Drosophila embryos. During this process, the latent proapoptotic activity of JNK becomes apparent following Dpp signaling suppression, which leads to JNK-dependent transcriptional activation of the proapoptotic gene reaper. Dpp signaling also protects cells from JNK-dependent apoptosis caused by epithelial disruption. We find that repression of reaper transcription by Dpp is mediated by Schnurri. Moreover, reporter gene analysis shows that a transcriptional regulatory module comprising AP-1 and Schnurri binding sites located upstream of reaper integrate the activities of JNK and Dpp. This arrangement allows JNK to control a migratory behavior without triggering apoptosis. Dpp plays a dual role during dorsal closure. It cooperates with JNK in stimulating cell migration and also prevents JNK from inducing apoptosis.Jun N-terminal kinase (JNK) often mediates apoptosis in response to cellular stress. However, during normal development, JNK signaling controls a variety of live cell behaviors, such as during dorsal closure in   •reaperDpp/BMP signaling prevents JNK from activating expression of proapoptotic •The transcriptional repressor Schnurri mediates the antiapoptotic effect of Dpp•reaperAP-1 and Schnurri binding sites integrate the inputs of JNK and Dpp on •Dpp signaling ensures the survival of dorsal edge cells during dorsal closure Drosophila embryos, JNK can direct dorsal closure because concurrent Dpp signaling, mediated by the repressor Schnurri, prevents activation of the proapoptotic gene reaper by JNK.JNK often mediates apoptosis in response to cellular stress, yet JNK signaling controls a variety of live cell behaviors during normal development. In  Drosophila eye, mitogen-activated protein kinase phosphorylates and destabilizes Hid, a proapoptotic protein transcriptionally activated by JNK signaling in this tissue  mediates one of the major stress response pathways . Indeed,s tissue . Anothern damage . Non-celn damage . All then damage . Here, wcrumbs (crb) (abbreviated as crb in genotypic descriptions) mutants, where JNK target genes are upregulated in response to loss of apicobasal polarity , which, in turn, orchestrates the cell shape changes required for dorsal closure . It is lpolarity . In suchDrosophila requires the H99 locus , and this was associated with a near-absence of apoptosis, as reported by activated caspase-3 immunoreactivity (reaper expression and apoptosis (highlighted with anti-activated caspase) appeared to mirror the early segmental activation of JNK signaling . No act embryos C, confireviously , JNK sigeviously  was stro embryos . Moreoveactivity D and S1E compare B, suggesreaper expression both in the dorsal epidermis of crumbs mutant embryos and, physiologically, at the dorsal edge of wild-type embryos. This was tested in embryos expressing a Dpp RNA interference (RNAi)-encoding transgene , which encodes an essential Dpp receptor  double mutants  repressor sequence  is flanked on either side by a predicted AP-1-binding site, making it a potential regulatory element. Because SEp is not an exact match to the consensus Schnurri binding site, we used an electrophoretic mobility shift assay (EMSA) to test whether it is recognized by Schnurri, using the previously characterized site from the brinker gene (cSE)  and the variants described later were introduced by PhiC31-mediated integration at the same genomic location to allow comparison without confounding influence from position effects. The wild-type reporter was essentially silent in wild-type embryos  are consistent with the notion that Schnurri represses reaper expression in the dorsal epidermis, thus allowing JNK signaling to control epithelial migration without triggering apoptosis.The promoter region of sequence . SimilarNNNGTCTG . Two relne (cSE)  as a poswith cSE A. Thus, tary DNA A. This r embryos B, as exp mutants D. Such d mutants E. Also,  mutants E. These Shn]-GFP A. This mShn]-GFP A, suggespidermis F. One mu compare D. Also, crumbs embryos, where the wild-type reporter is strongly activated. Mutating one or the other site reduced activation, while the double mutant reporter  had no detectable activity in crumbs mutants , indicating that the response to loss of epithelial integrity does not require p53. Overall, our results show that the two predicted AP-1 binding sites contribute redundantly to reaper upregulation in crumbs mutants. They also show that JNK signaling acts directly on the reaper promoter and not via a relay mechanism. We conclude that a small regulatory module allows JNK to trigger apoptosis, except in dorsal cells that are protected by Dpp signaling.We next assessed the function of the two predicted AP-1 binding sites by mutating them (TGACTCATA → TGACATTTA)  individu mutants E. This r mutants K, consis mutants . It is wschnurri mutants (and possibly other Dpp pathway mutants) would not only be caused by the failure of dorsal edge cells to migrate but also by their reduced survival. To evaluate the contribution of the latter, we assessed the extent of tissue loss in fixed and live schnurri mutant embryos, which, as previously reported   H–4M. In d around  and S4. d around . These o shrinks A–S4I, lid reaper G, even td reaper F–4G, sugreaper by Schnurri is direct and, hence, likely Brinker independent. By contrast, the migration of dorsal edge cells is mediated by Brinker repression, since schnurri brinker double mutant larvae have a sealed dorsal midline  triggers reaper expression . EMSAs were largely performed as described elsewhere (Details on materials and methods can be found in the exposure . The emblsewhere . Live emlsewhere . The cus


Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Specific therapeutic and prophylactic agents are not available. Epidemiological studies have established a correlation between long-term use of the commonly prescribed anti-diabetic drug metformin and a decrease in the incidence of breast and other cancers. Whether metformin might also have anti-HTLV-1 and anti-ATL activity is unclear. In this study we demonstrate an inhibitory effect of metformin on HTLV-1 transcription mediated through the activation of LKB1 tumor suppressor and downstream salt-inducible kinases (SIKs). Treatment of HTLV-1- transformed ATL cells or cells transfected with HTLV-1 molecular clone pX1MT with metformin led to reduction in cell-free virion production and inhibition of cell proliferation. This effect was attributed to the activation of LKB1/SIK1 which compromised Tax expression and HTLV-1 transcription. LKB1 and SIKs function as host restriction factors that counteract Tax activation of HTLV-1 long terminal repeats. Expression of LKB1 and activated SIKs effectively blunted Tax activity in a phosphorylation-dependent manner in LKB1-null HeLa cells, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function in LKB1-proficient HEK293T cells. Activated LKB1 and SIKs associated with Tax. Enforced expression of LKB1 or SIK1 in pX1MT-transfected cells and HTLV-1-transformed ATL cells repressed proviral transcription, whereas depletion of LKB1 boosted Tax expression. Taken together, our findings revealed a potential therapeutic and prophylactic agent for ATL as well as a new negative regulatory function of LKB1 and SIKs in HTLV-1 transcription. .


The innate ability of the human cell to silence endogenous retroviruses through RNA sequences encoding microRNAs suggests that the cellular RNAi machinery is a major means by which the host mounts a defense response against retroviruses. Indeed, cellular miRNAs target and hybridize to specific sequences of both HTLV-1 and HIV-1 viral transcripts. However, the virus itself contains various mechanisms that assist in the evasion of viral inhibition through control of the cellular RNAi pathway. Retroviruses can hijack components of the RNAi pathway, in some cases to produce novel viral miRNAs that can either assist in active infection or promote a latent state. Here, we show that HTLV-1 Tax contributes to the dysregulation of the RNAi pathway by altering the expression of key components. A survey of uninfected and HTLV-1 infected cells revealed that Drosha is present at lower levels in all HTLV-1 infected cell lines and infected primary cells, while other components such as DGCR8 were not dramatically altered. We show co-localization of Tax and Drosha in the nucleus in vitro as well as co-immunoprecipitation in the presence of proteasome inhibitors, indicating that Tax interacts with Drosha and may target it to specific areas of the cell, namely, the proteasome. In the presence of Tax we observed a prevention of primary miRNA cleavage by Drosha. Finally, the changes in cellular miRNA expression in HTLV-1 infected cells can be mimicked by the add back of Drosha or the addition of antagomiRs against the cellular miRNAs which are downregulated by the virus.


Hepatozoon are apicomplexan parasites transmitted by variety of hematophagous arthropods to a wide range of intermediate hosts. Hepatozoon infections are broadly distributed around the world and the presence of this parasite is confirmed both in cats and dogs. Until now, two species from canines  and a single species from felines (H. felis) have been reported. While the canine Hepatozoon spp. are transmitted by ticks, the vector for H. felis remains unknown. The aim of presented study was to determine the prevalence and the diversity of Hepatozoon in population of domestic cats and dogs living in close contact in rural communities of Samburu pastoralists in northern Kenya and to evaluate the existence of possible cross-transmissions between both hosts. Between years 2007-2012 in total, 135 and 258 blood samples from cats and dogs from the area of Mt. Kulal  was collected, respectively. The DNA from blood (preserved in ethanol) was extracted using phenol-chlorophorm method and followed by conventional PCR screening. First round of PCR was done by using Piroplasmid-F and Piroplasmid-R primers, amplifying 18S rRNA gene of Hepatozoon spp. (400 bp). A second PCR assay was performed in samples positive by Piroplasmid primers to amplify a larger fragment (1400 bp) of the 18S rRNA gene. All PCR amplicons comming from positive samples were sequenced and determined according to the BLAST match. In cats, this revealed 110 out of 135 (81.5%) positive samples, of which we obtained 104 sequences with an identity of 98% -100% to an existing GenBank accession. In total, 77 sequences were confirmed as Hepatozoon felis, 26 samples was proven to be Hepatozoon sp. and a single sample was determined as Hepatozoon canis with an identity of 96%. Regarding dogs, 121 out of 258 (47%) were positive and we gained 107 sequences of which 105 showed similarity to Hepatozoon canis and the remaining two proved to be Hepatozoon sp. Despite a close contact of hosts, obviously cats and dogs do not share the same parasite, which demonstrates a great majority of clearly identified Hepatozoon canis/Hepatozoon felis. Mentioned facts could be explained either by strict host specificity or by presence of different vector or by both statements.Species of the genus


