The next evolutionary milestone was the advent of cholesterol, embedded in the cell membranes of primordial eukaryotes, facilitating metabolism, oxygenation and locomotion, the triadic basis for vertebrate evolution. Lipids were key to homeostatic regulation of calcium, forming calcium channels. Cell membrane cholesterol also fostered metazoan evolution by forming lipid rafts for receptor-mediated cell-cell signaling, the origin of the endocrine system. The eukaryotic cell membrane exapted to all complex physiologic traits, including the lung and brain, which are molecularly homologous through the function of neuregulin, mediating both lung development and myelinization of neurons. That cooption later exapted as endothermy during the water-land transition (Torday, Hobson and Friston have hypothesized that the brain must actively dissipate heat in order to process information (Hobson et al.,  Torday, , perhaps The origins of consciousness and the evolution of physiologic pathways in mammalian brain are arguably among the most challenging of all evolutionary puzzles. It is becoming increasingly evident that the proper point of initiation of any understanding of these phenomena channels through a fuller understanding of the capacities of individual and networked cells and even more particularly, a reassessment of the significance of the unicellular zygotic phase of all eukaryotes  dissipation  (Pinheiro et al., There is an interesting fundamental mechanistic difference between the PTHrP and βAR receptor gene duplications and the GR mutation, and that of the type IV collagen matrix protein, all of which were responses to physiologic stress caused by increased blood pressure, generating oxygen radicals in the microcirculation (De Nigris et al., Given the described step-wise empiric adaptation to land, there were undoubtedly stages in this process at which the lung was inefficient for gas exchange, resulting in hypoxia, the most potent physiologic stressor known. Such stress conditions would have resulted in spates of catecholamine production by the adrenal gland, alleviating the constraint of an inefficient lung by stimulating surfactant production by the alveoli (Lawson et al., The evolution of endothermy/homeothermy is a milestone in vertebrate evolution shared by mammals and birds (Grigg et al., There are clues within this narrative toward the evolution of the central nervous system in the context of the convergence of thermodynamic, self-organizational and informational characteristics. Importantly, there are exaptive traits that fostered the higher consciousness of mammals and birds. The role of thermoregulation has been alluded to by Hobson et al. , invokinAnother co-evolved molecular mechanism common to the lung, adipose tissue and brain is leptin, which is secreted by both fat cells (Adamczak and Wiecek, Thus, the arc of vertebrate physiologic evolution is better understood as a continuum emanating from the water-land transition Torday, , 2015a, The evolution of the vertebrate lung from the fish swim bladder (Zheng et al., It is through understanding these sorts of biophysical mechanisms that the evolution of the brain, particularly as it relates to self-organizational processes, can be explored as a productive reconciliation between thermodynamic necessities and informational requirements. At each moment, organizational problems secondary to system wide epiphenomena are being solved. It has been hypothesized that the interaction between the evolving lung and neuroendocrine system gave rise to endothermy in a series of steps. Intermittent periods of hypoxia during the water-land transition would have caused physiologic stress, hypoxia being the most potent physiologic stressor known in vertebrates. The stress would have been alleviated by the production of catecholamines by the adrenal medulla, relieving the initial constraint on gas exchange by stimulating the alveolar secretion of surfactant, rendering the evolving alveoli more distensible, acutely increasing their surface area for gas exchange. Over the long haul, these bouts with hypoxia would have fostered more alveoli since the distension of the alveoli stimulates PTHrP signaling, fostering more alveoli. In tandem with the stimulation of lung evolution, catecholamines would have stimulated the secretion of fatty acids from fat cells, in turn leading to increased metabolism and body temperature. Consequently, endothermy evolves over time in adaptation to terrestrial life, as a thermodynamically efficient solution to the chain of informational transfer that supports life and upon which “self” is based. In support of this hypothesis, PTHrP signaling for ACTH appears in the mammalian and avian pituitaries and in the adrenal cortex in association with increased microvasculature in the adrenal medulla. These physiologic changes would have enhanced catecholamine production in response to stress, synergizing the evolution of both the alveoli and endothermy. Systematically, the physiologic effect of catecholamines on the gas permeability of the cell membrane promotes oxygenation- the catecholamines promote the population of the cell membrane by unsaturated phospholipids, rendering it more fluid and therefore more permeable to gas exchange. This property is likely causal since the opposite effect is seen during hibernation and torpor, regarding both the composition of the cell membrane phospholipids, and that of the lung surfactant.Therefore, factors that seem separable on an evolutionary basis are in fact united. They extend through demonstrable evolutionary paths that must remain adherent to those basic principles that underscore all such connections. This then provides for neuregulin mediation of both lung development and axonal myelinization, or the skin-brain connection, with their joint embryological connections Foster, . The FriComplex physiology emerged as exaptations from the unicellular realm Torday, . TherefoTherefore, the distributive nature of mammalian cognition across widely separated cellular networks can be concluded to be derivative of both cellular-based cognition and also physiological mechanisms permitting energy dissipation in a manner that yields neurohumoral coherence across space-time. Physiological mechanisms both permit and support cellular “self” as a state function that emanates from unicellular origins and perpetually exists within that frame. That resultant network of cellular self-identity is always adherent to thermodynamic limits and is further delimited by cellular homeostasis that is itself dependent upon physiological pathways extending forward from their unicellular origins. Multicellular networks reiterate toward mammalian cognition by purposing self-organization as responsiveness to cellular self-identification, ever dependent upon the maintenance of cellular homeostatic flux boundaries, and sustained and advanced by cellular physiologic mechanisms in continual adaptation to epiphenomena.JT contributed 50%; WM contributed 50%.JT has been supported by NIH Grant HL055268The 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 reviewer KF and handling Editor declared a current collaboration and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Blood donations in the US are routinely screened for markers of human T-lymphotropic virus (HTLV). Seroprevalence and risk factors associated with HTLV-1 and -2 infection from the US Retrovirus Epidemiology Donor Study (REDS-II) Transfusion-Transmitted Viral Infection (TTVI) Rate and Risk Factor Study are reported. Among 14,809,334 blood donations screened during 2011-2012, 516 HTLV confirmed seropositive cases were identified, with an overall prevalence of 3.5 infections per 1,0 donations (95% CI: 3.2-3.8). A case-control study of risk factors from 90 donors with serology-confirmed HTLV-1 infection, 102 with HTLV-2 (cases), and 1,587 donors with false-positive results (controls) was conducted. Frequencies and adjusted odds ratios (AORs) from separate multivariable logistic regression analyses for HTLV-1 and -2 cases compared to controls are reported. Mean age was 48.0 (SD: 12.4), 52.3 (SD: 11.0) and 41.7 (SD: 15.7) years for HTLV-1, HTLV-2 cases and controls, respectively. Being a first-time donor, older, non-white, non-Hispanic female were significant demographic factors associated with both infections. HTLV-1 cases were more likely than controls to be Black , born outside of the US , have migrated (family or self) from an endemic area , report sex with an IDU  or have multiple partners . HTLV-2 cases were more likely to be Black , Native Americans , report sex with an IDU  or have multiple partners . US blood donors with HTLV-1 or -2 infection present with the known risk factors. Migration from endemic areas is mainly associated with HTLV-1 infection, while HTLV-2 is associated with Native American donors. Sexual risk behavior and IDU continue to be risk factors for both viruses.


