N = 224) indicated significantly higher self-rated physical aptitude for prototypically strength-related activities  in a random sample of Smiths. The counterpart effect (higher aptitude for dexterity-related activities among Tailors) was directionally correct, but not significant, and Tailor-Smith differences in basic physique variables were nil. Study 2 examined two large total-population-of-interest datasets  of men’s national high-score lists for track-and-field events requiring different physiques. In both datasets, proportions of Smiths significantly increased from light-stature over medium-stature to heavy-stature sports categories. The predicted counterpart effect  was not supported. Related prior findings, the viability of possible alternative interpretations of the evidence , and directions for further inquiry are discussed in conclusion.Combined heredity of surnames and physique, coupled with past marriage patterns and trade-specific physical aptitude and selection factors, may have led to differential assortment of bodily characteristics among present-day men with specific trade-reflecting surnames (Tailor vs. Smith). Two studies reported here were partially consistent with this genetic-social hypothesis, first proposed by Bäumler (1980). Study 1 ( Readers of fiction will be well aware that some novelists and playwrights expend considerable artistic efforts on the naming of their characters. In literature, character names are often symbolic, meaningful, and semantically laden, rather than random, neutral, or irrelevant . Oftentiwere tailors, just as Smiths once were blacksmiths). For example, initially observed social status differences in English surnames, as evident from medieval sources, appear to have been persisted over centuries . In Bäumler 14], wherwww.oelv.at/lists), and for UK athletics rankings (www.thepowerof10.info). Occurrences of surnames Tailor and Smith (in the respective language of the country) in these high-score lists were determined. Spelling variants and appearance of these surnames in double surnames or as constituents of composite surnames  were included as well. The lists totalled 7001 entries for Austria and Germany , whilst 20532  and with institutional guidelines of the School of Psychology, University of Vienna. Study 2 comprised analyses of publicly accessible sports statistics and, as such, according to national laws (Austrian Universities Act 2002), was exempt from formal ethical approval. The Study 2 data are displayed in From , we adopAccording to the hypothesis of Bäumler , the freLater, in , configuFinally, in , medium-r(2)×c, wherein the two rows (r) constitute binary responses (events vs. non-events) and the columns (c) are groups ordered in some way . The Cochran-Armitage trend test has high power to detect a linear trend in the proportion of events to increase or decrease across the ordered groups. In our application of the test, the target surname proportions constitute the events recorded in the binary response variable  and the sports categories constitute the ordered groups (ranging from light-stature over medium-stature to heavy-stature sports). Analyses were conducted in StatXact v4.0.1 (Cytel Inc.) [p values (two-tailed) and confidence intervals for the trend parameter  because of the low target surname rates and unequal frequencies across sport-type cells in the contingency tables analyzed  . We repoanalyzed . Even wip values .p = .066) in this first, smaller, of the two studies [p = .029) only in the second, larger one [Study 2 results and reanalyses of prior studies , 14 are  studies , 14, beip = .000007) than any other effect emerging in the four samples compared here.Conversely, both Study 2 datasets did not show decreasing proportions of Tailors from light-stature to medium-stature to heavy-stature sports, a finding inconsistent with the hypothesis of Bäumler  and the In two studies, we tested the genetic-social hypothesis of differential assortment of somatotypes on Tailor vs. Smith surnames , 13 withStudy 1 showed higher physical-aptitude self-ratings for dexterity-related activities  among Tailors, as well as corresponding higher ratings for strength-related activities among Smiths. However, while these effect were hypothesis consonant, both were small and only the latter significant. In contrast to Bäumler , we obseStudy 1 was commensurate to the sample of Bäumler  and thusIt is also interesting to note that, taking Studies 1 and 2 together, we generally seem to have replicated the predicted effects for namebearers Smiths, but not the corresponding effects for namebearers Tailors. One conceivable explanation for this distinction could be that physical occupational premises are more clearly delineated for blacksmiths (strength and gross-motor skills) than for tailors (marked strength not needed), whilst fine-motor skills certainly are necessary for both trades. Given this conjecture is viable, it would point to one inherent conceptual difficulty of the hypothesis of Bäumler , becauseOne additional idea for interpretation of the apparently stronger association of strength and gross-motor skills with the surname Smith, as compared to any true association of dexterity and fine-motor skills with the surname Tailor, could be found in differential opportunities in assortative mating. That is, the namebearers Smith may have been more likely endogamous than the namebearers Tailor, perhaps due to their greater numbers in the population (see the different population figures in our Study 1), which, in turn, would result in larger phenotypic effects. Relatedly, it is obvious that the blacksmith occupation, due to differences in the equipment needed to work in this trade, always was more place bound than the tailor occupation. In a similar vein, such differences in the degree of sedentariness may have resulted in more pronounced patterns of endogamy and assortative mating and, in turn, in larger phenotypic effects among namebearers Smith.An alternative, entirely different , and superordinate interpretation of the prior , 14 and Vis-à-vis the hypothesis of Bäumler [Applied to our topic, this could then mean that Smiths, merely because of their surname, would feel more inclined to weight-train, be preferentially drawn into heavy-physique, strength-related sports, and so forth.  Bäumler , the relNeither Bäumler’s studies , 13, 14 We envisage a number of additional, not mutually exclusive, ideas for fruitfully advancing this line of inquiry. These include: tests of further candidate surnames ; generalFinally, bearing in mind that all general population tests so far were survey-based self-reports, it would be interesting to assess fine-motor vs. gross-motor skills and physique variables directly, although implementing the sampling frames (solely based on participants’ surnames) needed for such lab studies might be challenging. In any event, the present studies suggest that further work is necessary before firm conclusions can be drawn about Bäumler’s genetic-social hypothesis  of diffeS1 Dataset(SAV)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.


Childhood maltreatment is considered an important risk factor for the development of major depression. Research indicates an association between childhood adversity and altered emotion processing. Depression is characterized by mood-congruent cognitive biases, which play a crucial role in symptom persistence and recurrence. However, whether attentional biases in adult major depression are associated with experienced childhood neglect or abuse remains unclear.A sample of 45 patients suffering from major depression were recruited to examine correlations between maltreatment experienced during childhood and attentional biases to sad and happy facial expressions. Attention allocation was assessed using the dot-probe task and a history of childhood maltreatment was measured by means of the 25-item Childhood Trauma Questionnaire (CTQ).Our results indicate an association between childhood maltreatment and sustained attention toward sad facial expressions. This relationship was not confounded by severity of symptoms, age, verbal intelligence or more recent stressful experiences.Our findings confirm the hypothesis that a mood-congruent bias in emotion processing observed in major depression is related to early traumatic experiences.The online version of this article (doi:10.1186/s12888-015-0501-2) contains supplementary material, which is available to authorized users. Adversity and maltreatment during childhood and adolescence include forms of psychological and physical abuse, such as verbal humiliation, hostility against the child, rejection, or physical beatings, as well as sexual abuse and emotional and physical neglect , 2. PrioEvidence for an association between clinical depression and early emotional abuse seems to be more consistent than for relations with physical and sexual abuse , 7. HoweA history of childhood maltreatment seems to moderate higher amygdala reactivity in MDD . PhysicaOnly few psychological studies investigated effects of child maltreatment on processing of emotional cues. Healthy children and adults exposed to maltreatment exhibited a greater sensitivity in detecting threatening cues from emotionally ambiguous faces , 41, butHowever, depression is characterized by attentional biases to emotionally congruent stimuli such as sad faces or depression-related words , 45. FurIn general, the contradictory results for attentional biases to facial