The number of HTLV-1 infected persons in the world has recently been estimated to be at least at 5 to 10 million or perhaps higher due to unavailable data (Gessain and Cassar Front Microbiol 2012). We decided to undertake a similar estimation for HTLV-2 infection. A targeted review of the literature revealed HTLV-2 prevalence estimates in blood donors  and specific recognized high prevalence subpopulations in different regions of the world. Because blood donors are selected for low risk of viral infection and good health, we multiplied their prevalence by a factor of five to estimate the population prevalence. Data from studies using sensitive and specific assays for HTLV-2 antibody were preferred. Population data were obtained from national censuses or, for certain high-risk groups, Google searches. For each subpopulation, prevalence was multiplied by the size of the population. We estimate that there are 800,000  HTLV-2 infected persons globally. The largest number of such persons is in the United States  reflecting the confluence of endemic Amerindian, hyperendemic injection drug user (IDU) and secondary sexual spread to the general population. Brazil had the second-largest population of infected persons at 200,000-250,000 and a similar epidemiology. In Europe, where HTLV-2 infection is found almost exclusively among IDU, we estimate about 20,000-40,000 persons. Although they have the highest prevalence, other endemic Amerindian and Pygmy populations in Latin America and central Africa have very small populations and therefore contribute no more than 50,000-100,000 infected persons globally. In conclusion, the burden of HTLV-2 infection in the world is about 6 to 12 fold lower than that of HTLV-1. This represents a concentration of infection in specific high-risk groups and a lower degree of sexual and vertical transmission within the general population than for HTLV-1.


Serum uric acid (UA) has been known to have a positive association with blood pressure (BP). However, the relationship between serum UA and BP in different age groups is unclear.A total of 45,098 Koreans who underwent health examinations at Korea Association of Health Promotion with no history of taking drugs related with UA and/or BP were analyzed for determining the relationship between serum UA and BP.β = 0.25, p = 0.002) and diastolic BP  after adjustment for age, diabetes, dyslipidemia, body mass index, and estimated glomerular filtration rate. Men between ages 40 and 59 showed similar results regarding diastolic BP. The association between serum UA and BP was stronger in women <40  and in between 40 and 59 . The association was not significant in men and women ≥60. The odds ratios (ORs) of hyperuricemia for hypertension were 1.25  and 1.33  in men <40 and in between 40 and 59, respectively, in the multivariate analysis. The OR was 2.60  in women <40. The relationship between hyperuricemia and hypertension was not significant in other age/gender groups.In men <40, serum UA was significantly associated with systolic (In contrast to the elderly of 60 and over, the non-elderly showed significant associations between serum UA and BP. Hypertension in adults is the most common form of cardiovascular diseases. The prevalence of hypertension grows higher with aging, resulting in an increase in morbidity and mortality through various events such as myocardial infarction, heart failure, stroke, and renal failure -4.Hyperuricemia has been proposed to have an association with hypertension in various studies. Serum uric acid (UA) levels were demonstrated to be an independent predictor for developing hypertension -7. RegarTaking this into account, a hypothesis regarding the effect of serum UA-lowering agents which could have potential benefits in prevention and treatment of hypertension has emerged. Feig and Johnson  showed aAlso, studies mentioned above lack control over variables which could have effect on serum UA levels such as the history of taking diuretics, antihypertensive medication or other drugs, obesity, and renal function. Moreover, some of them were performed with only a small number of subjects.On the basis of the considerations above, we performed the present study to compare the relationship between serum UA and BP or hypertension by different age groups in a single large cohort with adjustment of all possible confounding factors. This study may identify a more specific target group in which the association between serum UA and BP or hypertension is the highest and controlling serum UA would have maximal benefit.A total of 91,882 subjects who underwent health examinations at Korea Association of Health Promotion (KAHP) during January, 2005 to December, 2009 were initially enrolled. Patients lacking at least 6 months of medical history in the Health Insurance Review and Assessment Service (HIRA) system were excluded. Informed consent was obtained according to the Helsinki Declaration for all of the enrolled patients in our study, and the study protocol was approved by the institutional review boards of KAHP, HIRA, and Korea University.Subjects with a history of taking antihypertensive and/or medications which could affect serum UA levels were also excluded. A flow diagram of the study protocol and medications for exclusion are presented in Figure Systolic and diastolic BP were measured in all of the subjects. The diagnosis of hypertension was based on a systolic BP of 140 mmHg or higher and a diastolic BP of 90 mmHg or higher. Height and weight were measured and body mass index (BMI) was calculated as the weight in kilograms (kg) divided by the square of the height in meters (m). Previous diagnoses which could affect serum UA levels, such as diabetes, chronic kidney disease, dyslipidemia, were thoroughly investigated. Fasting blood sugar levels, estimated glomerular filtration rate (eGFR), and lipid profiles including total cholesterol, triglyceride, high-density lipoprotein, and low density lipoprotein were checked for the evaluation of comorbidities. History of hospital admissions and previous medications were also taken through a cohort established between the network of KAHP and HIRA. Hyperuricemia was diagnosed in men and women each with a serum UA level over 7.0 mg/dL and 6.0 mg/dL .t-test, and correlations were assessed by Pearson coefficients. Analysis of covariance was used to test for differences owing to covariates and multiple linear and logistic regression modeling to distinguish each of the contributions of age, diabetes, dyslipidemia, BMI, and eGFR to the effect of UA on BP and hyperuricemia on hypertension. All continuous variables were expressed as means ± standard deviation. A p value of <0.05 was considered statistically significant, but to compensate the potential of an alpha error generating from the stratified analysis regarding age and gender  in the multiple linear and logistic regression model, Bonferroni correction was applied and a p value of 0.05/6 was considered statistically significant.All statistical analyses were performed using the SAS ver. 9.3 . Significance testing of the difference between means was done by an independent Student’s 2 and 23.2 ± 3.4 kg/m2 each. Systolic BP was significantly higher in group ≥60 compared to the other groups . Comparison of diastolic BP between the three groups also showed similar results . The prevalence of comorbidities such as hypertension, diabetes, and dyslipidemia was highest in group ≥60, whereas the prevalence of hyperuricemia was highest in group <40. Nearly twice as many subjects were diagnosed with hypertension in hyperuricemic subjects than normouricemic subjects   and diastolic BP  after adjustment for age, diabetes, dyslipidemia, BMI, and eGFR. However, men between the age 40 and 59 showed similar results regarding only diastolic BP . The association between serum UA and BP was stronger in women <40  and in between 40 and 59 regarding diastolic BP . The association was not significant in men and women ≥60  and 1.33  each in men <40 and in 40 to 59, respectively. In women <40, the OR was 2.60 . The relationship between hyperuricemia and hypertension was not significant in other age/gender groups  of hyperuricemia for hypertension were 1.25 , it was only significant in the non-elderly population under age 60 in both genders. There have been several studies suggesting that the strength of the relationship between serum UA and BP is more dominant in the younger age groups and decreases during the aging process as the duration of hypertension gets longer ,21-23. HThe prognostic significance of serum UA in different disease entities such as diabetes, chronic kidney disease, and cardiovascular diseases have been recognized in several previous studies ,9,24,25.There are several potential explanations for the attenuation of the relationship in the elderly. Previous studies implicating similar results have mentioned that the effect of a single estimate of serum UA in the young may decrease over time, and the higher background rate of hypertension incidence by other causes with increasing age may contribute to the reduction of the strength of the relationship between serum UA and BP . AlthougStudies using animal models and cell cultures have revealed mechanisms by which UA could cause hypertension. In short, hypertension was developed by UA-mediated renal vasoconstriction resulting from a reduction in endothelial levels of nitric oxide, with activation of renin-angiotensin system ,31. MicrRecent therapeutic trials with UA-lowering agents have demonstrated promising results for reducing BP. In one small study, the use of allopurinol, a xanthine oxidase (XO) inhibitor, resulted in reduction of BP in adolescents with newly diagnosed hypertension with hyperuricemia . In anotOur study has several limitations. First, its cross-sectional design could not reveal the causal role of serum UA in the development of hypertension. Increased UA levels at baseline are suggested to result in vascular dysfunction but after chronic exposure to high UA levels, the corresponding alterations in the vasculature diminish over time . There mThis single large cohort study confirmed that the relationship between serum UA and BP, hyperuricemia and hypertension is quite different in each age group. In contrast to the elderly of 60 and over, the non-elderly showed a significant association between serum UA and BP in both genders. Hyperuricemia increased the relative risk of hypertension by approximately 30% in men under 60 and by 2.6 fold in women under 40. We believe the present study suggests specific age/gender groups which would obtain maximal benefit from the treatment of hyperuricemia for the prevention and treatment of hypertension.