Interestingly, the Australian clade can be itself divided into two clusters: the first comprising strains characterized among most of the Indigenous Australians from the North and the second including a majority of individuals originating from the South and Central Australia. Thus, there is a clear evidence of a specific HTLV-1 clustering according to the childhood residence of the HTLV-1 infected individuals, and subsequently their language group affinity. Taking into account that non-human primates have never been found in Australia, we believe that these HTLV-1 subtype C variants have been present among the first ancestors of modern Indigenous Australians for several tens of millennia.HTLV-1 infects approximately 5-10 million people worldwide. It is widely distributed, with clusters of high endemicity in certain geographic areas or ethnic groups. Seven main HTLV-1 subtypes have been described and the Melanesian/Australian subtype C is only found in Oceania. In Australia, HTLV-1 is endemic with ATLL, TSP/HAM, bronchiectasis, ID and severe scabies cases reported. However, HTLV-1 clinical significance is debated and only one partial HTLV-1 sequence from an Aboriginal Australian (MSHR-1) is available. Therefore, establishing a large HTLV-1 sequence database is essential for the understanding of the epidemiology and pathogenesis of this virus in Indigenous people. Samples were obtained from 23 HTLV-1 patients originated from four broad geographical and language-based areas. Sequence comparison indicated that the 23 new HTLV-1 LTR and Tax-Gag sequences belong to the subtype C as MSHR-1 strain. Phylogenetic analyses evidenced two main clades (Solomon Islands/Vanuatu


Giardia as prevalent in both humans and dogs worldwide and have postulated the occurrence of anthroponotic, zoonotic and animal-specific cycles of transmission, which may be geographically and regionally unique in its epidemiology. The aim of this study was to utilise molecular tools to determine the prevalence and compare genotypes of Giardia duodenalis infecting humans and dogs living in a previously identified Giardia-endemic village in rural Cambodia in order to ascertain zoonotic transmission risk.A number of epidemiological studies have demonstrated G. duodenalis in humans and dogs was 18.3% (40/218) and 10.6% (10/94) by PCR, respectively. Molecular characterisation of the small subunit of ribosomal RNA (SSU rRNA) gene, triose phosphate isomerase (TPI) gene and sub-assemblage characterisation of the glutamate dehydrogenase (gdh) gene placed 27.5% (11/40) of Giardia positive humans into assemblage AII and 72.5% (29/40) into assemblage BIII of G. duodenalis. In dogs, 20.0% (2/10) of Giardia-positive samples were characterised as G. duodenalis assemblage BIII, 40.0% (4/10) as assemblage C and 40.0% (4/10) as mix infection between assemblage C and D.The prevalence of G. duodenalis in the studied communities and hence pose a minimal zoonotic risk for the transmission of Giardia to humans.Overall, just over 2% of dogs harboured potentially zoonotic assemblages of  Giardia is a protozoan flagellate that infects the intestinal tract of vertebrate hosts including humans and a considerable variety of other mammals through ingestion of infective cysts [Giardia species, only Giardia duodenalis has been found to infect humans and mammals. Eight distinct assemblages A to H have been reported and classified based on their genetic analysis and host specificity as reviewed by Ryan and Cacciò [ve cysts . Among td Cacciò . In detad Cacciò .G. duodenalis, however may also harbour potentially zoonotic assemblages AI, AII, BIII and BIV [G. duodenalis. In Cambodia, the prevalence of Giardia in humans varies from 2.9% to 8.0% [G. duodenalis to humans. Yet, documentation of prevalence and genotypes of G. duodenalis in canines and humans is virtually inexistent in many Southeast Asian countries and Cambodia in particular.Dogs are predominantly infected with canid-specific genotypes of  and BIV . This ab and BIV  and thei to 8.0% –8. In ruG. duodenalis cysts that primarily infect dogs (assemblages C and D) from those that have zoonotic potential (assemblages A and B), and this can only be based on their discrimination using a multilocus molecular typing approach [From a public health perspective, it is necessary to distinguish approach .Giardia by PCR targeting the SSU rRNA gene of G. duodenalis. In dogs, the prevalence of Giardia using zinc sulphate centrifugal flotation was 2.1% (2/94) [G. duodenalis in dogs living in the same village and a multilocus genotyping approach to assess the risk for zoonotic transmission.In May 2012, a total of 40/218 (18.4%) of humans from 67 households in Dong village, Preah Vihear province, Cambodia were found positive for % (2/94) . The objet al. [G. duodenalis cysts using zinc sulphate centrifugal flotation. In addition, risk factors for infection of humans and animals were assessed by questionnaire interviews with participants and head of households.For detailed information on study design and parasitological methods, refer to the study by Schär et al. . BrieflyGiardia status by microscopy, using PowerSoil DNA Kit . The extraction was performed according to manufacturer’s instructions with minor modification. ZIRCONIA/SILICA beads 0.5 mm in diameter  were used instead of the PowerBead provided by the manufacturer. Samples were disrupted using a Mini-BeadBeater-16  at maximum speed for 5 min. The DNA was stored at -20°C until used for PCR amplification.Dog faecal samples fixed in 2.5% potassium dichromate were subjected to DNA extraction regardless of Giardia by targeting a 174 bp fragment of the SSU rDNA gene of G. duodenalis[G. duodenalis on the SSU rDNA gene were further characterised at the TPI gene.A previously published nested PCR was utilised to screen dog faecal samples for odenalis, 12. Briodenalis samples G. duodenalis positive samples. The PCR was carried out in 25 μl volumes with each final reaction containing 1x CoralLoad PCR buffer (Qiagen Pty Ltd.), 12.5 pmol of each primer, 0.5 U of HotStar Taq DNA polymerase (Qiagen Pty Ltd.) and 2 μl of DNA. The cycling conditions were the same as the published protocol except for an initial denaturation of 5 min at 95°C. For all PCR assays, a positive control of G. duodenalis and a negative control of distilled water were included in each run.For humans, a pan-assemblage nested PCR targeting a 530 bp region of the TPI gene  and for G. duodenalis assemblage A and B at the SSU rDNA and TPI genes were further genotyped at a 530 bp region of the gdh gene using a previously published nested PCR assay [Dogs and humans positive for CR assay . The PCRG. duodenalis were subjected to DNA sequencing. The PCR products were purified using PureLink quick PCR purification kit  according to manufacturer’s protocol and submitted to the University of Queensland Animal Genetic Laboratory for sequencing using both forward and reverse primers. DNA sequences were visualised using Finch TV 1.4.0  and aligned using BioEdit version 7.2.0 (http://www.mbio.ncsu.edu/BioEdit/bioedit.html) and directly compared with reference isolates of the TPI and gdh genes of G. duodenalis assemblages A-E.PCR positive samples of the correct size for the SSU rRNA, TPI and gdh genes of http://www.epidata.dk). Analysis was carried out using STATA version 12 (StataCorp ltd.). Infection prevalence rates were calculated. χ2 test was used to associate infection status with risk factors. A p-value <0.05 was considered significant.The data was double entered and validated in Epidata  of G. duodenalis positive samples were characterized as assemblage C, 40.0% (4/10) as mix infection between assemblage C and D and 20.0% (2/10) as assemblage BIII  as assemblage AII  compared to older dogs , a factor consistently observed in previous epidemiological studies [Age was the only factor that was significantly associated with the prevalence of h humans  and dogs studies , 24. AgeG. duodenalis in dogs. Four out of 8 (50.0%) isolates from dogs classified as assemblage C using the 18S rRNA and the pan-assemblage PCR targeting the TPI [G. duodenalis to undergo recombination between isolates from different assemblages may also account for this finding [This study confirms the advantage of utilising the assemblage C- and D-specific PCR  for targ the TPI  gene wer the TPI , 14, the finding .G. duodenalis transmission in human and dog populations living closely together in small rural communities in Cambodia and concludes that in rural Cambodia, community dogs play a negligible role as zoonotic reservoirs for Giardia.This work contributes to the understanding of


Dear Editor,Ischemic stroke falls under the category of complex diseases, which do not obey the single-gene dominant or single-gene recessive Mendelian pattern of inheritance but rather arises from the combination of numerous genetic variants and environmental factors  and ursodeoxycholic acid (UA) are compounds extracted from Qingkailing injection, which was extensively used for treating acute ischemia stroke for decades in China  treatment groups.Firstly, the IPA results revealed 11 statistically significant networks between the JU and vehicle groups. The top 5 networks included 35, 35, 35, 34 and 35 nodes  (Table.S1). Network 1 includes gene expression, cell cycle and cellular compromise . Of these 33 canonical pathways, the combination JU treatment regulated as many as 13 pathways independently, including renin-angiotensin signaling and cAMP-mediated signaling, whereas the JU, JA and UA groups showed 6 overlapping pathways. Meanwhile 6 overlapping pathways were identified between the JA and JU groups, and 8 overlapping pathways were discovered between the UA and JU groups  was discovered between the JA and JU groups, and 2 overlapping functions  were discovered between the UA and JU groups. Meanwhile, a total of 2, 4 and 3 unique functions were identified in the JA, UA and JU groups, respectively . The top 10 functions of the JU group are cell death, cancer, cell cycle, cellular growth and proliferation, tissue morphology, DNA replication, recombination and repair, small molecule biochemistry, hematological disease, tissue development and hepatic system disease . Moreover, according to the IPA analysis of the 66 overlapping functions among the JA, UA and JU groups, 21 functions (31.82%) belong to the category of diseases and disorders, 21 functions (31.82%) are related to molecular and cellular functions, and 24 functions (36.36%) are involved in physiological system development and function. The distribution of these functions is shown as list .In our current study, based on the analysis of the top 5 differential networks, 3 overlapping network functions were identified in the JA, UA and JU groups, including cellular compromise, small molecule biochemistry and lipid metabolism. These functions have been reported to be involved in cerebral ischemia  and eukaryotic translation initiation factor 4GI (eIF4GI) correlates with the inhibition of protein synthesis and decreased viability at different time points during reperfusion  and State Project for Essential Drug Research and Development (2013ZX09303301).Guo Shanshan, Guo Li, Yu Yanan, Li Bing, Zhang Yingying, Li Haixia, Wu Ping, Wang Jie, Yuan Ye, Wang Zhong and Wang Yongyan declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.Below is the link to the electronic supplementary material.Supplementary material 1 (PDF 162 kb)