emotions as a function of childhood maltreatment might be explained by strong variations in sample characteristics such as age and psychopathological status and differences in terms of the experimental tasks. Several of the aforementioned studies used long stimulus presentation times whereas other studies administered rather short ones. In depression, there is growing evidence for attentional biases for long stimulus presentation durations , 47, 48.In our study, we examined attentional biases in response to sad and happy facial expressions as a function of childhood maltreatment in individuals suffering from MDD. To our knowledge, no previous study explored relations between child maltreatment and biased attention in adult depression. We administered the dot-probe task and a questionnaire to assess early childhood experiences to an inpatient group. We expected patients reporting childhood maltreatment to exhibit a stronger attentional bias toward sad faces independent of their symptom severity. In line with findings indicating an attentional avoidance of positive stimuli in depressed patients , we expeOur participants were 45 inpatients  recruited from a treatment program of the Department for Psychosomatic Medicine and Psychotherapy of the University of Leipzig. Age of participants ranged between 19 and 55 years. Demographic, questionnaire and clinical sample characteristics are presented in Table The Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I)  was admiPatients’ verbal intelligence was assessed by means of the Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B), a multiple choice test using artificial and existent vocabulary of the German language .The study was approved by the local ethics committee of the University of Leipzig. After a detailed explanation of the study, written informed consent was obtained from all participants and they received financial compensation after completion of all tasks.Following the SCID-I and HAMD interview during the first session, patients who met inclusion criteria were scheduled for the second experimental session within one week. . During the second session, participants completed the self-report questionnaires and afterwards the computer-based dot-probe task.The dot-probe task was administered to assess patients’ attentional biases to sad and happy facial expressions. Stimuli for the dot-probe task were colored photographs of 40 actors  depicting happy, sad and neutral facial expressions. Pictures were obtained from the Karolinska Directed Emotional Face database (KDEF) . At the Each trial of the dot-probe task began with a fixation cross presented for 500 ms in the center of the screen. It was followed by the paired photographs. After 1000 ms both pictures disappeared and were replaced by an asterisk appearing either on the left or right position of the face photographs. For each emotion (sad and happy) the asterisk substituted the emotional and neutral face with equal frequency. Participants were instructed to indicate the position of the asterisk (left vs. right) as quickly as possible by a button press on a keyboard. Therefore, the left and right index fingers were used. The asterisk remained on the screen until a response was given. The inter-trial interval was 1000 ms.Trials with response errors (1.6 %) and reaction times below 100 ms and greater than 1000 ms (0.6 %) were excluded from analyses. Using the equation of Mogg et al. , attentiZ was computed using formulas provided by Lee and Preacher [Pearson product–moment correlations were conducted to examine associations between the CTQ scales and attentional bias scores separately for happy and sad facial expressions. To assess possible differences in the strength of correlations between biases and CTQ subscales, Steiger’s Preacher .ps > .13). Thus, we did not include gender, comorbidity and medication status as predictors in the hierarchical regression model. To account for multiple testing a conservative significance level of p ≤ .01 was used for correlation and regression analyses and computations of Steiger’s Z.A set of subsequent two-stage hierarchical regression analyses was calculated with attentional bias as dependent variable. This method was chosen to control for potential modulatory effects of illness severity, current anxiety level, verbal intelligence, age and recent stressful experiences on the relationship between childhood maltreatment and attentional biases. Therefore, scores of the BDI, HAMD, BAI, MWT-B, PSS and LTE-Q, as well as age were entered as predictors in the first step of the regression model to regress out their possible influence on attentional biases. In a second step, the scales of the CTQ were entered as predictors of interest. Hierarchical