Sjögren syndrome has been diagnosed in patients with HTLV-1 associated myelopathy and dry mouth and dry eyes are documented in HTLV-1 carriers. However the diagnosis of Sjögren syndrome in these subjects has been contested. In this cross-sectional study, we evaluated the role of immunological factors and proviral load, in sicca syndrome associated with HTLV-1 in patients without myelopathy. Subjects were recruited in the HTLV-1 Clinic, from 2009 to 2011. The proviral load and cytokine levels  were obtained from a database containing the values presented by the subjects at admission in the clinic. Of the 272 participants, 59 (21.7%) had sicca syndrome and in all of them anti-Sjögren syndrome related antigen A (SSA) and antigen B (SSB) were negatives. The production of TNF-α and IFN-γ was higher in the group with sicca syndrome (P < 0.05) than in HTLV-1 infected subjects without sicca syndrome. Our data indicates that patients with sicca syndrome associated with HTLV-1 do not have Sjögren syndrome. However the increased production of TNF-α and IFN-γ in this group of patients may contribute to the pathogenesis of sicca syndrome associated with HTLV-1.The Sjögren syndrome, and systemic lupus erythematosus with HTLV-1 [ Sjögren syndrome was reported between 30 and 60% in patients who had HAM/TSP [ Sjögren syndrome is a chronic autoimmune disease of the exocrine glands that affects the salivary and lacrimal glands through a lymphocytic infiltrate, leading to xerostomia (dry mouth) and xeroftalmia (dry eye). However, more recently the association between autoimmune diseases and HTLV-1 has been contested [ Sjögren syndrome was not observed in patients with the sicca syndrome associated with HTLV-1 infection [The human T lymphotropic virus type 1 (HTLV-1) infection is distributed worldwide with high prevalence in Central Africa, Central and South America, and South west of Japan . The HTLh HTLV-1 –6. HTLV- HAM/TSP –9. Sjögrontested , 11. Theontested , 13. Lymontested . But occnfection . Moreovenfection . Therefoβ and IFN-γ and a decrease in the expression of IL-10 and regulatory T cells in this tissue [Sjögren syndrome related antigen A (SSA) and anti-Sjögren syndrome related antigen B (SSB) antibodies with sicca syndrome associated with HTLV-1.The role of the inflammatory response and proviral load in the pathogenesis of clinical manifestations related to HTLV-1 has been well documented. Proinflammatory cytokines and chemokines are higher in supernatants of peripheral blood mononuclear cells (PBMCs) culture and in serum of HAM/TSP than HTLV-1 carriers , 17 and s tissue , 22. Furs tissue , 24. TheThis is a cross-sectional study comparing proviral load and cytokine levels among HTLV-1 infected subjects with or without sicca syndrome. Participants of this study include 272 HTLV-1 infected subjects with age range from 18 to 60 years, of both genders, followed at the HTLV-1 Multidisciplinary Clinic of the Hospital Universitário Professor Edgard Santos in Salvador, Bahia, Brazil. Subjects admitted to the clinic are referred from blood banks or from other clinics due to a positive serology for HTLV-1 and HTLV-2, by enzyme-limited immunosorbent assay . The diagnosis of HTLV-1 is confirmed by Western blot . The inclusion criteria for participation in the study were the presence of a positive serology for HTLV-1 confirmed by Western blot. Exclusion criteria were presence of human immune deficiency virus (HIV) and diagnosis of HAM/TSP based on the Osame motor disability score (OMDS) ≥ 1. Moreover 27 patients were excluded due to coinfection with hepatitis B or hepatitis C virus. All subjects answered a questionnaire regarding dry mouth and dry eyes and had clinical examination. Dry mouth was determined by oral examination and the salivary flux by the Saxon test . Sicca sSerum samples were screened for antinuclear antibodies by immunofluorescence and anti-SSA and anti-SSB by ELISA as previously described , 27.6 cells/mL were resuspended in RPMI 1640  supplemented with 10% of fetal bovine serum and antibiotics. Unstimulated cells were incubated for 72 hours at 37°C 5% CO2 and the supernatants were harvested. Determination of IFN-γ, TNF-α, IL-5, and IL-10 was performed by ELISA using reagents from BD Biosciences Pharmingen, San Jose, CA.Cytokines were determined in supernatants of unstimulated PBMCs cultures as previously described . Briefly6 PBMCs using proteinase K and salting-out method. The HTLV-1 proviral load was quantified using a real-time TaqMan PCR method as previously described using the ABI Prism 7700 Sequence detector system (Applied Biosystems) [6 and expressed as the number of HTLV-1 copies per 106 PBMCs.DNA was extracted from 10systems) . Albumint-test. The comparison between proportions was performed by Fisher exact test. The data on cytokine levels and proviral load were expressed as median and interquartile (IQ) range and were analyzed by the Kruskal-Wallis test. The correlation between proviral load and cytokine levels was performed by the correlation of Spearmen. The GraphPad Prism 5  was used to perform the statistical evaluation and P values < 0.05 were considered statistically significant.The comparison between the ages in the 2 groups was performed by Student's P = 0.847) and the female gender predominates in both groups without statistical significance. There were more blacks in the group with sicca syndrome (P = 0.03).Of the 272 participants of the study, 59 (21.7%) had sicca syndrome. The age, gender, and ethnic group of HTLV-1 infected subjects with sicca syndrome and without sicca syndrome are shown in P > 0.5). There was also no difference regarding polyarthralgia in the 2 groups and synovitis was detected in only 2 patients. One patient had mixed connective tissue disease and sicca syndrome and the other had a seronegative rheumatic arthritis and did not have sicca syndrome.The diagnosis of sicca syndrome was based on oral examination and a reduction in the salivary fluid by Saxon test . Regardiα, IFN-γ, IL-5, and IL-10) levels in supernatants of PBMCs are shown in α in patients with sicca syndrome  were higher  was higher . Cytokine levels were undetectable or were very low in supernatants of PBMCs of patients with sicca syndrome.The spontaneous cytokines (TNF-P = 0.58) in patients with sicca syndrome  and in patients without sicca syndrome . There was a direct correlation between proviral load and IFN-γ and proviral load and TNF-α when values obtained in the whole sample were analyzed (The proviral load in HTLV-1 infected subjects with and without sicca syndrome is shown in analyzed . HoweverAntinuclear antibodies and anti-SSA and anti-SSB antibodies were determined in the two groups. Anti-SSA and anti-SSB antibodies were absent in all subjects. Antinuclear antibodies were detected in 2 subjects, one in the group with and another in the group without sicca syndrome.γ and TNF-α were higher in HTLV-1 infected patients with sicca syndrome than in HTLV-1 infected subjects without sicca syndrome, indicating that the exacerbated proinflammatory response observed in HTLV-1 infection may play a role in the destruction of the salivary and lacrimal glands observed during this viral infection. Moreover our data indicate that autoimmune rheumatic diseases are rarely associated with HTLV-1 and that there is no evidence of Sjögren syndrome in HTLV-1 infected subjects without HAM/TSP.In the present study we show that the proinflammatory cytokines IFN- Sjögren-like syndrome in HTLV-1 infected subjects ranges in accordance with the population studied. Initial studies showed that this association was mainly found in patients with HAM/TSP [The prevalence of HAM/TSP , 8. Howe HAM/TSP . Poetker HAM/TSP . Herein, HAM/TSP . HAM/TSP HAM/TSP , 30, 31. Sjögren syndrome [ Sjögren syndrome have not been documented in such patients, the occurrence of Sjögren syndrome associated with HTLV-1 has been argued [ Sjögren syndrome, HTLV-1 infected subjects have a sicca syndrome due to destruction of the salivary glands.The documentation of a lymphocytic infiltration and the tax gene expression in the salivary gland of patients with dry mouth infected by the virus are the main evidences that salivary gland destruction in HTLV-1 infection is mediated by T cells , 32, 33.syndrome . Howevern argued , 35. Herα, and IFN-γ [The pathogenesis of the clinical manifestations related to HTLV-1 has been mainly studied in patients with HAM/TSP and is likely multifactorial. The neurologic disease has been associated with high proviral load –20 and ind IFN-γ , 37. In nd IFN-γ , 39. Givnd IFN-γ , in patind IFN-γ , and in nd IFN-γ .α and IFN-γ in patients with HTLV-1 associated with sicca syndrome indicate that viral factors and an increased inflammatory response participate in the pathogenesis of sicca syndrome associated with HTLV-1.The previous documentation that salivary glands in HTLV-1 infected subjects are infiltrated by lymphocytes and the present study showing an increased production of TNF-


Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade’s complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance. Signaling cascades, such as the PI3K/Akt/mTOR pathway, are often depicted as a linear cascade, their activation akin to a row of dominoes falling, with individual signaling arms running parallel (at the same speed) with occasional feedback loops. However, the reality is more in line with a Rube Goldberg Machine. These pathways have evolved out of more primitive cascades, often with different functions, have recruited proteins and whole side arms and thus created overlapping or even diametrically opposite functions. A signaling cascade is not maintained in a population – be it mammal, human or tumor – due to its efficacy or elegance, but remains active in a population if it is the best current option that a) does what it needs to do and b) is available to said population. This, in turn, means that there is no simple linear relationship between degree of inhibition and tumor cell death. In other words our data, published and unpublished, as well as others clearly indicate maximal PI3K inhibition does not equal maximal sensitization for cell death , 6.Taking the evolutionary origins of cellular signaling pathways into account, the notion of a survival pathway that can be inhibited by taking out a central component appears greatly simplistic. The notion of distinct signaling cascades that overlap is a human construct, probably not dissimilar to the Linnæan classification system, useful most of the time, but not reflecting the whole biological truth. For example, there is mounting evidence that the PI3K/Akt/mTOR pathway and the Ras/MEK/Erk signaling cascade are – at least in some cellular systems – so entwined that one could really view them as a single, even more complex survival machinery  . TherefoModern cancer therapy aims at eradicating tumors by predominately inducing apoptosis, a form of programmed cell suicide, via DNA damage and is thus limited by emerging resistance of cancerous cells and toxic side effects on healthy tissue. In order to circumvent these limitations, combination therapy (CT) that combines cytotoxic agents, such as chemo- or radiotherapy at metronomic doses with at least one molecular-targeted agent, i.e. a pharmacological inhibitor of signaling cascades, has been proposed to break apoptosis resistance, while concurrently lowering adverse side effects . The PI3Is the PI3K signaling network still a promising target for cancer therapy? is Yes, but it is not the magic bullet hoped for.Taking these two caveats into account our answer to the question Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults  and within vitro data regarding mTOR inhibition in Glioblastoma cells does not translate well into an in vivo setting .de novo within 3–6 months [Activation of PI3K signaling functions as a driver mutation for the cell of origin to re-acquire stem cell characteristics/re-enter the cell cycle. While the cell of origin is still strongly debated in GBM , primary6 months , suggest6 months , but de-6 months , and wou6 months , 29. The6 months .PI3K/Akt facilitate the invasive phenotype which is characteristic for GBM, both in terms of motility and survival under stress. An association with FAK and Src has long been established for PI3K  and proliferation (point 1). This would suggest that PI3K signaling has several contradictory functions in GBM. For example, high proliferation is usually associated with therapy sensitivity , yet inhOur own initial data analyzing a panel of Glioblastoma cell lines responding to CT combining inhibition of PI3K signaling and various chemotherapeutic agents, as well as death receptor ligands also yielded several interesting points , 24: PI3Interestingly, the importance of the last point is emphasized by our work mainly conducted on a different tumor system, Neuroblastoma (NB).NB is a common childhood neoplasia of the sympathetic nervous system that is generally characterized as a highly heterogeneous disease and categorized into four stages, of which stage 1 and 2 have a good prognosis. However, prolonged survival for patients with stage 3 and 4 is only 18-30% , 39. UnfHowever, more recently following some previous hints concerning the underlying molecular mechanisms of how PI3K signaling affects chemosensitivity in NB , we wereImportantly, as we found a similar temporal effect in GBM cells, this led us to propose a model which de-emphasizes the maximal inhibition of a target signaling cascade  and concentrates on the temporal relationship of the two treatment components, i.e. sequential dosing .Next, one needs to consider at which point in the signaling cascade to intervene. While in the past a preferred target seems to have been the dual inhibition of PI3K and mTOR . HoweverTo consider the optimal target of PI3K signaling inhibition one has first to understand its role. Our data  providesThe approach we – and also, apparently, the Djuzenova group – favor is the use of existing, clinically evaluated pharmacological inhibitors of the PI3K signaling, while optimizing the treatment schedule so as concurrently to maximize the effect on survival and minimize the effect on proliferation/metabolism , 6. Altein vitro and in vivo models in the setting of GBM [The epidermal growth factor receptor HER1/EGFR) is one of the most frequently dysregulated oncogenes in glioblastoma . About hg of GBM , 54, 55.g of GBM –58. Treag of GBM . Thus, a/EGFR is In vitro, Fan and coworkers showed that PTEN mutant U87 cells were much less responsive to a treatment with erlotinib alone when compared to PTEN wild type LN229 cells [29 cells . Others 29 cells . In both29 cells .While identification of potential upstream targets seems less advanced in NB than in GBM, ALK presents itself as a promising candidate, but – although pharmacological inhibitors such as crizotinib are available – preclinical and early clinical trials do not appear promising. It seems that an almost complete inhibition of ALK is needed for a clinical response, while resistance to the inhibitor can develop relative rapidly, as is also the case with HER1/EGFR . SimilarThese findings in GBM and NB clearly indicate that CT with several inhibitors  of which some are upstream of PI3K can lead to enhanced therapeutic responses.To avoid the inhibition of additional side arms of the signaling cascades or activation of compensatory mechanisms rather specific individual targets should be considered, but therefore the precise executor molecule for survival needs to be identified. We have identified DNA-PK, i.e. the DNA repair axis of PI3K signaling, as the crucial inhibitor of survival when GBM cells are challenged with Doxorubicin . HoweverImportantly, our data suggest that one does not have to pick a single or – in case of the dual PI3K/mTOR inhibitors - a double target, but that multiple, carefully timed inhibitions of what is generally considered a single signaling cascade can cooperate and thus produce a greater sensitizing effect . TherefoCrosstalk between proneoplastic signaling pathways  is abundant in both GBM  and NB , 67 and As a consequence, multi-targeting has been developed as a therapeutic strategy to overcome this potential mechanism of resistance by combining two or more agents targeting different oncogenic signaling pathways, or targeting a single oncogenic signaling pathway differently in the sense of a combined forces alliance driving the cancer cells to undergo cell death , 69–72. In single therapy inhibition of PI3K signaling often leads to a cytostatic effect, not only in the aforementioned Hodgkin lymphoma , but alsa priori reason to assume that other tumors will not be subject to the principles discussed here. For example, sequential dosing, has already been demonstrated to also be important in other malignancies, such as breast cancer [While this review focuses on glioblastoma and neuroblastoma, the inhibition of PI3K-mediated signaling is currently also being clinically evaluated in several additional tumor entities, such as lymphocytic leukemias, colorectal cancer, head and neck cancer, several forms of lymphoma, non-small cell lung cancer and renal cancer . Indeed,t cancer . HoweverWith the current rapid advancement of sequencing techniques , 83, pro


Background. The aim of this study is to investigate whether (-)-epigallocatechin-3-gallate (EGCG) can prevent the UA-induced inflammatory effect of human umbilical vein endothelial cells (HUVEC) and the involved mechanisms in vitro. Methods. HUVEC were subjected to uric acid (UA) with or without EGCG treatment. RT-PCR and western blots were performed to determine the level of inflammation marker. The antioxidant activity was evaluated by measuring scavenged reactive oxygen species (ROS). Functional studies of the role of Notch-1 in HUVEC lines were performed using RNA interference analyses. Results. UA significantly increased the expressions of IL-6, ICAM-1, TNF-α, and MCP-1 and the production of ROS in HUVEC. Meanwhile, the expression of Notch-1 and its downstream effects significantly increased. Using siRNA, inhibition of Notch-1 signaling significantly impeded the expressions of inflammatory cytokines under UA treatment. Interestingly, EGCG suppressed the expressions of inflammatory cytokines and the generation of ROS. Western blot analysis of Notch-1 showed that EGCG significantly decreased the expressions of inflammatory cytokines through Notch-1 signaling pathways. Conclusions. In summary, our findings indicated that Notch-1 plays an important role in the UA-induced inflammatory response, and the downregulation of Notch-1 by EGCG could be an effective approach to decrease inflammation and oxidative stress induced by UA. Hyperuricemia has been reported to increase the risk of gout, renal diseases, and cardiovascular diseases, such as hypertension and atherosclerosis . Though Emerging evidence confirms that Notch signaling play a key role in inflammatory response involved in the pathogenesis of cardiovascular diseases –14. Notc2O2-induced oxidative stress by Akt/GSK-3β/caveolin signaling in vitro and in vivo [EGCG is a flavanol derived from green tea extracts (GTE) and recently has been explored in disease therapy because of its antioxidant, anti-inflammatory, and anticancer effects –21. Prev in vivo . In addi in vivo . EGCG in in vivo , 25. Rec in vivo . HoweverIn this study, we evaluated that treatment of HUVEC with UA activated inflammatory response and oxidative stress. Next, we examined the potential mechanism which revealed that Notch-1 was essential for UA-induced inflammatory response and oxidative stress. Further experiments indicated that EGCG mediated vascular endothelial cells protection in an UA-induced inflammatory response and oxidative stress through Notch pathway, at least partly.UA and EGCG were purchased from Sigma-Aldrich . EGCG stock solution was prepared in sterile double distilled water at 20 mM. UA was dissolved in deionized water and filtered and was free of crystals (by polarizing microscopy).μg/mL; Sigma-Aldrich) at 37°C in a humidified atmosphere of 5% CO2. HUVEC were cultured with UA (8 mg/dL) for another 24 hours after pretreating with or without EGCG (20μM).The human umbilical vein endothelial cells (HUVEC) were purchased from ATCC . HUVEC were grown in EGM-2 Bullet kit  containing penicillin G  and streptomycin sulfate (100 5/mL cells were seeded onto 60 mm dish and transfected with Notch-1 siRNA (50 nmol/L) using Lipofectamine 2000  according to manufacturer's protocol. The medium was replaced with complete medium and incubated at 37°C for 48 hours before further analysis. The transfection efficacy was evaluated by western blot.Small interference RNA (siRNA) targeting Notch-1 (numbered 1–3) and a scrambled siRNA were designed and purchased from GenePharma Co., Ltd. . The effective complementary (upper) sequences in the two RNA duplexes were 5′-GCACGCGGAUUAAUUUGCAdTdT-3′ and 5′-UGCAAAUUAAUCCGCGUGCdTdT-3′. The full cDNA of Notch-1 was cloned in the pcDNA3.1 vector (Invitrogen) and was confirmed by DNA sequencing. For transient silencing, 5 × 10μmol/L and mixed vigorously for 1 hour at 37°C. Fluorescence of CellROX was measured with a laser scanning confocal microscope  at 488 nm of excitation wavelength and 510 nm of emission filter. The semiquantified ROS was expressed as relative fluorescent units (RFU) and all experiments were performed in duplicate and repeated three times.To determine whether the ROS levels of HUVEC are affected by the presence of UA or EGCG, a chemiluminescence assay was assessed using CellROX Green Reagent (Life technologies). The examined HUVEC were seeded onto 24-well plates and treated with various processing. CellROX Green Reagent was incubated to each well at a concentration of 10 μL containing 10 pmol of each primer by One Step SYBR PrimeScript RT-PCR Kit II . The oligonucleotide primers that were used for the PCR amplifications were synthesized by Shanghai Sangon Technologies, Inc.  and are listed as follows: forward primer: Hes1 forward primer: 5′-CCTGTCATCCCCGTCTACAC-3′, reverse primer: 5′-CACATGGAGTCCGCCGTAA-3′; MCP-1, forward primer: 5′-CAGCCAGATGCAATCAATGCC-3′, reverse primer: 5′-TGGAATCCTGAACCCACTTCT-3′; NF-κB, forward primer: 5′-GAAGCACGAATGACAGAGGC-3′, reverse primer: 5′-GCTTGGCGGATTAGCTCTTTT-3′; ICAM-1, forward primer: 5′-TTGGGCATAGAGACCCCGTT-3′, reverse primer: 5′-TGGAATCCTGAACCCACTTCT-3′; TNF-α, forward primer: 5′-CCTCTCTCTAATCAGCCCTCTG-3′, reverse primer: 5′-GAGGACCTGGGAGTAGATGAG-3′; GAPDH, forward primer: 5′-ACAACTTTGGTATCGTGGAAGG-3′, reverse primer: 5′-GCCATCACGCCACAGTTTC-3′. A melting curve analysis was performed for each of the primers used, and each showed a single peak indicating the specificity of each of the primers tested. All values were calculated using the delta Ct method and expressed as the change relative to the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The amplification conditions were 40 cycles of denaturation at 94°C for 1 min, annealing at 60°C for 30 s.Total RNA from cells was extracted using Trizol (Invitrogen Corp) following the manufacturer's protocol. cDNA was synthesized using 500 ng of total RNA by Transcriptor First Strand cDNA Synthesis Kit . The resulting first-strand cDNA was amplified in a final volume of 20 α , ICAM-1, Hes5 and MCP-1 , Hes1 , Hey1 and Hey2 , and phospho-p65 . Anti-GAPDH antibody  was used as the loading control in all western blots. The secondary antibodies, anti-mouse and anti-rabbit IgGs conjugated to horseradish peroxidase, were obtained from Kangchen . Finally, protein bands were visualized using Supersignal West Femto Substrate .Cell lysates were rinsed with ice-cold PBS and prepared using lysis buffer with 1% Triton, 1% Nonidet P-40, 0.1% sodium dodecyl sulfate (SDS), and 1% deoxycholate and protease inhibitors cocktail (Roche). Protein concentration was determined by Bradford protein assay kit (Bio-Rad) and equal amount of protein was separated by 12% SDS-PAGE using Bio-Rad apparatus. The membranes were blocked for 2 hours in 5% skim milk at room temperate after protein was transferred to PVDF membrane . The proteins were incubated with the following primary antibodies: IL-6 and TNF- t-test or analysis of variance (ANOVA). A P value of <0.05 was considered statistically significant.The results were presented as means ± SD. The statistical significance of differential findings was statistically evaluated using GraphPad StatMate software . Statistical significance for comparisons between groups was determined using Student's paired two-tailedα at a concentration of 8 mg/dL (P = 0.010).Previous studies indicated that hyperuricemia was associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling . To inve 8 mg/dL  in HUVECP < 0.05). The expression of Notch-1 induced by UA was also time-dependent, being significantly higher than that of control by 8 hours, peaking after 24 hours of stimulation  level and significantly elevated serum antioxidant capacity in healthy individuals [Previously, we have shown the cardioprotection of EGCG against inflammatory lesions induced by UA via the NF-ividuals . These rRecent studies have shown that hyperuricemia characterized by high serum uric acid level was associated with hypertension, gout, systemic inflammation, and cardiovascular disease mediated because of endothelial dysfunction and pathologic vascular remodeling , 13, 27.2O2-induced oxidative stress via the Akt/GSK-3β/β-catenin and caveolae signaling [Previous study showed that EGCG has potent properties of antioxidant and radical-scavenger , 24, 25.ignaling . It remiignaling , in ordeIn summary, our current findings suggested that EGCG inhibited the UA-induced inflammatory responses and oxidative stress through Notch-1 medicating inflammatory chemokines and ROS production. However, further investigations are required to determine the real effect in vivo.