The purpose of this study was to investigate the expression of Wnt and Notch signaling pathway-related genes in inflammatory bowel disease (IBD) treated with mesenchymal stem cell transplantation (MSCT).TNBS  was used to establish IBD in a rat model. Mesenchymal stem cells (MSCs) were transplanted via tail vein transfusion. Saline water was used in a control group. The expression of Wnt and Notch main signaling molecules was screened by gene chips and verified by quantitative reverse transcription-polymerase chain reaction in the IBD rat model on day 14 and day 28 after transplantation.Olfm4 mRNA expression in the IBD group (2.54±0.20) was significantly increased compared with the MSCT group (1.39±0.54) and the normal group (1.62±0.25) (P <0.05). The Wnt3a mRNA was more highly expressed in IBD rats (2.92±0.94) and decreased in MSCT rats . The expression of GSK-3β mRNA was decreased in the setting of inflammation  but returned to normal levels after MSCT (0.81±0.17). The expression of β-catenin was observed to increase in IBD tissues (1.76±0.44) compared with normal tissues , but no difference was found in the MSCT group (1.12±0.36). Wnt11 declined at 14 days and returned to normal levels at 28 days in the IBD group; in comparison, a significantly lower expression was found in MSCT rats. There were no differences in the expression of Fzd3, c-myc, TCF4, and Wnt5a in inflammation, but all of those genes declined after MSCT treatment.The IBD rat models were successfully established and MSCs were transplanted into those models. Genome-wide expression profile chips identified a total of 388 differentially expressive genes, of which 191 were upregulated and 197 were downregulated in the MSC-transplanted group in comparison with the IBD control group. Real-time quantitative polymerase chain reaction results showed that the level of The canonical Wnt and Notch signaling pathways are activated in IBD and may be suppressed by stem cell transplantation to differentiate into intestinal epithelium after MSCT. Moreover, the non-canonical Wnt signaling may be inhibited by canonical Wnt signaling in the setting of inflammation and may also be suppressed by MSCT. Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). These conditions produce recurrent chronic inflammatory illnesses of the intestinal tract. Studies show that IBD comprises heterogeneous disorders of various etiologies, in which hereditary predisposition, environmental factors, and abnormal immune response work together to induce this disease , 2. Currin situ hybridazation and immunohistochemistry that allogenic transplanted hematopoietic stem cells or MSCs could populate the injured regions of the colon [Mesenchymal stem cells (MSCs) have proliferation, differentiation, and engraftment capacity in appropriate target tissues . Severalhe colon . MSCs nohe colon . HoweverWnt3a) activates the canonical Wnt signaling pathway, which is a prominent member of the Wnt family. The other members of the Wnt ligand family—such as Wingless-type MMTV integration site family, member 5A (Wnt5a) and Wingless-type MMTV integration site family, member 11 (Wnt11)—activate the non-canonical Wnt signaling pathway [Atoh1) gene expression, which determines cell fate [The Wnt signaling pathway and Notch signaling pathway are major pathways in stem cell proliferation and differentiation capacity. Wnt signaling is classified as two types: canonical pathway and non-canonical pathway . Wingles pathway . The Notell fate . The Wntell fate . Wnt andIn this study, we explored the differential expression of genes associated with the Wnt and Notch signaling pathways in MSCT of an IBD rat model. Using a cDNA chip, we verified these related genes by quantitative reverse transcription-polymerase chain reaction (RT-PCR). We will discuss the mechanism of differentiation of implanted MSCs in the repair of damaged intestinal epithelium.Eighteen Sprague Dawley male rats weighing 180 to 200 g were maintained in accordance with the guidelines of the Committee for Animal Research of Guangzhou Medical University. This study was conducted in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals. All animal experiments were approved by the Guangdong Medical Laboratory Animal Center. Eighteen male rats were randomly divided into three groups, and each group included six rats. There are three groups: normal control group, IBD group, and MSC transplantation group (MSCT group).2 in low-glucose Dulbecco’s modified Eagle’s medium  containing 10 % fetal bovine serum (Gibco) and 100 μg/ml penicillin and streptomycin . The medium was changed every 1 to 3 days. After two or three passages, MSCs were used for transplantation to treat IBD. The immunophenotyping of MSCs was analyzed by flow cytometry for CD44+ and CD54+ antigen markers. When MSCs covered 80 % to 90 % of the area of the culture bottle, they were passaged. Transplantation was performed with passage 3 to passage 5 cells.MSCs, which were labeled with green fluorescent protein (GFP), were obtained from Cyagen Biosciences Inc. . MSCs were re-suspended at 37 °C, 5 % COIBD experimental colitis rats model were induced by delivering 1.0 ml of 20 mg 2,4,6-trinitrobenzene sulfonic acid (TNBS)  in 50 % ethanol solution. A rubber infusion tube was positioned 8 cm from the anus to instill TNBS into the lumen of the colon. To ensure allocation of TNBS within the entire colon, rats were maintained vertically for 1 minute. The normal group received 0.1 ml of normal saline.6/ml. After 24-hour IBD model yielding, the rat tail was wiped with a warm towel and alcohol for vein dilation. Then 1.0 ml of previous MSCs was transplanted via the tail vein. Removal of colon tissue lesions from normal rats, IBD rats, and MSCT rats was done at 14 and 28 days after MSCT. Samples, which covered lesion region, were removed from colon tissue 8 cm far from anus.MSCs were transfected by virus to stable GFP fluorescence expression. Before MSCT models were established, the concentration of MSCs was adjusted to 2×10Four to six rats were killed on days 14 and 28 in the IBD and MSCT groups. First, the colon tissues were observed with the naked eye and with a microscope. Second, the lesion tissues were fixed in 4 % buffered formaldehyde and embedded in paraffin wax; histological samples were cut from paraffin-embedded blocks and stained with hematoxylin and eosin for light microscope and fluorescent microscope examination.P <0.05 and fold change (FC) >2). Mircoarray data are available at Gene Expression Omnibus under accession number GSE68653.Total RNA was extracted from IBD colorectal tissues and colorectal tissues at 28 days after MSCT and transcribed into cDNA. The cDNA was scanned by the Axon GenePix 400B microarray analysis scanner . Data were analyzed by NimbleScan version 2.6 software  . The PrimeScript RT Master Mix   and 500 ng of total RNA and poly-dT primers were used for synthesis of cDNA. All gene-specific primers listed in Table P <0.05, **P <0.01.Experiments were reproduced three times. In Table Anatomic examination revealed pronounced colonic damage, including bowel wall edema, luminal dilation, mucosal erosions and ulcers, and even perforation Fig. . We alsoHistochemical analysis of the colonic tissues revealed mucosal lesions, edema, ulcers, and intense inflammatory cell infiltrate in TNBS-induced colonic epithelium Fig. . The his+ and CD54+ antigen markers. The positive cells of CD44+ were 89.6±6.0 %, and those of CD54+ were 95.5±3.9 % [Sry gene and Y chromosome were detected by PCR and fluorescence in situ hybridization (FISH) to determine the location of male donor cells in the female colon after transplantation [The result of flow cytometry showed that MSCs expressed CD44.5±3.9 % . Well-grantation .Fig. 3ThP <0.05 and FC >2 were screened for, a total of 388 differentially expressive genes were found; of these, 191 were upregulated and 197 downregulated in the MSCT group in comparison with the IBD control group. These genes were involved mainly in inflammatory reaction, immune reaction, and cell differentiation. The top 10 and bottom 10 genes are shown in Tables At 14-day treatment with MSCT, main lesion colon tissues were collected for chip analysis. Genome-wide expression profile chips showed very good sample data trend and study repeatability. When Atoh1 and olfactomedin 4 (Olfm4) were associated with the Notch signaling pathway, which regulated cell proliferation and differentiation [Atoh1 in the MSCT group was significantly higher than in the MSC , normal , or IBD rat models  (there were no significant differences among these three groups). The expression of Olfm4 in MSCT rats was downregulated in comparison with IBD rats (P <0.05). No difference was found when compared with normal rats (P >0.05)  and cyclin D exhibited downregulated expression in the IBD rat group at 14 days and demonstrated upregulation at 28 days compared with the normal group. There were no differences in the expression of Fzd3, TCF4, and c-myc between IBD model rats and the normal group . Wnt11 showed lower expression in the MSCT group compared with the IBD group at 14 and 28 days (P = 0.048); in the IBD model, Wnt11 decreased at 14 days (P = 0.019) and was restored to normal level at 28 days (P >0.05) (Table 5) Table , Fig. 7.The intestinal stem cells showed renewal, proliferation, and differentiation capacity and were able to restore the intestinal mucosa . TransplWnt3a enhances the proliferation of MSCs and suppresses MSC osteogenic differentiation, whereas non-canonical Wnt signaling activated by Wnt5a maintains MSC numbers and promotes osteogenesis [Wnt3a and Fzd3 were reported to increase expression in IBD colon tissues compared with non-IBD colon tissues [β-catenin was found to increase in colonic epithelial crypts from damaged mucosa [Intestinal stem cells have several signaling pathways, such as Wnt, BMP, PI3K/Akt, Hedgehog, and Notch pathways. Wnt and Notch signaling pathways play important roles in determining intestinal stem cell fate, including maintenance of stem cell homeostasis, inhibition of cell differentiation, and control of Paneth cell development . Meanwhiogenesis . The Notogenesis . In rece tissues . The prod mucosa .Sry gene using PCR and Y chromosome FISH in female recipients, and the donor cell rate was evaluated by brown positive cells labeled by bromodeoxyuridine (BrdU) immunohistochemistry. MSCs not only were engrafted in the damaged areas but also were the major source for intestinal epithelia renewal [Wnt3a and inhibited by GSK-3β and APC, and the transcription of downstream-related factors would be regulated. These changes promoted intestinal stem cell proliferation and repaired the intestinal mucosa. On the other hand, the expression of Fzd3, c-myc, and cyclin D did not change significantly in IBD rats. These results suggest that Wnt3a and Fzd3 may not work together in activating canonical Wnt signaling to accelerate intestinal stem cell proliferation by promoting the transcription of c-myc and cyclin D. After MSCT, canonical Wnt signaling-related genes such as Wnt3a, Fzd3, β-catenin, TCF4, and cyclin D exhibited downregulation, and GSK-3β exhibited upregulation, compared with IBD rats; the canonical Wnt signaling pathway may be inhibited when treated with MSCs.In our study, we successfully established the IBD and MSCT model rats and then found that MSCs labeled with green fluorescence were populated in the damaged areas after MSCT. In our previous study, we have demonstrated that hematopoietic stem cells or MSCs could be implanted in the ulcerated experimental colitis region of a rat model after transplantation; male donor cells were followed by  renewal . The oth renewal . In thisAPC differed from that of c-myc. APC declined on day 14 and increased to normal levels on day 28 in IBD rats after MSCT. The expression of c-myc was increased on day 14 and decreased on day 28 in the MSCT group. C-myc was reportedly the target gene of the APC pathway [c-myc in the early stage, inhibiting APC expression, and promoting the proliferation of the MSC itself. On day 28, the