such as amplifications of 7q22.3-31.31 and 12p11.23-13.2, and previously unidentified aberrations such as deletion of 11q12.3-13.3 were also detected. To enhance our ability to identify key acting genes residing in these regions, we combined array CGH results with gene expression profiling performed on the same tumor samples. We identified a set of genes with concordant changes in DNA copy number and expression levels, i.e. overexpressed genes located in amplified regions and underexpressed genes located in deleted regions. This set included members of the Wnt/beta-catenin pathway, genes involved in DNA replication, and matrix metalloproteases (MMPs). Functional enrichment analysis of the genes both overexpressed and amplified revealed a significant enrichment for DNA replication and repair, and extracellular matrix component gene ontology annotations. We verified the changes in expressions of MCM2, MCM6, RUVBL1, MMP1, MMP12 by real-time quantitative PCR. Our results provide a high resolution map of copy number changes in non-small cell lung cancer. The joint analysis of array CGH and gene expression analysis highlights genes with concordant changes in expression and copy number that may be critical to lung cancer development and progression.

The non-homologous end-joining pathway is not involved in the radiosensitization of mammalian cells by heat shock.

A synergistic increase in cell killing is observed when a heat-shock is administered prior to, during, or immediately after exposure to ionizing radiation (IR). This phenomenon, known as heat-radiosensitization, is believed to be mediated by inhibition of repair of radiation-induced double strand breaks (DSB) when cells are exposed to temperatures above 42 degrees C. However, the mechanism by which heat inhibits DSB repair is unclear. The bulk of radiation-induced DSBs are repaired via the non-homologous end-joining pathway (NHEJ). Several reports indicate that the Ku70 and Ku80 subunits of the mammalian DNA-dependent protein kinase (DNA-PK), a complex involved in NHEJ, appear to be susceptible to a heat-induced loss of DNA-binding activity, with Ku80 representing the heat-sensitive component. Since the heat-induced loss and subsequent recovery of Ku-DNA binding activity correlates well with heat-radiosensitization, a role for Ku80 and NHEJ in heat-radiosensitization has been proposed. However, direct evidence implicating Ku80 (and NHEJ) in heat-radiosensitization has been indeterminate. In this study, we demonstrate that equitoxic heat treatments at 42.5-45.5 degrees C induce a similar amount of aggregation of Ku80 in human U-1 melanoma cells. These data suggest that the time-temperature-dependent relationship between heat lethality and Ku80 aggregation are similar. However, the aggregation/disaggregation of Ku80 and its transient or permanent inactivation is unrelated to heat-radiosensitization. When survival curves were obtained for irradiated or irradiated and heated Ku80(-/-) mouse embryo fibroblasts (MEFs) and compared with survival curves obtained for wild-type (WT) cells, we found that heat-radiosensitization was not reduced in the Ku80(-/-) cells, but actually increased. Thus, our findings indicate that Ku80 is not essential for heat-radiosensitization. Non-involvement of Ku-dependent or Ku-independent NHEJ pathways in heat-radiosensitization was confirmed by comparing clonogenic survival between DNA ligase IV-defective and WT human cells. Our data therefore implicate homologous recombination in inhibition of repair of radiation-induced DSBs and as a target for heat-radiosensitization.

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling.

Androgen deprivation therapy for advanced prostate cancer is often effective, but not curative. Molecular pathways mediating the therapeutic response and those contributing to the subsequent hormone-refractory cell growth remain poorly understood. Here, cDNA microarray analysis of human CWR22 prostate cancer xenografts during the course of androgen deprivation therapy revealed distinct global gene expression profiles in primary, regressing and recurrent tumors. Elucidation of the genes involved in the transition between these states implicated specific molecular mechanisms in therapy failure and tumor progression. First, we identified a set of androgen-responsive genes whose expression decreased during the therapy response, but was then systematically restored in the recurrent tumors. In addition, altered expression of genes that encode known targets of rapamycin or that converge on the PI3K/AKT/FRAP pathway was observed in the recurrent tumors. Further suggestion for the involvement of these genes in hormone-refractory prostate cancer came from the observation that cells established from the recurrent xenografts were strongly inhibited in vitro by rapamycin. The results of this functional genomic analysis suggest that the combined effect of re-expression of androgen-responsive genes as well as the activation of rapamycin-sensitive signaling may drive prostate cancer progression, and contribute to the failure of androgen-deprivation therapy.

Epithelial cell contact-induced alterations in Salmonella enterica serovar Typhi lipopolysaccharide are critical for bacterial internalization.

The invasion of Pseudomonas aeruginosa and Salmonella enterica serovar Typhi into epithelial cells depends on the cystic fibrosis transmembrane conductance regulator (CFTR) protein as an epithelial receptor. In the case of P. aeruginosa, the bacterial ligand for CFTR is the outer core oligosaccharide portion of the lipopolysaccharide (LPS). To determine whether serovar Typhi LPS is also a bacterial ligand mediating internalization, we used both P. aeruginosa and serovar Typhi LPS as a competitive inhibitor of serovar Typhi invasion into the epithelial cell line T84. P. aeruginosa LPS containing a complete core efficiently inhibited serovar Typhi invasion. However, neither killed wild-type Typhi cells nor purified LPS were effective inhibitors. LPS from mutant Typhi strains defective in O side-chain synthesis, but with an apparently normal core, was capable of inhibiting invasion, but LPS obtained from a deeper rough mutant strain with alterations in fast-migrating core oligosaccharide failed to inhibit invasion. Lastly, exposure of wild-type serovar Typhi to T84 cultures before heat killing resulted in a structural alteration in its LPS that allowed the heat-killed cells to inhibit invasion of wild-type serovar Typhi. These data indicate that the serovar Typhi LPS core, like the P. aeruginosa LPS core, is a ligand mediating internalization of bacteria by epithelial cells, and that exposure of this ligand on wild-type Typhi is induced by the bacteria's interaction with host cells.