regression analyses were calculated only for those CTQ scales showing significant associations with attentional bias scores in the previous correlation analyses. For all scales of the CTQ and attentional bias scores there were no differences between men and women, no differences in medicated compared to unmedicated patients and no differences between depressed patients with and without comorbid diagnoses .Correlation analyses yielded a positive association between the total CTQ score and attentional bias toward sad facial expression see Fig. . IndividZ, only the strength of correlation with bias to happy faces and emotional abuse differed significantly from the correlation with physical abuse (p < .01).Furthermore, results indicated marginally significant negative relationships between emotional maltreatment (abuse and neglect) and attentional bias for happy faces. Here, higher scores in both CTQ subscales predicted lower scores in attentional bias to happy faces. Computing Steiger’s r = .14, p = .37 and for HAMD, r = .06, p = .67) nor with attentional bias to happy faces .Notably, severity of depressive symptoms was neither correlated with attentional bias to sad  = 0.46, p = .86). Thus, severity of depression, anxiety, verbal intelligence, age, and recent stressful life events did not predict attentional bias to sad faces. However, entering the total score of the CTQ in the second step did significantly increase the predictive value of the model  = 2.05, p = .07; see Table ΔR2 = .25, p < .01; F = 2.19, p = .05) and physical neglect  = 1.98, p = .08). Both factors of the CTQ enhanced the explained variance in attentional bias to sad faces significantly. Hence, the predictive value of childhood maltreatment for attentional biases toward sad faces remained significant after controlling for the potential influence of symptomatology, verbal intelligence, age, and recent stressful life events. Correlations between attentional bias to sad faces and emotional neglect and between attentional bias to happy faces and emotional maltreatment (abuse and neglect) did not survive correction for multiple testing. Thus, we excluded these CTQ scales from regression analyses.In the first step of hierarchical regression analyses, variance in attentional biases for sad faces was not significantly explained by any predictor (all  .08; F7,4 = 0.46,The aim of our study was to investigate attentional biases to sad and happy facial expressions as a function of childhood maltreatment in individuals suffering from MDD. To our knowledge, this was the first study examining the relations between early adverse experiences and attention to sad and happy faces in adult depression. Hence, we extended previous research on associations between childhood maltreatment and emotion processing biases in healthy individuals –42 and iAccording to hierarchical regression analyses childhood maltreatment is related to attention bias toward sad faces after controlling for possible mediating effects of current depression and anxiety symptoms, verbal intelligence, age, subjectively experienced stress during the past month or the occurrence of stressful life events within the last year. Nevertheless, it is important to note that the majority of patients received antidepressant medication and we could not control for possible influences of different dosages or types of medication on attentional biases. Gibb et al.  found noMood-congruent biases in processing of depression-related stimuli have been repeatedly observed in patients suffering from MDD compared to healthy controls. Negative biases in emotion processing have been discussed as a cognitive vulnerability factor for the development, maintenance, and recurrence of depressive symptoms . Our resNeuroimaging studies have provided evidence for a negatively biased emotion processing in limbic brain regions, such as the amygdala, as a function of early experienced maltreatment –39, 72. Our data also suggest a non-significant trend toward an inverse association between emotional maltreatment and attentional biases to happy faces. This negative relationship denotes an attentional avoidance of positive facial emotions in individuals with a more severe emotional maltreatment history. Two previous studies already documented non-significant trends to avoiding happy faces among abused students , and amoRegarding mood-congruent attentional biases to emotional faces, our study identified a stronger link to emotional maltreatment and physical neglect, rather than to physical or sexual abuse. This finding is in line with the assumption of Rose and Abramson  that parSome further limitations of our study must be noted. Our depressed patients suffered also from comorbid anxiety, somatoform, and eating disorders. We did not find statistical evidence for confounding effects of comorbidity, but these analyses might be underpowered due to our small sample size. Anxiety disorders are frequently coexisting with depression . Our samIn sum, our results provide support for the assumption that mood-congruent biases in emotion processing are associated with traumatic childhood experiences in depression. It has been argued that negative cognitive biases play an important role in the maintenance and recurrence of depressive symptoms and might be relevant for treatment outcome . There i