decreased expression of c-myc promoted the differentiation of MSCs into intestinal stem cells.The expression of  pathway  and showWnt11 can either activate or inhibit the canonical pathway [Wnt11 decreased on day 14 and increased to normal levels on day 28. But the expression of Wnt5a did not differ between the IBD group and the normal group. In IBD rats treated with MSCT, both Wnt5a and Wnt11 expressions were lower than in IBD and normal rats. We speculated that the non-canonical Wnt signaling activated by Wnt11 may have been inhibited by canonical signaling in IBD, but the non-canonical Wnt signaling activated by Wnt5a did not change in inflammatory conditions. Regardless of which signaling molecule activated the non-canonical signaling pathway, both may be inhibited after MSCT.In the non-canonical Wnt signaling pathway,  pathway , 33. In Olfm4 was the target gene of Notch signaling and participated in stem cell fate. The expression of Olfm4 in the intestine rapidly decreased after Notch inhibition, and increased Olfm4 expression was observed after activation of Notch signaling [Olfm4 significantly increased in IBD rats compared with normal rats and MSCT rats. This increased expression in IBD is consistent with the conclusions of Gersemann et al. [Atoh1 was an inhibitor of the Notch signaling pathway and essential to the differentiation of intestinal stem cells [Olfm4 was downregulated and Atoh1 was upregulated. This suggests that Notch signaling may be suppressed in the process of MSCT treatment.ignaling . In the n et al. . Atoh1 wem cells . After Mc-myc and low expression of APC mRNA facilitate MSC proliferation, and then differentiation into intestinal epithelial cells in the anaphase, by reducing the expression of c-myc.In this study, we investigated the effect of Wnt and Notch signaling in the process of MSCT repair of inflammatory bowel disease in a rat model. Our results suggest that canonical Wnt and Notch signaling pathways are activated to promote the proliferation of intestinal stem cells in IBD, countering inflammation. Non-canonical Wnt signaling may be suppressed by canonical signaling during inflammation. In treatment with MSCs, Notch and Wnt signaling pathways are inhibited to prevent stem cell proliferation and promote MSC differentiation to intestinal epithelial cells. Shortly after MSCT, the high expression of


In this review, we compare knowledge about the recently discovered strigolactone signaling pathway and the well established gibberellin signaling pathway to identify gaps of knowledge and putative research directions in strigolactone biology.Communication between and inside cells is integral for the vitality of living organisms. Hormonal signaling cascades form a large part of this communication and an understanding of both their complexity and interactive nature is only beginning to emerge. In plants, the strigolactone (SL) signaling pathway is the most recent addition to the classically acting group of hormones and, although fundamental insights have been made, knowledge about the nature and impact of SL signaling is still cursory. This narrow understanding is in spite of the fact that SLs influence a specific spectrum of processes, which includes shoot branching and root system architecture in response, partly, to environmental stimuli. This makes these hormones ideal tools for understanding the coordination of plant growth processes, mechanisms of long-distance communication and developmental plasticity. Here, we summarize current knowledge about SL signaling and employ the well-characterized gibberellin (GA) signaling pathway as a scaffold to highlight emerging features as well as gaps in our knowledge in this context. GA signaling is particularly suitable for this comparison because both signaling cascades share key features of hormone perception and of immediate downstream events. Therefore, our comparative view demonstrates the possible level of complexity and regulatory interfaces of SL signaling. SLs have a long research history in the context of interactions between plants and other organisms. They were identified in 1966 as plant-derived molecules used by parasitic plants to interact with their hosts , GA3, GA4, GA5, GA6 and GA7 are biologically active. These GAs show different affinities to their receptors  but a higher bioactivity. This is presumably due to increased GA3 stability caused by a double bond at the C2 position , the identification of the active forms 5DS as well as its unnatural enantiomer GR24ent−5DS -dependent pathway inducing germination after wildfires  is involved in SL secretion into the rhizosphere  in Arabidopsis  ubiquitin ligase (E3) complex via the F-box protein SLEEPY1 (SLY1), which provides substrate specificity to the complex  show much milder phenotypic alterations than gid1a/b/c mutants do, although they accumulate comparable or even higher levels of DELLAs. Intriguingly, overexpression of the GID1 receptor suppresses these alterations  , which does not contribute to SL or KAR responsiveness  in rice . D3 is the rice ortholog to MORE AXILLARY GROWTH2 (MAX2) from Jatropha curcas , the only DELLA protein found in rice  essential for binding to GID1 , REPRESSOR OF GA1-3 (RGA), RGA-LIKE1 (RGL1), RGL2 and RGL3 carry such a domain  and an amino acid substitution that changes a positively charged Arg into a Thr  was identified in sis Fig. . The smaO-GlcNAcylation catalyzed by the GlcNAc transferase SPINDLY (SPY) promotes DELLA activity  gene and to the RGA protein , a co-chaperone required for tubulin folding, translocates after GA-induced DELLA degradation and increases the amount of active tubulin subunits promoting cell expansion  providing plenty of opportunities for interactions with other molecules. Indeed, D53/SMXL proteins carry a putative ethylene-responsive element binding factor-associated amphiphilic repression (EAR) domain that can interact with TOPLESS (TPL)  from entering the nucleus and degrading the light-responsive protein LONG HYPOCOTYL5 (HY5) (Tsuchiya et al. Apart from being secreted by plant roots and their role in biotic interactions (Xie and Yoneyama in planta and unwrap their distinct adaptive values. The spatio-temporal dynamics of SL signaling is another interesting aspect for which hardly any information is available. Do all cells have the capacity to sense SLs or is this mainly restricted to vascular tissues? Does sensitivity change over time or in different environments? The identification of events downstream of D53/SMXL proteolysis will certainly provide important insights and tools for addressing these questions. The dissimilarity of D53/SMXL proteins to any other group of known developmental regulators suggests the existence of unique molecular mechanisms and argues for surprising findings in the future.Due to recent fundamental breakthroughs in SL biology research, we expect the unfolding of another complex signaling network in plants soon. In particular, the identification of the D53/SMXL protein family as repressors of SL signaling and direct targets of SL-dependent proteolysis opens up novel avenues to core events in the signaling cascade. Their characterization will be tremendously helpful for integrating the SL pathway into known regulatory networks and for understanding primary effects of SL signaling. Comparisons to other signaling cascades, like GA signaling, are certainly helpful as a first guideline in this regard. Such a comparison demonstrates the degree of complexity possible on the level of transport, perception, and targeted processes and emphasizes experimental pitfalls to be taken into consideration. For example, it will be essential to decipher the roles of the different SLs EW, VL and TG wrote the manuscript. All authors read and approved the manuscript.


Being the first second messenger described  is a second messenger of paramount biological importance, involved in the regulation of a significant number of cellular functions To our belief, this aim has been successfully fulfilled. The present collection of articles highlights, in a representative (but certainly not exhaustive) way, the research activity and emerging concepts in the field, while it also reveals the therapeutic potential that targeted pharmacological manipulation of intracellular cAMP levels could exert on a number of pathological conditions. We organized the papers of this Research Topic/e-Book into three sections (A–C).Frontiers in the role of cAMP in cellular function, homeostasis and disease”) opens with a very informative review article on the reciprocal regulation between cAMP signaling and the ubiquitin-proteasome system, as well as its relevance to certain human diseases . A more focused perspective on the importance of cAMP in cardiac physiology and pathophysiology is presented by the review article of Boularan and Gales and the mini review article of Froese and Nikolaev; both articles provide an up-to-date account of recent developments in the field and should be considered by readers as complementary to each other. Later in section A, readers will discover an elegant mini review on the role of cAMP signaling in neural plasticity, learning and memory (Lee), that summarizes findings generated by research on the fruit fly Drosophila melanogaster and briefly highlights implications of this signaling pathway to potential therapeutic applications. Section A concludes with an original article on the role of cAMP signaling in human trophoblast fusion , and with a perspective article on the spatiotemporal regulation of cAMP signaling in blood platelets .The first section  includes an informative review article on state-of-the-art methodologies which can be utilized toward the study of cAMP-mediated signal transduction via G-protein coupled receptors , as well as two excellent review articles on the pharmacological manipulation of intracellular cAMP levels through interference of the molecular interactions between the A-kinase anchoring proteins and other signaling protein intermediates . This section also accommodates a contribution by Röck et al. with an original research article in which analysis of protein kinase A (PKA) dynamics following the integration of patient mutations into its catalytic (PKAc) and regulatory (RIa) subunits is presented. The section is completed with two analytical review articles that present recent developments in the utilization of genetically encoded tools for cAMP measurement in health and disease .The second section  is introduced with a perspective article on the role of patients' sex toward a more targeted (cAMP pathway-regulated) therapeutic approach to brain tumors , followed by two original research articles on the role of cAMP signaling in the context of hematological malignancies and the potential therapeutic applications that could arise through its pharmacological manipulation . The current Research Topic / e-Book is concluded with a well-written review article on cAMP signaling in trypanosomatids that provides an overview of the complex functions of cAMP in these protozoan parasites, as well as a fine perspective on how potential targets for the trypanosomatid-specific cAMP pathway could provide efficient therapeutics for serious human diseases such as the sleeping sickness and other trypanosomatid-induced pathological entities .The third section (C: “The recruited articles cover multiple aspects of the ongoing research in the cAMP field and allow an appreciation of the difficult task ahead in fully-understanding the complexity of this ubiquitous signaling cascade and taming it to develop efficient therapeutic applications. Hopefully, readers will consider this collection of papers as a small step toward these goals.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.