The rfaH gene, which affects lipopolysaccharide synthesis in Salmonella enterica serovar Typhi, is differentially expressed during the bacterial growth phase.

We have cloned and sequenced the rfaH gene from Salmonella enterica serovar Typhi strain Ty2. The gene showed a high degree of similarity to the rfaH genes from Escherichia coli K-12 and S. enterica serovar Typhimurium. A rfaH mutant was constructed by site-directed mutagenesis. This mutant produced a rough lipopolysaccharide (LPS), with an incomplete core region. The defect in LPS expression that results from the rfaH mutation was corrected by a plasmid carrying the intact gene. The plasmid-borne rfaH gene also restored normal LPS synthesis in a rfaH mutant of E. coli. Reverse transcription-polymerase chain reaction analyses were performed to determine the effects of various environmental conditions on the expression of rfaH. The transcription of rfaH showed a growth-phase-dependent regulation, with maximal expression at the late exponential phase. Other environmental conditions, such as temperature or medium osmolarity, did not affect transcription of rfaH.

Induction of gene expression as a monitor of exposure to ionizing radiation.

The complex molecular responses to genotoxic stress are mediated by a variety of regulatory pathways. The transcription factor TP53 plays a central role in the cellular response to DNA-damaging agents such as ionizing radiation, but other pathways also play important roles. In addition, differences in radiation quality, such as the exposure to high-LET radiation that occurs during space travel, may influence the pattern of responses. The premise is developed that stress gene responses can be employed as molecular markers for radiation exposure using a combination of informatics and functional genomics approaches. Published studies from our laboratory have already demonstrated such transcriptional responses with doses of gamma rays as low as 2 cGy, and in peripheral blood lymphocytes (PBLs) irradiated ex vivo with doses as low as 20 cGy. We have also found several genes elevated in vivo 24 h after whole-body irradiation of mice with 20 cGy. Such studies should provide insight into the molecular responses to physiologically relevant doses, which cannot necessarily be extrapolated from high-dose studies. In addition, ongoing experiments are identifying large numbers of potential biomarkers using microarray hybridization and various irradiation protocols including expression at different times after exposure to low- and high-LET radiation. Computation-intensive informatics analysis methods are also being developed for management of the complex gene expression profiles resulting from these experiments. With further development of these approaches, it may be feasible to monitor changes in gene expression after low-dose radiation exposure and other physiological stresses that may be encountered during manned space flight, such as the planned mission to Mars.

Analysis of expression patterns: the scope of the problem, the problem of scope.

Studies of the expression patterns of many genes simultaneously lead to the observation that even in closely related pathologies, there are numerous genes that are differentially expressed in consistent patterns correlated to each sample type. The early uses of the enabling technology, microarrays, was focused on gathering mechanistic biological insights. The early findings now pose another clear challenge, finding ways to effectively use this kind of information to develop diagnostics.

Comparative study of ovatifolin antioxidant and growth inhibition activities.

A comparative study on the effect of arturin (1), ovatifolin (3), deacetylovatifolin (5), and their 1-acetoxyarturin (2), 8-acetoxyovatifolin (4), 1,10-epoxyovatifolin (6), and 11,13-dihydroovatifolin (7) derivatives, isolated from Podanthus ovatifolius and Podanthus mitiqui, on the seedling growth, germination, and respiration of several monocot and dicot weedy target species was carried out. In addition to the inhibitory activity on the bleaching of crocin induced by alkoxyl radicals, these compounds also displayed scavenging properties toward DPPH in TLC autographic and spectrophotometric assays. The results indicate that ovatifolin (3), deacetylovatifolin (5), epoxyovatifolin (6), dihydroovatifolin (7), and the CH(2)Cl(2) extract interfere with pre-emergence of seedlings at the level of respiration. These compounds appear to have selective effects on the radicle and shoot growth of Physalis ixocarpa and Trifolium pratense. Their allelopathic effects are comparable to those of parthenolide, a know natural growth inhibitor.

Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation.

The Tax protein of human T-lymphotropic virus type 1 (HTLV-1), an oncoprotein that transactivates viral and cellular genes, plays a key role in HTLV-1 replication and pathogenesis. We used cDNA microarrays to examine Tax-mediated transcriptional changes in the human Jurkat T-cell lines JPX-9 and JPX-M which express Tax and Tax-mutant protein, respectively, under the control of an inducible promoter. Approximately 300 of the over 2000 genes examined were differentially expressed in the presence of Tax. These genes were grouped according to their function and are discussed in the context of existing findings in the literature. There was strong agreement between our results and genes previously reported as being Tax-responsive. Genes that were differentially expressed in the presence of Tax included those related to apoptosis, the cell cycle and DNA repair, signaling factors, immune modulators, cytokines and growth factors, and adhesion molecules. Functionally, we provide evidence that one of these genes, the mixed-lineage kinase MLK-3, is involved in Tax-mediated NF-kappa-B signaling. Our current results provide additional insights into Tax-mediated signaling.