Gessain and Cassar, Front Microbiol, 2012). Our estimation was based (i) on most reliable available publications regarding the HTLV-1 prevalence and (ii) the global repartition of individuals by age and sex in each studied country. Our best estimates range from 5-10 million HTLV-1 infected individuals. However, these results were based solely on the 1.5 billion individuals living in the known endemic areas or regions with reliable epidemiological data. Correct estimates in other highly populated regions  is currently not possible, thus, the current number of HTLV-1 carriers is very probably much higher.HTLV-1, identified 32-years-ago, is present throughout the world with clusters of high endemicity such as Southwestern Japan, sub-Saharan Africa, South America, the Caribbean area and foci in Middle-East and Australo-Melanesia. The origin of this puzzling geographic/ethnic distribution is probably linked to founder effects in some groups with the persistence of a high viral transmission rate. Twenty-years-ago, de-Thé and Bomford estimated the number of HTLV-1 carriers to be 10-20 millions. At that time, large regions had not been investigated, few population-based studies were available and the assays used for HTLV-1 serology were not specific enough. Despite the lack of data for some large areas of the world, and the fact that most of the HTLV-1 studies concern blood donors, pregnant women or high-risk groups, we tried to revisit HTLV-1 world distribution and estimate, for the first time, the number of HTLV-1 infected persons by continent, regions and countries when possible (