Arabidopsis thaliana genome encodes 11 ROPs that form a distinct single subfamily contrarily to animal or fungal counterparts where multiple subfamilies of Rho GTPases exist. Since Rho proteins bind to their downstream effector proteins only in their GTP-bound “active” state, the activation of ROPs by upstream factor(s) is a critical step in the regulation of ROP signaling. Therefore, it is critical to examine the input signals that lead to the activation of ROPs. Recent findings showed that the plant hormone auxin is an important signal for the activation of ROPs during pavement cell morphogenesis as well as for other developmental processes. In contrast to auxin, another plant hormone, abscisic acid, negatively regulates ROP signaling. Calcium is another emerging signal in the regulation of ROP signaling. Several lines of evidence indicate that plasma membrane localized-receptor like kinases play a critical role in the transmission of the extracellular signals to intracellular ROP signaling pathways. This review focuses on how these signals impinge upon various direct regulators of ROPs to modulate various plant processes.Rho-like GTPase from plants (ROPs) function as signaling switches that control a wide variety of cellular functions and behaviors including cell morphogenesis, cell division and cell differentiation. The  Arabidopsis thaliana genome encodes 11 ROPs and most of them are associated with the plasma membrane (PM), where they transmit the signal from membrane-localized receptors  which appears to have evolved prior to the divergence of fungal and animal Rac, Rho, and CDC42. The eceptors . Thus thArabidopsis . These cells form a puzzle piece shape with interdigitated lobes and indentations, and their developmental processes are involved in the establishment of multi-polarity within each cell and the coordination of the multi-polarity between adjacent cells. ROP signaling plays a critical role in regulating the formation of both lobes and indentations during PC patterning. ROP2 and ROP4, two functionally overlapping ROPs, promote the lobe growth by activating the ROP-interactive CRIB motif containing protein 4 (RIC4)-mediated accumulation of fine cortical actin microfilaments (MFs). On the other hand, ROP2 and ROP4 inactivate ROP-interactive CRIB motif containing protein 1 (RIC1)-mediated microtubule (MT) bundling by disrupting its RIC1-association with cortical MTs , which regulate auxin-mediated gene expression in the nucleus. Instead, it was shown that activation of ROP2 and ROP6 by auxin requires AUXIN BINDING PROTEIN1 (ABP1). ABP1 is a 22-kDa glycoprotein, carrying the endoplasmic reticulum (ER) retention signal KDEL sequence and was implicated as an extracellular auxin receptor for the regulation of rapid auxin responses such as auxin promotion of cell expansion  in the auxin binding-pocket, or an inducible ABP1 antisense line were not rescued by auxin, suggesting that ROP2 and ROP6 signaling is regulated downstream of ABP1 . Genetic analysis further revealed that ROP6/RIC1 act downstream of ABP1 to regulate clathrin-dependent endocytosis . The SPK1-ROP6-RIC1 signaling pathway was demonstrated to regulate PIN2 distribution through the regulation of clathrin-dependent endocytosis in roots. It will be interesting to determine whether TMKs are also involved in ROP signaling downstream of auxin that inhibits PIN endocytosis in roots.The regulation of ROP signaling by extracellular auxin appears to be a common signaling mechanism in plants. Apoplastic ABP1 promotes clathrin-dependent endocytosis, which leads to PIN internalization in roots. Auxin binding to ABP1 inhibits the positive action of ABP1 in endocytosis  form of ROP2 preferentially binds to FER. These data suggest that FER is an upstream receptor of ROP signaling in the auxin-dependent root hair development. FER activates NADPH oxidase-dependent production of reactive oxygen species (ROS), which is a second messenger for polar growth  form of ROP2, ROP4, and ROP6 induced isotropic growth and elongation of root hair cells, whereas the dominant-negative (DN) form of ROP2 inhibited the tip growth of root hair  identifir growth . It woult manner . Both auchannels . Since i pH pHi; , ABP1-TMArabidopsis ROP1, a pollen-specific member of ROPs, is the central regulator of pollen tube tip growth. The active ROP1 protein is localized in the apical cap of the PM of pollen tubes as an apical cap, corresponding to the expanding region (REN1 (ROP1 enhancer 1) encodes a Rho GTPase-activating protein (RhoGAP), which confines ROP1 activity to the tip of pollen tube. REN1 localizes in vesicles that accumulate in the apex of pollen tubes and at the PM of pollen tube tip, where ROP1 is activated. It was reported that ROP1 function is required for both the localization and the function of REN1, indicating that both spatial distribution and function of REN1 are downstream of ROP1 signaling  were discovered  is tightly associated with the coordination of asymmetric cell division. Stomatal complexes consist of a pair of guard cells flanked by a pair of subsidiary cells that regulate the function of guard cells. At first, guard mother cell (GMC), which eventually produces the guard cell pair, is formed by asymmetric cell division. Before formation of a guard cell pair, the nuclei of subsidiary mother cells (SMCs), which are lateral neighbors of GMC, are polarized toward GMC as well as forming a cortical F-actin patch at the boundaries between GMC and SMCs. And then the subsequent asymmetric cell division produces the subsidiary cells.The development of stomatal complex in maize , a leucine-rich repeat receptor-like protein with inactive kinase domain, is localized in SMCs and newly formed subsidiary cells at sites of contact with GMCs. PAN1 and actin patches appeared after GMC formation and before nuclear polarization, and PAN1 patches were detectable before actin patches. Thus, PAN1 promotes the premitotic polarization of SMCs by receiving the cue from the GMC rather than intrinsic cues . Given textracts . These dbidopsis . Since tbidopsis , it is tThe phytohormone ABA is a pivotal hormone that is involved in seed germination, plant development, and abiotic stress responses. Several putative ABA receptors including those localized to the PM have been proposed, and biochemical studies have also implied the existence of both cell surface and intracellular ABA receptors. However, only the pyrabactin resistance1 (PYR)/PYR1-like (PYL)/regulatory component of ABA receptor (RCAR) family ABA receptors, which are localized to the cytoplasm or nucleus, have been widely accepted . The ABAROP10 loss of function mutants exhibit hypersensitivity to ABA in root elongation response, and stomatal closure. These mutants also displayed the enhanced seed dormancy, which is regulated by ABA and enhanced responses to ABA inhibition of seed germination. CA-ROP10 and DN-ROP10 mutants exhibited the insensitivity and hypersensitivity to ABA, respectively. The promoter-GUS analysis revealed that the ROP10 promoter activity in root tips is down-regulated by ABA -ROP is conserved among higher plants for acquisition of cell polarity (Table 1). The identification of RLKs or receptor-like proteins that interact with upstream regulators of ROPs like RopGEFs will be critical to further our understanding of ROP-mediated signaling. Another critical facet of RLK-ROP modules regards the roles of the interaction between RLKs and upstream regulators of ROP. Binding of the C terminal region of AtRopGEF12 with AtPRK2a results in the loss of C terminal inhibition of AtRopGEF12 activity and contributes to the activation of downstream ROP signaling in the tip growth of pollen tube (Rho-like GTPase from plants signaling acts downstream of diverse signaling pathways such as auxin, ABA, and cytosolic calcium. Increasing evidence reveals that several ROPs are involved in RLK-mediated signaling. Given the diverse roles of ROP signaling in cellular processes such as actin accumulation, ordering of MTs, calcium concentration, Hbreaking , multipllen tube . In rootlen tube . In PC ilen tube . UnderstThe 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 Human T Lymphotropic Virus type 1 (HTLV-1) subtype C is endemic to central Australia where each of the major sequelae of HTLV-1 infection has been documented in the socially disadvantaged Indigenous population. Nevertheless, available epidemiological information relating to HTLV-1c infection is very limited, risk factors for transmission are unknown and no coordinated program has been implemented to reduce transmission among Indigenous Australians. Identifying risk factors for HTLV-1 infection is essential to direct strategies that could control HTLV-1 transmission.Risk factors for HTLV-1 infection were retrospectively determined for a cohort of Indigenous Australians who were tested for HTLV-1 at Alice Springs Hospital (ASH), 1st January 2000 to 30th June 2013. Demographic details were obtained from the ASH patient management database and the results of tests for sexually transmitted infections (STI) were obtained from the ASH pathology database.Among 1889 Indigenous patients whose HTLV-1 serostatus was known, 635 (33.6 %) were HTLV-1 Western blot positive. Only one of 77 (1.3 %) children tested was HTLV-1 infected. Thereafter, rates progressively increased with age  reaching 48.5 % among men aged 50–64 years. In a multivariable model, increasing age , male gender , residence in the south  or west  of central Australia and previous STI  were associated with HTLV-1 infection. Infection was acquired by three of 351 adults who were tested more than once during the study period  per 100 person-years).This study confirms that HTLV-1 is highly endemic to central Australia. Although childhood infection was documented, HTLV-1 infection in adults was closely associated with increasing age, male gender and STI history. Multiple modes of transmission are therefore likely to contribute to high rates of HTLV-1 infection in the Indigenous Australian population. Future strategies to control HTLV-1 transmission in this population require careful community engagement, cultural understanding and Indigenous leadership. The Human T