Large advances in high-throughput sequencing (HTS) technology have allowed for an increased understanding of the role of L1 in human cancer; however, researchers are still limited by the ability to validate potentially rare L1 insertion events detected by HTS that may occur in only a small fraction of tumor cells. Additionally, HTS detection of rare events varies greatly as a function of read depth, and new tools for de novo element discovery are needed to fill in gaps created by HTS.The active human mobile element, long interspersed element 1 (L1) currently populates human genomes in excess of 500,000 copies per haploid genome. Through its mobility via a process called target primed reverse transcription (TPRT), L1 mobilization has resulted in over 100 We have employed droplet digital PCR (ddPCR) to detect rare L1 loci in mosaic human genomes. Our assay allows for the detection of L1 insertions as rare as one cell in every 10,000.ddPCR represents a robust method to be used alongside HTS techniques for detecting, validating and quantitating rare L1 insertion events in tumors and other tissues.The online version of this article (doi:10.1186/s13100-014-0030-4) contains supplementary material, which is available to authorized users. De novo L1 retrotransposition has been responsible for numerous germline diseases, as well as being implicated in tumorigenesis [de novo L1 insertions have been identified in numerous cancer types including lung, colon, prostate, ovarian, and hepatocellular carcinoma through the use of high-throughput sequencing (HTS) technology [The human retrotransposon, long interspersed element 1 (L1) exists in over half a million copies per genome and constitutes 17% of genomic content . These aigenesis ,10,12. Nchnology -11.de novo L1 insertion events detected by HTS in tumors can be problematic [de novo L1 somatic insertions have been reported to be as low as 67% [Because tumors are often heterogeneous in genomic content, discovery and validation of blematic . Validatw as 67% . One expw as 67% ,7,10 butTaq polymerase cleaves the probe, which separates the 5’-fluorescent nucleotide of the probe from the 3’ quencher, generating a fluorescent signal.Droplet digital PCR (ddPCR) has recently emerged as a robust tool to provide precise measurements of nucleic acid target concentrations ,15. In dde novo L1 insertion events [Sequestration of template DNA occurs in ddPCR, such that some droplets contain no copies and others one or more copies of the template target DNA ,16. Idenn events .de novo L1 insertion events in a heterogeneous tumor sample and to quantitate their frequency within an individual tumor sample. Additionally, L1 ddPCR allows heterozygote and homozygote loci to be easily distinguished through parallel detection of a second genomic locus.Due to the high copy number of L1 sequence in the human genome, detection of specific polymorphic loci in a heterogeneous sample by traditional qPCR approaches is particularly difficult due to the high background signal created from nonspecific amplification from templates that do not contain the polymorphic L1. Partitioning of template DNA in ddPCR not only affords a reduction of this nonspecific background due to template dilution, it also allows an accurate determination of the concentration of the polymorphic L1 of interest in the input DNA. In this report, we apply ddPCR technology to the detection of rare L1 elements, allowing detection levels as low as one in every 10,000 cells. Our ddPCR assays incorporate L1 primers and probes that are common to each 5’ or 3’ junction ddPCR and specifically detect the youngest, actively mobile, L1Hs subfamiliy. By using universal L1 5’- and 3’-end primers and probes, paired with locus-specific flanking primers, this L1 detection method will prove useful as a way to rapidly identify de novo L1 insertion events, we designed assays to detect either the 5’- or 3’-insertion junctions at specific genomic loci. The core of each assay is a single primer and probe specific to the youngest L1 subfamily, L1Hs [Taq polymerase. For each experiment, a threshold of fluorescence is set relative to negative controls to measure