Leucine-rich repeat-containing G protein-coupled receptors were identified by the unique nature of their long leucine-rich repeat extracellular domains. Distinct from classical G protein-coupled receptors which act via G proteins, LGR4 functions mainly through Wnt/β-catenin signaling to regulate cell proliferation, differentiation, and adult stem cell homeostasis. LGR4 is widely expressed in tissues ranging from the reproductive system, urinary system, sensory organs, digestive system, and the central nervous system, indicating LGR4 may have multiple functions in development. Here, we focus on the digestive system by reviewing its effects on crypt cells differentiation and stem cells maintenance, which are important for cell regeneration after injury. Through effects on Wnt/β-catenin signaling and cell proliferation, LGR4 and its endogenous ligands, R-spondins, are involved in colon tumorigenesis. LGR4 also contributes to regulation of energy metabolism, including food intake, energy expenditure, and lipid metabolism, as well as pancreatic β-cell proliferation and insulin secretion. This review summarizes the identification of LGR4, its endogenous ligand, ligand–receptor binding and intracellular signaling. Physiological functions include intestinal development and energy metabolism. The potential effects of LGR4 and its ligand in the treatment of inflammatory bowel disease, chemoradiotherapy-induced gut damage, colorectal cancer, and diabetes are also discussed. Leucine-rich repeat-containing G protein-coupled receptors (LGRs) are a distinct group of highly conserved proteins of the GPCRs family, characterized by a large extracellular domain (ectodomain) that harbors multiple copies of leucine-rich repeats (LRRs) . LRRs reLGRs are divided into three subgroups (groups A–C) , 6. GrouThe ligands of LGR4-6 remained unidentified for a prolonged time. In 2011, the secreted R-spondin proteins (Rspo1-4) were identified as the endogenous ligands for these receptors to regulate cell proliferation, differentiation, and adult stem cell maintenance through the activation of Wnt signaling pathways , 14. DetDrosophila and sea anemone  of 951 amino acids, whereas LGR5 from human placenta has 4,208 base pairs with a 907 amino acids ORF . SimilarIdentification of this expanding family of LGRs promoted studies to identify putative ligands and to unravel the evolutionary origin of proteins in this subfamily of receptors.The R-spondin (Rspo) protein family is a group of four secreted proteins (Rspo1-4) that were isolated as strong potentiators of Wnt/β-catenin signaling –20. ThesBeginning in 2011, several groups have demonstrated that R-spondins (Rspo 1-4) are endogenous ligands for LGR4 and LGR5. A fusion gene construct (mRspo1-Fc), encoding the mature form of mouse Rspo1 and the Fc fragment of mouse IgG2a, is biologically active . When inExperiments using an unbiased screening strategy have also identified LGR4 and LGR5 as receptors of Rspo proteins . DepletiThe extracelluar domain (ECD) of LGR4 exhibits a twisted horseshoe-like structure. Rspo1 adopts a flat and fold architecture and is bound in the concave surface of LGR4 through electrostatic and hydrophobic interactions . All theStudies have suggested that interaction between Rspo proteins and LGR4 potentiates canonical Wnt/β-catenin signaling, but does not activate Gi, Gs, or Gq pathways. Structurally, LGR4 and LGR5 are quite similar to other LRR-containing GPCRs which are coupled to heterotrimeric G protein signaling by ligand binding. The intracellular signaling pathway by which Rspo and LGR4 potentiate Wnt/β-catenin signaling remains largely unknown.By examining proteins co-immunoprecipitated with LGR4, Kendra et al. identified IQGAP1 and IQGAP3 as potential candidates that could mediate the intracellular signaling of Rspo–LGR4 to the Wnt signalosome . InteracOther signaling pathways have also been reported for LGR4. LGR4 (GPR48) participates in the development of the male epididymis and efferent ducts through regulation of ERalpha expression via the cAMP/PKA signaling pathway . LGR4 G.A common feature of the LGR4/5/6 receptors is their expression in distinct types of adult stem cells. LGR5 is a marker for resident stem cells in Wnt-dependent compartments, including the small intestine, colon, stomach, and hair follicles . LGR6 seThe expression of LGR4 was investigated using an animal model with disrupted LGR4 gene by a trap vector carrying two biological markers, β-geo  and a placental alkaline phosphatase (PLAP) . Due to in situ hybridization  15  15 . Differey (P) 15 , suggestEx vivo experiments have demonstrated that LGR4 is required for the maintenance of crypt stem cells. Crypts cultured from P15 wild-type or heterozygous mice differentiated into multi-fingered organoids after 3 days in culture. After generation of hollow spheres containing mainly stem and TA cells (day 0.5–1), structures grown from P15 Lgr4-knockout intestine did not increase further in size and became filled with cellular material (days 1.5–2)  . Lgr4-kn present .In situ hybridization revealed that LGR4 mRNA is highly expressed in the cortex, hippocampus, amygdala, and the hypothalamus  neurons and proopiomelanocortin (POMC) neurons. NPY neurons express higher levels of LGR4 compared with POMC neurons in the ARC. All POMC neurons in the ME express LGR4 at the highest levels. In the VMH, LGR4 is expressed by the majority of BDNF neurons  and inguinal WAT (iWAT), whereas brown adipose tissue (BAT) content remained unaltered , both male and female Lgr4 mutant mice showed a resistance to HFD-induced body weight gain, with improved glucose tolerance and insulin sensitivity  is critical in development, and Gpr48 mutant mice display early neonatal lethality. Wang et al. have established the Gpr48 (LGR4) hypomorphic mutant mice by microinjecting gene trap-mutated Gpr48 ES cells into C57BL/6 blastocysts. The insertion of the trap vector into intron 1 of the Gpr48 gene resulted in approximately 90% knockdown efficiency in the kidney and adrenal gland of adult LGR4 mutant mice. Approximate half of LGR4 mutant newborns died within 28 h after birth, but no further deaths occurred in the following 20 h . Studiesnaltered . Consistsitivity . Higher ant mice . Consistd TMEM26  were alsenditure .LGR4 locus, were found to be significantly correlated with body mass index. A low-frequency non-synonymous LGR4 variant (A750T) was identified more than twice as commonly in obese patients when compared with controls , it is not surprising that dysfunction of genes involved in intestinal development, proliferation, and differentiation will increase susceptibility to IBD. When Lgr4 hypomorphic mice are subjected to the dextran sulfate sodium (DSS)-induced IBD, a more severe colitis developed in e anemia . Althouge anemia , the relant mice . Infiltrresponse . Signifineration .+ intestinal stem cells in vitro through activation of Wnt/β-catenin signaling –internal ribosome entry site (IRES)–CreERT2 (Lgr5–GFP) mice to detect the intestine stem cells  and radiation-induced gut damage, including radiation-induced gastrointestinal syndrome (RIGS) –66. Receem cells , the letMin/+ mice with spontaneous intestinal adenomas were treated with DSS to induce inflammation-related intestinal carcinogenesis, a murine model of multifactorial human colorectal cancer (CRC)  . Adminisval rate , demonstColorectal cancer is the fourth most prevalent cancer, accounting for over 50,000 deaths per year in the United States. Approximately 15% of CRCs have microsatellite instability arising from defects in the DNA mismatch-repair system, whereas the other 85% of microsatellite-stable CRCs are the result of chromosomal instability .Using RNA-seq data, Seshagiri et al. have identified 36 rearrangements that result in gene fusions , includiThe development of type 2 diabetes mellitus (T2DM) usually requires the presence of insulin resistance, impaired β-cell function, and the loss of β-cells . Type 1 in vitro and in vivo studies using animal models and human genetic analysis. Although significant progress has been made in our understanding of how Rspo binds with LGR4 and regulates the Wnt signaling pathway at the molecular level, the following fundamental questions remain unanswered. How does LGR4 interact with FZD (Wnt receptor) after binding with Rspo proteins? Does LGR4 have a specific intracellular signaling pathway or simply function as a potentiator of Wnt signaling? Additionally, discrepancy between gain and loss of LGR4 function exists. While LGR4-knockout mice showed an improvement in glucose metabolism, Rspo1 has been reported to significantly induce β-cell proliferation and insulin secretion. Further studies on the functions and signaling mechanisms of the LGR4 and Rspo proteins will facilitate the development of therapeutic strategy for human diseases, such as IBD, CRC, and diabetes, by targeting Rspo-LGR4 (Table The importance of LGR4 and its ligands-Rspos in the regulation of canonical and non-canonical Wnt signaling pathways has been established in a variety of ZL, WZ, and MM wrote, discussed, and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The HTLV-DNA burden in PBMCs is a risk factor for HAM/TSP and ATL development. We investigated the contribution of monocyte subsets  to the total viral burden in 23 HTLV-1 infected individuals by assessing their frequency, their chemotactic and phagocytic functions, as well as their infectivity status. Classical monocytes differed between infected and uninfected individuals, their frequency was lower and their expression level of the chemokine receptors CCR5, CXCR3 and CX3CR1 was higher. While the percentage and surface chemokine receptor expression did not differ between HTLV-1 infected and uninfected individuals, intermediate monocytes from HTLV-1 infected individuals had increased migratory capacity to CCL5, the ligand for CCR5. Non-classical monocytes from HTLV-1 infected individuals increased in frequency and expressed high levels of CCR1, CXCR3 and CX3CR1. All three purified monocyte subsets were infected by HTLV-1. The level of viral DNA in monocyte subsets correlated directly with their migration capacity to CCL2, CCL5 and CX3CL1 for the classical subset, with lesser phagocytosis for the intermediate monocytes, and with the level of viral DNA in CD8+ and CD4+T-cells for the non-classical subset. These data suggest a model whereby HTLV-1 infection augments classical monocytes migration to tissues resulting in their infection, and non-classical monocytes frequency, resulting in increased transmission of virus to CD4+ and CD8+T-cells. Our data in humans together with prior animal experiments supports the notion that infection of monocytes in vitro is crucial for viral infectivity and persistence in humans, rendering infected monocytes desirable therapeutic targets.


It is estimated that currently 5 to 10 million people are infected with HTLV-1 worldwide. In Brazil, Salvador is the city with the highest prevalence of HTLV-1 (2% in women and 1.2% in men). Tropical spastic paraparesis/ HTLV associated myelopathy (TSP/HAM) is an insidious and disabling chronic neurological disease. The incidence of TSP/HAM varies in different geographical regions with low rate in Japan and Caribbean islands and higher in Minas Gerais, Brazil. The incidence of TSP/HAM among patients attending the CHTLV in Salvador/BA, from 22 to 2013 was estimated. The outcome of interest was the evolution from asymptomatic status for TSP/HAM diagnosis, which was based on the Belem criteria. The follow-up for individuals that remained asymptomatic was the time between the year of the last medical consultation and the year of the HTLV-1 serological diagnosis and for those that developed TSP/HAM the time between the year of diagnosis of TSP/HAM and the year of HTLV-1 serological diagnosis. The exclusion criteria were a diagnosis of TSP/HAM at the first medical consultation, records with incomplete data and TSP/HAM possible diagnosis. From a sample of 243 patients, 91 were included. Two patients developed TSP/HAM definite and four had TSP/HAM probable diagnosis. The incidence density of TSP/HAM definite was 6.9 and 13 per 1,0 HTLV-1 infected individuals per year, respectively. The cumulative incidence to TSP/HAM definite was 2.29% while to TSP/HAM probable was 4.39%. The incidence rate found herein was higher than that observed in previous studies in Japan and Caribbean, however, similar to that reported in Brazil. More accurate cohort studies should be conducted to measure the actual risk of developing this disease.