Lymphotropic Virus type 1 (HTLV-1) is an oncogenic retrovirus that preferentially infects CD4+ T cells . One suc2 , ii) as part of a blood borne virus (BBV) surveillance program among patients receiving haemodialysis  and iii) after enrollment as subjects without current clinical evidence of HTLV-1 associated conditions in HTLV-1 pathogenesis studies . Conditions that are associated with HTLV-1 infection for which HTLV-1 serology is ordered at ASH include haematological malignancies, neurological disorders, strongyloidiasis, chronic lung disease and dermatological conditions. However, the test is most often ordered to accompany strongyloides serology due to concerns that HTLV-1 coinfected patients are more likely to fail therapy and to develop complicated strongyloidiasis -GTCCGGCGCTCCCTTAGAGCC-[BHQ1] labeled with fluorophor FAM and Black Hole Quencher 1.Samples were initially screened at the Royal Darwin Hospital (RDH) or Institut Pasteur, Paris, using the Serodia HTLV-1 particle agglutination assay  and Murex HTLV-I + II test kit . After November 2008, HTLV-1 screening at the RDH was with the Architect rHTLV-I/II assay. HTLV-1 serostatus was then confirmed by Western blot  according to the kit manufacturer’s criteria at the National Serological Reference Laboratory (NRL), Melbourne, or Institut Pasteur, Paris. Attempts were made to confirm HTLV-1 infection for subjects with indeterminate Western blot results using HTLV-1 polymerase chain reaction (PCR) at the NRL. Primers and probes were designed to target a highly conserved 88 bp fragment of the All analyses were performed using Stata software version 13.0 . Comparison of patient characteristics between HTLV-1 infected and HTLV-1 uninfected subjects was performed using chi-squared tests of association, independent t-tests, or Mann-Whitney tests as appropriate. Seropositivity rates among Indigenous patients according to age and gender were calculated using the proportion of patients that tested positive for HTLV-1 within each category. Logistic regression with age category, gender and age category X gender was used to assess the influence of age on the difference in seropositivity rates according to gender. The independent associations between patient demographics and the odds of HTLV-1 infection were assessed using binary logistic regression. In order to assess whether the effects of STI were similar for the 3 different patient groups in our cohort we included a patient group X interaction term in the logistic regression model for HTLV-1 status. The interaction term was non-significant and the associations between STI and HTLV-1 status were similar across the 3 groups. We therefore included all patients in a single model and included a term for group to adjust for the small differences in HTLV-1 prevalence across groups.The proportion of seroconversions amongst those adults tested twice was calculated as a proportion with binomial 95 % confidence intervals. Repeat testing for HTLV-1 infection was ordered when clinically indicated by the treating physician and not as part of any scheduled clinical monitoring program. Duration of follow-up in each case was from the date of the initial negative serological test to the date on which a positive test was recorded.The HTLV-1 serostatus was known for a total of 1889 patients of whom 1254 were HTLV-1 seronegative and 635 were HTLV-1 infected    Fig. .Table 1Dp = 0.01; age, p < 0.001). Men aged 50–64 years were twice more likely than women of similar age to be HTLV-1 infected after adjusting for region, gender and STI history .Rates were lowest among residents of remote communities north of Alice Springs 12.6 %) and highest among those from communities to the south (61.1 %) and west (42.2 %). When compared according to residence type, seropositivity rates were highest among town camp residents of Alice Springs (40.4 %) (Table 2.6 % andp = 0.826). Similarly, there was no difference in rates of infection between these groups after adjusting for age and gender.There were no differences in HTLV-1 seropositivity rates according to the reason for testing Table . SeroposC.trachomatis and N.gonorrhoeae NAAT (Table p < 0.001) (Table There were no differences between HTLV-1 seropositive and seronegative groups in the proportion of patients who tested positive for 1) Table .Among 351 adults who were tested more than once during a total of 1231 years at risk and under observation, two Indigenous women and one man  acquired HTLV-1 infection. The seroconversion rate in this sub-group was therefore 0.24 per 100 person-years (95 % CI = 0.18–2.48). Serodia PA were negative for both women at ages 29 and 51 years, but positive results were subsequently recorded and confirmed by Western blot at 37 and 53 years, respectively. The man was HTLV-1 seronegative by serodia PA when 62 years old. A positive result was recorded two years later at which time a Western blot was indeterminate. He was finally confirmed to be HTLV-1 infected by HTLV-1 PCR at age 65 years. A review of medical records for each case failed to reveal iatrogenic risk factors for acquiring HTLV-1 infection, such as haemodialysis or a history of blood transfusion.Seropositivity rates among women of childbearing age 15–40 years) varied according to their place of residence relative to Alice Springs  . We also2 .Consistent with studies in other endemic areas , 18–23, Sexual transmission is also likely in central Australia. Higher numbers of sexual partners –32 and aWe also document childhood infection, which is likely to be responsible for the cases of ATLL  and infeS.stercoralis coinfected subjects who require closer follow-up. We have previously demonstrated that only 36 % of such patients are HTLV-1 infected and that strongyloides seropositivity is not associated with HTLV-1 serostatus [S.stercoralis in communities with poor sanitation is independent of HTLV-1 infection. Selection bias is also likely to affect our estimate of the number of infants at risk because this was extrapolated from seropositivity rates for hospitalized women of childbearing age, which may over-estimate community-based HTLV-1 prevalence in this group. The number of children at risk of mother-to-child HTLV-1 transmission may therefore be less than our estimate of 297 children over three years or 99 children per year. We are also unable to determine the modes of HTLV-1 transmission for childhood infection or for those adults whose seroconversion was documented later in life. However, the literature suggests that vertical transmission is most likely to account for the former [The retrospective design and hospital-based setting for this study results in a number of limitations. Firstly, our data is derived from a large cohort of hospitalized subjects for whom HTLV-1 serology was most often requested for clinical reasons. The resulting seropositivity rates are therefore subject to selection bias and community-based prevalence may be lower. The absence of any difference in HTLV-1 seropositivity between patients tested for clinical reasons and those who were recruited as asymptomatic controls is likely to reflect the fact that most HTLV-1 tests at ASH are ordered to accompany strongyloides serology . The purrostatus , presumae former , 42, 43 e former , 29, 33.In a hospital-based cohort, we report childhood HTLV-1 infection that is suggestive of mother-to-child transmission, an increased risk of infection among older men that may reflect past cultural practices and document horizontal transmission that is likely to result from sexual contact. Community-based epidemiological studies are now needed to determine the true HTLV-1 prevalence and to define the relative contributions of the various modes of transmission. However, our findings suggest that multiple modes of transmission are likely to contribute to the high prevalence of HTLV-1 infection among Indigenous Australians. The development of any intervention to control HTLV-1 transmission therefore requires careful community engagement, cultural understanding and Indigenous leadership. High seropositivity rates , signifi


In the soil soluble Pi that is readily available for uptake, occurs at very low concentrations  of the phylum Glomeromycota. The fungi efficiently take up phosphate and other mineral nutrients and deliver them to the host, in exchange for carbohydrates. Thereby, arbuscular-mycorrhiza compatible plants have two Pi uptake pathways, which are defined by different sets of phosphate transporters: a direct uptake pathway through the epidermis and root hairs, and a symbiotic uptake pathway for the Pi provided by the fungus  starvation, and to a lesser extent by potassium, calcium or iron starvation  and leads to transcriptional activation of symbiosis-related genes by the transcription factor CYCLOPS  development requires a common set of genes called common SYM genes. Their protein products belong to a signal transduction cascade that is triggered by perception of fungal signals (Myc factors) through receptor-like-kinases  concentrations  and P1BS that are often located close to each other (Karandashov et al., g Figure . Repressi signaling remains to be found. Strigolactone exudation, the DELLA/GA signaling module and the P1BS element-binding transcription factor are excellent candidates for local mediators between nutrient status and AM development in the root. Additionally, the co-occurrence of MYCS and P1BS cis-elements in AM-inducible promoters strongly suggests that Pi starvation signaling and AM signaling are required simultaneously for symbiotic gene expression and consequently colonization (Figure i should help to pinpoint the important regulators and to detangle how plants integrate symbiosis, phytohormone and nutrient signaling to control AM development in function of their nutrient status.In summary, the mechanisms of how AM development is controlled by nutrient signaling are yet elusive. However, circumstantial evidence suggests that control occurs at multiple levels, and includes nutrient, phytohormone and symbiosis as well as systemic and cell-autonomous signaling. The signal operating in systemic shoot-to-root Pn Figure . TransgeThe 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.


Although woody encroachment occurs world-wide, Africa’s tourism and livestock grazing industries may be particularly vulnerable. Forecasts of responses of African wildlife and available grazing biomass to increases in woody cover are thus urgently needed. These predictions are hard to make due to non-linear responses and poorly understood feedback mechanisms between woody cover and other ecological responders, problems further amplified by the lack of long-term and large-scale datasets. We propose that a space-for-time analysis along an existing woody cover gradient overcomes some of these forecasting problems. Here we show, using an existing woody cover gradient (0–65%) across the Kruger National Park, South Africa, that increased woody cover is associated with (i) changed herbivore assemblage composition, (ii) reduced grass biomass, and (iii) reduced fire frequency. Furthermore, although increased woody cover is associated with reduced livestock production, we found indigenous herbivore biomass (excluding elephants) remains unchanged between 20–65% woody cover. This is due to a significant reorganization in the herbivore assemblage composition, mostly as a result of meso-grazers being substituted by browsers at increasing woody cover. Our results suggest that woody encroachment will have cascading consequences for Africa’s grazing systems, fire regimes and iconic wildlife. These effects will pose challenges and require adaptation of livelihoods and industries dependent on conditions currently prevailing.With grasslands and savannas covering 20% of the world’s land surface, accounting for 30–35% of worldwide Net Primary Productivity and supporting hundreds of millions of people, predicting changes in tree/grass systems is priority. Inappropriate land management and rising atmospheric CO Savanna is a unique biome since it covers a wide range of woody cover, yet neither “drifts” towards fully closed canopy forest/thicket, neither does it drift to fully open grassland—savannas maintain a spatially and/or temporally variable tree/grass mix under nearly all conditions of environmental forcing . The exp2), with the current concentration of 390 ppm [2 concentration keeps rising [Woody densification and encroachment occur world-wide and is a common phenomena in savannas . Woody e 390 ppm ,18 highe 390 ppm . It is p 390 ppm ,20,21. Is rising .Although studies documenting shifts in the tree/grass ratio at various spatial and temporal scales are numerous, and our understanding is growing on the mechanisms driving these shifts ,10,20,232 KNP. We employed a “space-for-time” approach in which we compared fire return period, herbaceous biomass, herbivore abundance (separately for each of 12 herbivore species) and herbivore biomass  along a woody cover gradient within two contrasting geological settings. The assumption was that characterizing current patterns across a gradient of existing woody cover conditions (0–65%), with all other conditions kept similar, would allow making predictions as to how the system would respond in future to expected shifts in woody cover to a more dense system . Our approach is analogous to studies exploring changes and trends along an altitudinal and/or rainfall gradient in order to predict how changes in rainfall and/or temperature may influence species distribution and/or migration/movement patterns .2 of semi-arid savanna with the full complement of large mammals indigenous to these African savannas. The rainfall ranges from 350 mm yr-1 in the north to 750 mm yr-1 in the south [The study was conducted in Kruger National Park (KNP), South Africa, which was established as a conservation area in 1902 and proclaimed a national park in 1926. The park covers about 20 000 kmhe south . The areMost of the data used in this project were collected in-house by the managing authority of the Kruger National Park  with the necessary internal approval. Data collected by external researchers were registered and approved by SANParks Scientific Services and Conservation Management and had the necessary permissions and permits for conducting the fieldwork.2), while the eastern sector is predominantly underlain by basalt-derived erosion products (about 5500 km2). The clayey basaltic soils are generally more nutrient rich than the sandy granitic soils. The geology of the remainder of the park include rhyolite, gabbro, ecca shale and aeoleon sands , but these cover too small areas with too few data points spread across the woody cover gradient to allow for separate analysis.Geological maps were used to delineate the park into different geological landscapes . GraniteThe woody cover map was generated by calibrating 73 field points (collected in 2006) with four Landsat ETM+ scenes (collected in 2000 and 2001) and eleven JERS-1 Synthetic Aperture Radar (SAR) scenes (collected in 1995–1996). The field plots (250m x 250m) were laid out to cover the rainfall gradient and main geology of the park and to represent the range of woody cover existing in the park. At each plot woody canopy cover  was estimated using a hand-held spherical densitometer. The cover for each plot was estimated by averaging 30 measurements collected on a regular grid. The plot measurements were then used to calibrate a multiple regression model between the remote sensing data  (predictor variables), and the field collected woody cover (response variable). The best predictive model was selected from the models containing all the possible variable combinations using the Akaike information criterion (AIC). The best model was then used to extrapolate woody cover across the entire park at a 90m resolution using the remote sensing variables. The model predictions were validated using an independent Light Detection and Ranging (LiDAR) dataset obtained from the Carnegie Airborne Observatory in 2008 (see  and has 2 co-kriged interpolated surface of average herbaceous biomass. This interpolation employed average long-term field-collected disc-pasture meter herbaceous biomass as primary variable and vegetation indices derived from satellite imagery as secondary variable. Herbaceous biomass was measured each year between 1989–2005 at more than 500 plots spread throughout the park. Plots were 50m x 60m and 100 disc pasture meter measurements were collected on transects within each plot. Disc-pasture meters estimate herbaceous biomass by measuring the height a disc of standardised dimensions is obstructed from the ground (by the herbaceous layer) when dropped from a fixed height (i.e. the height relates to the herbaceous biomass under the disc). The 100 height measurements at each plot were then averaged before using a calibration equation specific to Kruger National Park to convert height (cm) into herbaceous biomass (kg.ha-1) [2 NDVI metrics derived from AVHRR imagery (employing 19 673 grid cells). This co-kriged herbaceous biomass surface is described in more detail in [We used a 1 kmkg.ha-1) . The annetail in  and has etail in ,34 and fetail in .KNP has kept extensive records of fire scars, resulting in a spatially explicit fire scar history since 1941  between 1987–1993 to estimate long-term average herbivore density, biomass and diversity. The aerial census data consists of herbivore counts mapped from a fixed-wing aircraft flying regularly spaced strip transects covering the park from north to south. The aerial census dataset is described in detail in . AlthougFor twelve herbivore species the survey data were of high quality and are included in the analysis . Due to -2) for each species. Secondly, Total Herbivore Biomass (THB) (kg.km-2) was estimated by adding the biomass of all the herbivore species occurring in the same grid cell, and was calculated as follows (for each 1 km2 grid cell):Three herbivore variables were derived from the aerial survey data explained above. Firstly, average herbivore density was calculated by averaging aerial herbivore counts observed between 1987–1993 to estimate the average herbivore density .2 pixel.Thirdly, based on the average abundance of the 12 herbivore species listed in 2 in order to do regression analysis between the series of overlaid grids. As such, the woody cover grid was linearly regressed with the three herbivore variable grids outlined in the previous section  to determine how these variables change along a woody cover gradient. The relationships between woody cover and all the variables were also visually presented as line graphs by averaging the parameters in woody cover bins of 5% increments. All spatial analyses were conducted in ArcMap (ver. 9.2) and its extensions and statistical analysis in Statistica (version 11).All datasets described above were re-sampled to a common grid of 1 kmHerbaceous biomass decreases and fire return period increases with increasing woody cover . These pEquus burchellii, blue wildebeest–Connochaetus taurinus, sable antelope–Hippotragus niger, roan antelope–H. equinus, tsessebe–Damaliscus lunatus) as well as one of the mixed feeding species (common eland–Tragelaphus oryx) decrease along the woody cover gradient, whilst the two browsing species  and a mixed feeding species that mostly browse in the dry season  [-2) compared to granites (0.150 ind.km-2), we focused on the trend on the granites as a more reliable indicator of sable’s tendency to decrease with increasing woody cover). Buffalo (Syncerus caffer), white rhinoceros (Ceratotherium simum) and waterbuck (Kobus ellipsiprymnus) showed no consistent trends along the woody gradient on the two geological landscapes (The five meso-grazer species (plains zebra–elampus)  increasendscapes ; Fig 2.When all species are combined the average Total Herbivore Biomass (THB) remains constant between 20–65% woody cover in both geological landscapes THB: . As specSyncerus caffer) and white rhinoceros (Ceratotherium simum), as well as the strong water association of waterbuck (Kobus ellipsiprymnus) [As hypothesized, browser densities increase as woody cover increases, whilst most meso-grazer densities decrease along the same gradient. Our results also clearly illustrates that this is most probably due to changed forage availability with herbaceous biomass decreasing as woody cover increases. To our knowledge these patterns have not been demonstrated previously over a woody cover gradient spanning most of the dynamic range typical of savannas (0–65%) (cf. ) or baseprymnus)  introducprymnus) ). These prymnus) ), and asOur most unexpected, and in our opinion most insightful finding, was that even though we observed statistically significant directional increases or decreases along the woody cover gradient for most of the individual herbivore species (as described above), these species balance each other out, almost “kilogram for kilogram”, along the woody cover gradient. This is even more remarkable considering the wide range of average body mass between the species  are at, or close to, all-time highs since population estimates started in the 1960s in Kruger National Park, yet species preferring more open landscapes  are at or close to all-time low population estimates . Various causes, including artificial water provision, predation [2 since the 1950s) may be another explanatory factor, possibly interacting with some of these other system changes, to be considered.In summary, our results predict that if woody densification continues due to inappropriate landuse practises and increasing atmospheric COredation  and climredation  have beeDichrostachys cinerea), and as such an area exposed to woody densification may have a different composition and vertical structure compared to an area of similar woody cover where cover is naturally high and not due to the process of woody densification. A second potential limitation of our study is the time stamps of our datasets that are variable. However, we do not consider this a major concern, as there is no indication that the long-term fire return period, herbaceous biomass and herbivore distribution patterns have changed considerably  over the study period . Also, changed; . We therOur results provide empirical support for various hypotheses that were previously posed, but that largely remained untested at large spatial scales. As such, our results predict that the increases in woody cover observed and forecasted for African savannas may have wide-ranging impact on various patterns and processes at the regional scale  as well as the global scale . These changes may have cascading effects on atmospheric cycles, biodiversity, tourism, the livestock industry and subsistence livelihoods, and it will require novel ideas to counter or adjust to these changes  . Conside