Rhus verniciflua Stokes, to modern medicine against diverse inflammation mediated diseases. Traditionally, this remedy has been used in Eastern Asia for the treatment of gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of Rhus verniciflua Stokes against such disorders and diseases. Various chemical constituents have been identified from this plant, including phenolic acid, and flavonoids. Cell-based studies have exhibited the potential of this as antibacterial, antioxidant, neuroprotective, anti-inflammatory, growth inhibitory, and anticancer activities. Enormous animal studies have shown the potential of this against proinflammatory diseases, neurodegenerative diseases, diabetes, liver diseases, and chemical insults. At the molecular level, this medicinal plant has been shown to modulate diverse cell-signaling pathways. In clinical studies, Rhus verniciflua Stokes has shown efficacy against various cancer patients such as colorectal, gastric, hepatic, renal, pancreatic, and pulmonary cancers. Thus, this remedy is now exhibiting activities in the clinic.Despite the fact that numerous researches were performed on prevention and treatment of inflammation related diseases, the overall incidence has not changed remarkably. This requires new approaches to overcome inflammation mediated diseases, and thus traditional medicine could be an efficacious source for prevention and treatment of these diseases. In this review, we discuss the contribution of traditional medicine, especially  Inflammation is an essential part of the body's natural responses against harmful stimuli, such as pathogens, toxin, damaged cells, irritants, stress, or injury. Initially, although the symptoms of acute inflammation are unpleasant, they are absolutely necessary for the healing processes. However, sometimes inflammation can cause further inflammation (chronic inflammation), which can last for several months and even years. It can result from failure to eliminate an acute inflammation, an autoimmune response to a self-antigen. Chronic inflammation can eventually cause several diseases and conditions, including some cancers, asthma, rheumatoid arthritis, atherosclerosis, periodontitis, ischemic heart disease, and ulcerative colitis. Therefore, inflammation needs to be well regulated . Toxicodendron vernicifluum, formerly Rhus verniciflua Stokes, which has been used for thousands of years, mostly in Asian countries. Rhus verniciflua Stokes is an Asian tree species of genus Toxicodendron, which belongs to Anacardiaceae family, and is cultivated in regions of China, Korea, and Japan  that were stimulated by the treatment with both PMA and A23187. Rhus verniciflua Stokes inhibited the nuclear translocation of nuclear factor- (NF-) κB via inhibition of the phosphorylation of IkB-α, which are important processes in controlling inflammatory responses as well. Some of the other cancer types in which Rhus verniciflua Stokes has shown anti-inflammatory activities are listed in  Rhus verniciflua Stokes on inflammation are listed in Chronic inflammation has been associated with numerous human chronic diseases, including cardiovascular, pulmonary, autoimmune, and degenerative diseases, cancer, and diabetes . Many recrophage –19, 22. ytokines . One stutivation . The tre Rhus verniciflua Stokes against numerous cancer cells. For instance, Rhus verniciflua Stokes inhibited the growth of cell proliferation in HeLa  and CT-26  tumor cells [ Rhus verniciflua Stokes in human B, BJAB, and T lymphoma cell lines, Jurkat [ Rhus verniciflua Stokes was highly cytotoxic to exhibit sensitive growth inhibition in human osteosarcoma cells as well [ Rhus verniciflua Stokes exhibited a selective growth inhibition on SV40-mediated transformed embryonic hepatic cells [ Rhus verniciflua Stokes showed a synergistic inhibitory effect on cell growth in gastric cancer cells at 50 μg/mL [ Rhus verniciflua Stokes inhibition of the clonogenic growth of small numbers of UACC-812 breast cancer cells cocultured with fibroblasts in vitro [Many studies have indicated the growth inhibitory effects ofor cells . One stu, Jurkat , 15. Rhu as well . In anotic cells . Rhus ve50 μg/mL . Anotherin vitro . The extin vitro .Rhus verniciflua Stokes acts as a free radical scavenger in a number of in vitro studies  radical, site-specific Fenton-reaction deoxyribose, and a model lipid emulsion test system against hydroxyl and peroxyl radicals. In the cultured mouse brain, neurons were protected against glucose oxidase-induced hydroxyl radical in the presence of the fractionated Rhus verniciflua Stokes extract  [ Rhus verniciflua Stokes is supported by results from other in vitro assays as well [ Rhus verniciflua Stokes prevented the cell cytotoxicity of cells induced by H2O2, respectively, and exhibited antioxidant activities, such as DPPH, superoxide anion, and hydroxyl radical scavenging activities [ studies . In one  4.9 uM) . The ant as well , 26. In tivities , 30.Rhus verniciflua Stokes has been shown to inhibit the growth of viruses. In one study, the remedy inhibited the growth of fish pathogenic infectious hematopoietic necrosis virus (IHNV) and viral hemorrhagic septicemia virus (VHSV) in flounder spleen (FSP) or chinook salmon embryo- (CHSE-) 214 cells system [s system . Rhus verniciflua Stokes exhibited numerous other neuroprotection activities by in vitro studies. For example, in one study, Rhus verniciflua Stokes protected the murine hippocampal HT22 cells against glutamate-induced neurotoxicity [ Rhus verniciflua Stokes protected dopaminergic neuronal cells in a rotenone model of Parkinson's disease (PD) [ Rhus verniciflua Stokes protected against rotenone-induced toxicity by preventing the downregulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in human dopaminergic cells, SH-SY5Y [Additionally, except for the activities discussed above,toxicity . In anotase (PD)  and agai SH-SY5Y , 36. Rhus verniciflua Stokes exhibited numerous other activities by in vitro studies. For example, in one study, Rhus verniciflua Stokes showed dose-dependent inhibitory activity towards adenosine diphosphate- (ADP-), collagen-, and arachidonic acid- (AA-) induced aggregation of human platelets [ Rhus verniciflua Stokes showed Aldo-keto reductase family 1 B10 (AKR1B10), which may be responsible for detoxification of reactive aldehydes, inhibitory activity [ Rhus verniciflua Stokes (RVS glycoprotein) has an inhibitory activity of T-helper type 2 (Th2) cytokines (IL-4 and -10) in bisphenol A (BPA), one of the estrogen mimic environmental hormones-stimulated primary cultured mouse lymphocytes [In addition to the activities discussed above,latelets . In anotactivity . Glycoprphocytes . Rhus verniciflua Stokes has shown the potential against diabetes in many animal models. For instance, in streptozotocin- (STZ-) induced rat model, Rhus verniciflua Stokes exhibited a decrease in blood glucose levels and blood thiobarbituric acid reactive substance (TBARS) concentrations [ Rhus verniciflua Stokes against hyperlipidemia in WR-1339-induced hyperlipidemic mice model [Diabetes is a group of metabolic diseases in which a person has high blood sugar, and this disease increases the risk of long-term complications, and, therefore, it should be well regulated like inflammation.trations . Anotherce model . This reRhus verniciflua Stokes has exhibited the potential against proinflammation in animal models as well. For instance, this remedy reduced carrageenan-induced mouse paw edema [aw edema . In anotaw edema . Rhus verniciflua Stokes exhibited antioxidative activities by in vivo studies. For example, Rhus verniciflua Stokes increased the activities of detoxicant enzymes , superoxide dismutase (SOD), and glutathione peroxidase (GPx)) in Triton WR-1339-induced hyperlipidemic mice [In addition to the activities discussed above,mic mice .Rhus verniciflua Stokes has been shown to suppress an aflatoxin B1- (AFB1-) induced increase in serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), prevent malondialdehyde (MDA) formation, and block decreases in glutathione levels and SOD in mouse model [ Rhus verniciflua Stokes protected from liver damage through inhibition of radical scavenging ability [se model . In anot ability .Rhus verniciflua Stokes has been shown to protect the normal cells, tissues, and organs against the damage caused by external insults. For instance, this remedy exhibited potential against cisplatin-induced cytotoxicity and reactive oxygen species (ROS) production in animal model [al model . Rhus verniciflua Stokes has shown potential is Parkinson's disease (PD). Multiple pathways including oxidative stress and mitochondrial damage have been implicated in neurodegeneration during PD. One study evaluated the neuroprotective property of Rhus verniciflua Stokes increased in BDNF and GDNF protein levels, which are critical for the survival and function of developing and adult neurons, learning and memory, and synaptic plasticity, in the rat brain of PD model [The most common neurodegenerative disease in whichPD model . Rhus verniciflua Stokes modulated 12-O-tetradecanoylphorbol 13-acetate- (TPA-) induced apoptosis, cytokine production, and T/B cell proliferation in mouse splenocytes [α1(I) collagen and tissue inhibitor of metalloproteinase- (TIMP-) 1 mRNA on liver fibrosis induced by carbon tetrachloride (CCl4) in rat model [In addition to the activities indicated above,enocytes . This reat model . Rhus verniciflua Stokes has been tested for its potential in human subjects, with about a dozen studies completed to date. Most of these studies have indicated the safety and efficacy of Rhus verniciflua Stokes. The most promising effect of Rhus verniciflua Stokes has been reported against cancer  at doses of 450 mg of Rhus verniciflua Stokes that was prescribed [ Rhus verniciflua Stokes continued for several months, hematologic toxicity was not observed and minor adverse effects-mild pruritus and dyspepsia was reported in only 2 of the 36 patients. However, a large scale study is required to further confirm the efficacy and safety of Rhus verniciflua Stokes in mCRC patients and this study has the limitation that 44.4% of patients have chosen Rhus verniciflua Stokes as the complementary therapy with conventional treatment including chemotherapy or radiotherapy. In another study, Rhus verniciflua Stokes treatment was well tolerated in advanced pancreatic cancer patients for whom orthodox therapy is unavailable and might prolong overall survival either alone or in combination with chemotherapy [ Rhus verniciflua Stokes oral administration was not observed; minor nonhematologic adverse reactions were reported such as mild dyspepsia and pruritus in each patient with toxicity grade 1 pruritus and grade 2 pruritus, respectively. Gemcitabine has emerged as the standard chemotherapy for advanced pancreatic cancer [ Rhus verniciflua Stokes and concurrent chemotherapy, 19.0% of patients with grade 3 or 4 toxicity were required to discontinue gemcitabine treatment, all patients were not observed a synergistic effect of gemcitabine and Rhus verniciflua Stokes compared to alone. Although Rhus verniciflua Stokes oral administration was very tolerable, no specific drug interactions between Rhus verniciflua Stokes and chemotherapy agents were noted, but additional randomized and well-controlled clinical trials with larger number of patients are necessary to confirm its efficacy and safety in the treatment of pancreatic cancer.Standard modern therapies for cancer treatment include surgery, radiation, chemotherapy, hormone therapy, and palliative care. Cancer surgery still remains the foundation of treatment for cancer patients. However, patients with locally advanced disease such as gastric cancer showed high rates of locoregional or distant recurrence even after potentially curative surgery . Standart cancer . One stuotherapy . Three oc cancer . Many clc cancer , 109. In Rhus verniciflua Stokes has also been reported to have anticancer activity in various kinds of cancers including gastric, liver, lung, renal, and pulmonary. In the 82-year-old female gastric cancer patient case, orally administered Rhus verniciflua Stokes decreased the polypoid mass at the mid body and a slight decrease in the flat elevated lesion at the prepyloric antrum at 5 months after starting daily therapy with 900 mg [ Rhus verniciflua Stokes 3 times a day with 450 mg being orally administered [ Rhus verniciflua Stokes three times in a day with 450 mg capsules for 4 months exhibited a complete response in all pulmonary metastases including resolution of right pulmonary artery thrombosis, and the other case showed reduction in the size of the metastatic masses in both adrenal glands at 9 months after receiving Rhus verniciflua Stokes 3 times a day with 450 mg capsules being orally administrated. Another study reported the case of a 52-year-old female who had been diagnosed with pulmonary adenocarcinoma with malignant pleural nodules [ Rhus verniciflua Stokes remedy without orthodox therapies) and no significant adverse effects. Orally administered Rhus verniciflua Stokes showed an obvious cytostatic effect and could increase the quantity of survival in pulmonary adenocarcinoma; however, further studies with larger populations are required to confirm the claims of the study.In addition to the clinical research indicated above,h 900 mg . Anothernistered . Moreovenistered . Of thes nodules . The patRhus verniciflua Stokes is chemically diverse in composition. To date, around 40 compounds, primarily phenolic acids and flavonoids, have been identified from this remedy  and liquid chromatography-mass spectrometry (LC-MS) analysis of some other compounds identified from Rhus verniciflua Stokes are shown in Figures s remedy  [14, 18, Rhus verniciflua Stokes like aspirin which was first discovered from the bark of the willow tree in 1763 by Edward Stone of Wadham College, Oxford University. Recently flavonoids from Rhus verniciflua Stokes have been found to have various biological activities, including antiproliferative, anti-inflammatory, and apoptotic activities in human cancer cell lines and in vivo model. For example, butein from Rhus verniciflua Stokes inhibited clonogenic growth of human breast cancer cells cocultured with fibroblasts [ in vitro and in vivo [κB activation and infiltration reduction of inflammatory cells and apoptosis after spinal cord injury in animal model [ in vivo model. Their activities could come from a similar structure base. Some of the other constituents in which Rhus verniciflua Stokes has shown biological activities are listed in Many researches have been studied to identify the clinically active ingredient fromroblasts , human croblasts , and pro in vivo . Moreoveal model . In anotal model . Other m Toxicodendron spp. In sensitive individuals, urushiol can cause an allergic response [ Rhus verniciflua Stokes. All clinical studies indicated in  Rhus verniciflua Stokes and the treatment of this remedy has no severe adverse effect. However, this is still controversial because more detailed confirmative works on safety will be also required to use this remedy clinically in the world.Urushiol is an allergen found in Anacardiaceae family, especiallyresponse . Many re Rhus verniciflua Stokes is an Asian tree species of genus Toxicodendron, which belongs to Anacardiaceae family. Traditionally, the remedy has been used for enormous purposes since ancient times. Modern science has provided the molecular basis for the properties of Rhus verniciflua Stokes against human diseases using in vitro and in vivo model, and the existing human studies have provided a logical basis for further investigation of this remedy for the prevention and treatment of human diseases, especially cancer. In addition to this accomplishment, clinical studies have demonstrated the safety and efficacy of Rhus verniciflua Stokes in human subjects. The absence of any significant adverse effect associated with this remedy has made it superior to others. However, future studies should focus on employing larger, high-quality clinical trials, demonstrating its efficacy in terms of cancer patients' survival and quality of life, and measuring cost-effectiveness in clinical practice. Additionally, Rhus verniciflua Stokes is a rich source of numerous biologically active constituents such as flavonoids, phenolic compounds which have anti-inflammatory activity, and chalconoids, which have antibacterial, antifungal, antitumor, and anti-inflammatory properties.Whereas modern medicine has developed chemotherapy drugs for single-targeted agents, the traditional medicine is for multitargeted agents. The usage of entire or part extraction from a plant probably alleviates the adverse effects and drug resistance which are major problems in modern medicine . Rhus ve