It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts NER.The melanocortin 1 receptor (MC1R) is a melanocytic G The melanocortin (MC) receptor family is the smallest member of the class A (rhodopsin-like) family of G-protein coupled receptors (GPCRs)  and consextension locus extension locus display a reddish blonde coat color instead of the darkly pigmented black coat color typically found on the C57BL/6 background, thus providing the first genetic evidence that MC1R may play an important role in the regulation of pigment . Unique to the MC receptor subfamily compared to other GPCRs is the lack of one or two cysteines in the first and second extracellular domains and lack of proline in the fourth and fifth TM domains  domains with a DRY motif at the junction of the third TM domain, an intracellular C-terminus with a palmitoylation site, and an extracellular N-terminus with an N-linked glycosylation site   functions both for ligand affinity . A pentapeptide present on the C-terminal tail contains the invariant tripeptide sequence T314, C315, and W317 present in all MC receptors. The pentapeptide, and specifically the invariant tripeptide, are required for translocation of the receptor to the plasma membrane  and have conserved sequences found across many MC receptors. MC1R els are small compared to most GPCRs but are critical for basal constitutive signaling activity  are found between the transmembrane regions . Six mutations have been reported in il1, four of which cause a loss of signaling function . In melanocytes, increased cAMP levels lead to a host of downstream signaling events including activation of effector proteins such as cAMP-dependent protein kinase (PKA)  . In thisse (PKA)  and resise (PKA) . The disse (PKA) . MC1R, lse (PKA) . This hase (PKA)  and murise (PKA) , human Mse (PKA) . Geneticactivity .There are two major types of pigment present in the skin, the darkly pigmented eumelanin and the red/yellow sulfated pheomelanin. Eumelanin is chemically inert and is highly photoprotective by absorbing UV radiation  and oxidFigure 3)  . The firigure 3) . Pheomeligure 3) , the preextension locus . Mice with the recessive yellow mutation (mutation of the extension locus) produce a non-functional MC1R and exhibit a blonde pheomelanotic coat color as a result (somber (constitutive active receptor) or tobacco (hyperactive receptor) mutation is associated with an increase in eumelanin synthesis and a darker coat color  inhibiting which diminishes basal Mc1r activity  phenotype . Individa result . Conversat color  althoughactivity .The ability of the skin to respond to UV radiation by increasing melanin production is dependent on the functionality of MC1R. The adaptive pigmentation pathway represents a major innate protective mechanism by which the skin prevents further damage from ultraviolet radiation and is dependent upon MC1R signaling. UV radiation causes DNA damage to keratinocytes in the epidermis of the skin and the subsequent increased expression of the POMC protein in a p53 dependent manner . CleavagBesides its role in regulating melanocyte pigment production, MC1R is a critical determinant of cellular genome maintenance pathways . MelanocNucleotide excision repair is the major genome maintenance pathway by which cells remove bulky DNA lesions that distort the DNA double helical structure including UV induced photoproducts . The NER pathway involves the coordinated action of multiple factors that recognize, excise, and repair damaged nucleotides. There are two types of NER - global genome nucleotide excision repair (GG-NER) and transcription coupled nucleotide excision repair (TC-NER). They differ in the initial stages of damage recognition, ultimately converging on a common repair pathway. TC-NER is invoked when transcription is stalled by nucleotide lesions in actively transcribed genes , 2001. TFigure 5)  . cAMP siigure 5) , and repigure 5) .Although it has been known for a decade that MC1R signaling accelerates NER kinetics , the molRecently, we reported that enhancement of NER by cAMP is dependent on a post-translational modification of ATR protein. Specifically, we found that MC1R stimulation by melanocortins or pharmacological cAMP induction caused PKA to phosphorylate ATR at S435. This event promoted enhanced binding to the NER factor XPA in the nucleus and together pS435-ATR and XPA localized to UV photodamage in an accelerated and robust manner. Without PKA-mediated phosphorylation of ATR on S435, we observed no enhancement of NER in melanocytes. Therefore we concluded that MC1R signaling regulates genomic stability through this ATR-dependent mechanism . In subsActivation of MC1R has also been shown to facilitate repair via an increase in DNA damage response proteins. Treatment with α-MSH leads to an increase in XPC and γH2AX levels promoting formation of DNA repair complexes in primary human melanocytes . There iFigure 6). The major melanocortin for MC1R, α-MSH, functions to increase cAMP levels after binding to MC1R whereas binding of ASIP to MC1R competes with α-MSH binding to prevent melanocortin activation and results in a decrease in basal cAMP levels. Binding of βD3 to MC1R does not affect basal cAMP levels, however, it functions as a competitive inhibitor and interferes with binding of either α-MSH or ASIP.Melanocortin 1 receptor signaling is complex and dynamic, with signaling heavily influenced by receptor interactions with melanocortins, agouti signaling protein (ASIP), or β-defensin 3 (βD3). Melanocortins enhance MC1R signaling, ASIP inhibits MC1R signaling directly, and the neutral antagonist βD3 blunts melanocortin-induced signaling by competing with MC1R agonists for MC1R binding , and each has varying receptor binding affinities across the MC family. The POMC gene contains three exons and two introns with the bioactive peptides present in exon 3 . Melanocortins are derived as cleavage products of the pro-opiomelanocortin (POMC) protein  , a dominant gain of function mutation resulting in ectopic and ubiquitous ASP expression, have a yellow/blonde coat color and are obese with hyperinsulinemia due to binding of the overexpressed ASP to MC4R  are associated with eumelanotic phenotypes similar to that seen in either a mutation causing loss of function Agouti mutations or a gain of function Mc1r mutation , βD3 functioned as a weak agonist and promoted cAMP accumulation and MAP kinase activation . However to MC1R . Similar to MC1R . Thus mo to MC1R .MC1R gene is a highly polymorphic genetic locus and inherited defects in MC1R function are common among fair-skinned, UV-sensitive and melanoma-prone persons. Indeed, there may be up to 6–8 million Americans harboring double allele polymorphisms and millions more being hemizygous for MC1R (Mc1r-defective C57BL/6 animals and protected the skin against UV damage (The for MC1R . IndividV damage . SimilarV damage . These pV damage , but theTaking into account the abundance of data linking MC1R function to the vigor of melanocytic UV physiologic responses, it is clear that the MSH-MC1R signaling axis represents a critical innate UV-protective mechanism in the skin. Whereas its importance was first appreciated based on its contribution to melanin biosynthesis, more recent studies have documented a direct link between cAMP signaling and melanocyte genomic stability. It is now well-established that melanoma ranks among the highest of human tumors with respect to somatic mutational load  and thatEMW and MCB wrote the review article along with JAD who helped write and edit the manuscript and figures.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.


Primate T-lymphotropic virus species comprise four members (HTLV-1 to -4) that have been discovered in human. Only the HTLV-1 infection leads to adult T-cell leukemia/lymphoma (ATLL). All the four viruses share a similar genomic organization and encode transforming Tax oncoproteins. In contrast to HTLV-2 and 4, HTLV-1 and 3 Tax proteins contain a PSD-95/Drosophila Discs Large/Zona Occludens-I (PDZ) binding motif at their C-terminal that has been shown to play crucial roles in the distinct transforming properties of the Tax proteins.Here, we used a collection of human full-length protein-coding open reading frames (ORFeome v3.1) to identify novel PDZ domain containing proteins that specifically interact with HTLV-1 Tax. Novel Tax interactors include syntenin-1 and -2, LNX2, DVL3, GIPC2, INTU, PDLIM4 and -7, RADIL and RGS3. These proteins are involved in diverse biological processes including cell division, cell fate determination, and cell survival. We further characterized interaction between Tax and syntenins and showed that, FJ9 a small molecule able to disrupt Tax/PDZ interactions, could antagonize Tax-transformation activity in a Rat-1 model.Our study identify novel PDZ-containing proteins interacting with HTLV-1 Tax and provides the first example where Tax protein-protein interactions with PDZ containing proteins and Tax-transformation capacity could be inhibited by a small molecule.


Northeast of Iran is a new endemic. Area for HTLV-1 and for the first time. Farid and his Immunology Dep at Mashhad University published paper and then Farid and safae in Aids research and human Retro virology volt 12 November 12 1996. Published prevalence of HTLV-1 in Iran several. Publication describes the prevalence of HTLV-1 in Jewish individuals born in city of Mashhad Iran. Then we reported serological and generic studies in the non Jewish population of Mashhad as well as Neishabour. Seropositive rate of HTLV-1 in Mashhad is 3.0% (21of 694). DNA sequence were amplified by PCR directly from the fresh PRMCs of seropositive individuals from Mashhad. Phylogenetic analysis of the viral DNA sequence indicated that HTLV-1 in Mashhad belong to the cosmopolite clade. ATL and HAM/TSP is common in the northeast of Iran.