The objective of this study was to investigate the prevalence of HTLV in the south of Bahia and to verify the interfamilial transmission of this virus. Initially, blood was collected from pregnant women in hospitals in southern Bahia.The HTLV-1 status was analyzed by ELISA and confirmed by Western Blot and PCR. The HTLV positive women were contacted and visited. In this opportunity, it was explained the results and collected samples from family members. They signed a consent informed and it was applied questionnaire. A total of 2766 pregnant women were analyzed. The prevalence was 1.05% (n=29) . Besides, it was possible to follow 18 mothers (16 positives and 2 indeterminates) for 2 years. During the following, it was collected samples from 34 family members, including: partners (n=8), mothers (n=7), father (n=1), sisters (n=2), brothers (n=4), sons (n=5), daughters (n=4), others (n=3). Specific reactivity was observed in 11/34  individuals, of which two samples were from children . The others members were: 3 mothers, 1 father, 3 partners, 2 sisters. In one case, we had three generation HTLV-1 positive: grandmother, mother and daughter. These results are very relevant because: (1) so far no studies of HTLV-1 seroprevalence in pregnant/puerperal women from the South region of Bahia had been described, (2) previous studies in areas endemic for the HTLV in Brazil found: 0.84% - Salvador, Bahia and 1.1% in Belo Horizonte, Minas Gerais, (3) evidence of important interfamilial transmission in this area.


The phytohormone gibberellic acid (GA) has essential signaling functions in multiple processes during plant development. In the “Green Revolution”, breeders developed high-yield rice cultivars that exhibited both semi-dwarfism and altered GA responses, thus improving grain production. Most studies of GA have concentrated on germination and cell elongation, but GA also has a pivotal role in floral organ development, particularly in stamen/anther formation. In rice, GA signaling plays an important role in spikelet fertility; however, the molecular genetic and biochemical mechanisms of GA in male fertility remain largely unknown. Here, we review recent progress in understanding the network of GA signaling and its connection with spikelet fertility, which is tightly associated with grain productivity in cereal crops. Gibberella fujikuroi that causes uncontrolled cell elongation and various disease symptoms in infected plants .,26.GAMYB tetrads during anther development [ent-copalyl diphosphate synthase1-1 (oscps1-1) produces defective stamens with whitened and shrunken anthers and abnormal tapetum [oscps1-1 and gid1-4 mutants in rice show a morphological abnormality of the tapetum, although it is uncertain how GA-deficiency induces the phenotype [Development of stamens and anthers requires GA signaling, as malfunction of GA signaling results in male sterility. Most GA-insensitive or -deficient mutants in rice, petunia, maize, tomato, barley and  flowers ,40,41,42 flowers ,12,35. F tapetum . DELLA p tapetum ,44,45,46henotype .CYP703A3 and KAR encoding a cytochrome P450 hydroxylase and β-ketoacyl reductase, respectively [The formation of male reproductive organ in plants is influenced by numerous internal factors, including microspore maturation, meiosis, differentiation of sporogenous cells, and stamen specification ,48,49,50ectively ,53.gamyb-1 mutants have defective anthers [CYP703A3 and KAR, which are responsible for pollen formation, is dramatically suppressed in gamyb-2 mutants, resulting in defective anther development [TAPETUM DEGENERATION RETARDATION (TDR), during anther development [OsC6 and OsCP1, encoding a lipid transfer protein and a cysteine protease, respectively; TDR directly controls expression of these genes [OsC6 by directly interacting with its promoter [GAMYB expression is necessary for the normal development of male reproductive organs and thus for spikelet fertility in rice  ecotype [OsSPY, which encodes a factor that post-translationally modifies SLR1, developed few fertile spikelets [EL1, a casein kinase I phosphorylating SLR1, negatively affects spikelet fertility in rice [Although recent studies of GA signaling have focused on the consequences of GA deficiency in stamen development, defects in GA signaling also negatively affect silique fertility in bidopsis . Severalbidopsis ,7. Overeoduction . Overexpbidopsis . In Arab ecotype . In mono ecotype ,21,38. Tpikelets . Recentl in rice .In plants, several mutants exhibiting male sterility are sensitive to temperature and photoperiod, suggesting that the response to environmental conditions also closely associates with development of reproductive organs . For exaOryza sativa L.) is a staple food for more than a half of the world population, mainly in Asia. To increase rice grain production, yield-related components such as panicle number per plant, spikelet number per panicle, spikelet fertility, and grain weight need to be improved. In addition, it will be crucial to maintain the balance of agronomic traits; for instance, excessive tillering often gives rise to a decrease in grain production, because tillers can contend with the main culm for resources and negatively affect seed filling rate [Rice  also likely affect stamen development. In the GA signaling cascade, GAMYB is a central regulator of anther development. Several direct target genes of GAMYB in anther development have been established [GAMYB downstream of SLR1 remains to be identified. In Arabidopsis, DELLA activity in the Ler ecotype is not essential to maintain seed fertility; however, the mutation of DELLA genes in Col-0 ecotype induces male sterility, due to post-meiotic defects in pollen formation. [EL1, and thus have defects in EL1, the kinase that phosphorylates SLR1 to increase its activity and stability [SLR1, or completely unknown regulatory mechanisms, may govern spikelet development. Therefore, further studies to find as-yet-undetermined mechanisms are necessary to expand our knowledge of GA signaling in spikelet fertility.There are many open questions about GA and spikelet development in rice. First, it is as yet unknown what the SLR1-interacting factor(s) and direct target(s) of SLR1 are in the stamen during spikelet development. DELLAs directly interact with several proteins, such as PIF, MYC2, JAZ, and EIN3 in other hormone pathways in bidopsis ,68,69,70ablished , but thermation. ,71,72. Rrmation. ; H143 extability ,29. ThesFurthermore, analyses of the relationship between plant hormones and grain productivity are necessary to pioneer crop science in the future. In addition, world climate change will likely have a major effect on the grain productivity of many crops. We currently know the relationship between environmental cues and GA in reproductive organ formation. However, the molecular analysis of those relationships is still at an early stage. Therefore, a deeper understanding will provide more insights to help in the improvement of crop productivity.


Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia.


We recently developed a high-throughput sequencing method for analysis and quantification of HTLV-1 integration sites in the host genome . Using this method we investigated the effect of the genomic environment on integration targeting, clonal expansion and spontaneous HTLV-1 proviral expression . HTLV-2 preferentially infects CD8+ T cells, with a minority of the proviral load in CD4+ T cells. Here we describe the use of our high-throughput technique to investigate the distribution of HTLV-2 proviral integration sites in the host genome, in peripheral blood mononuclear cell (PBMC) DNA of HTLV-2 infected individuals (n=28). We also mapped and quantified proviral integration sites separately in flow-sorted CD4+CD8- and CD4-CD8+ populations. We quantified the clone frequency distribution and clonal survival over time in 10 individuals, using samples from 2 time points separated by a median of 10 years. The results show that the clone frequency distribution of HTLV-2 in PBMCs is distinct from that of HTLV-1 and resembles that of HTLV-1-infected CD8+ T cells. These results suggest that in both HTLV-1 and HTLV-2 infections, there is a greater degree of selective oligoclonal clonal expansion in infected CD8+ T cells than in CD4+ T cells. We are now investigating the selection forces that underlie this dichotomy between T cell lineages.