the quantity of droplets that do or do not contain template target DNA. Through separation of DNA templates for PCR in up to 20,000 droplets and measurement of fluorescence for each droplet at the terminal plateau phase of PCR, ddPCR-based L1 detection is capable of a high degree of discrimination that is not possible with standard TaqMan™ assays [For validation or discovery of ly, L1Hs . One pri™ assays . AdditioBecause they exist in high genomic copy number, L1 elements can contribute to significant background signal in PCR-based assays. In our assay designs, the L1Hs 5’ and 3’ end probes anneal to the same DNA strand as the locus-specific primer in each assay to ensure fluorescent signal is generated by extension of the primer at the L1-occupied chromosomal locus  has proven itself capable of detecting extremely low frequency events . In thisTumor cells undergo constant evolution and produce subclonal populations of cells, each containing different signatures of genomic rearrangements . These cBRAF V600E allele has been previously demonstrated by ddPCR [Detection of rare alleles in the human population such as single-nucleotide polymorphisms, small insertions or deletions, or mobile element polymorphisms allows determination of disease-causing candidate genomic loci through association studies and shows regions of our genome that have been subject to selective pressures ,32. Estaby ddPCR .de novo L1 insertions for a given sample, establishment of a minimum of residual disease detection for a cancer cell-specific L1 insertion, or sampling of pools of human genomic DNA for rare L1 allele detection.Retrotransposition of long interspersed element 1 (L1) in human germline and somatic cells contributes to genomic variation in human populations and is implicated in tumorigenesis. In this study, we designed droplet digital PCR (ddPCR) assays to detect rare L1 insertion events in heterogeneous human genomic DNA samples. Traditional qPCR methods are unable to confidently discern rare target DNA sequences among input DNA as complex as a human genome due to low-chance priming events that cause background signal and lead to false-positive determinations. This effect is exacerbated when the target DNA involves L1 sequence, which occupies approximately 17% of the human genome. Using universal 5’ and 3’ L1 primers and probes in ddPCR, paired with a locus-specific primer near the assayed insertion site, we detected polymorphic L1 5’ and 3’ junctions in genomic DNA from a heterogeneous sample when as few as 0.01% of the cells contained the polymorphic L1. The ability to confidently detect and simultaneously quantify the level of a L1 insertion locus in a mosaic sample, such as tumor biopsy genomic DNA, will allow rapid validation of high-throughput sequencing data on Polymorphic L1 elements were detected from genomic DNA from fibroblast cell lines GM01630, GM01631 and GM01632  using Sequencing Identification and Mapping of Primed L1 Elements (SIMPLE) . These polymorphic elements were previously confirmed by PCR. An identified polymorphic L1Hs locus was selected on the basis of identity to the L1Hs consensus sequence: a Chromosome 15 full-length L1Hs locus , andBsaJI- or BamHI-digested input DNA. Restriction enzyme digestions were done according to manufacturers’ protocol . In the 5’ junction ddPCR assays, 900 nM 5’ L1Hs primer, 900 nM locus-specific primer, and 250 nM 5’ L1Hs probe was used. The 5’ junction ddPCR assays for the Chromosome 15 AC216176 locus included detection of the housekeeping gene RPP30 with 900 nM of each RPP30-specific primer and 250 nM RPP30 probe. Because the two loci are not linked, each droplet has a probability of being positive for either one of the loci, and some droplets will be either negative or positive for both. The relationship between presence/absence of each locus in a droplet is defined by the Poisson distribution and allows robust, digital quantification of the two loci relative to one another. Droplet generation was performed as per the manufacturer’s instructions. Cycling conditions were 95°C for 10 min, followed by 40 cycles of 94°C for 30 seconds and 64°C for two minutes, and then a final 10-min incubation at 98°C. Droplet reading was performed on a QX100 ddPCR droplet reader  for the Chromosome 15 AC216176 locus, a QX200 ddPCR droplet reader  for the other loci tested and analysis was done using QuantaSoft Analysis software .Genomic DNA from fibroblast cell lines was extracted using the DNEasy Blood and Tissue Kit . The 5’ junction ddPCR assays were performed in 20-μL reactions using ddPCR Supermix for Probes  and 150 to 200 ng of BamHI-digested input DNA. In the 3’ junction ddPCR assay of the Chromosome 4 esv4912 polymorphic L1, 900nM of 3’ L1Hs primer, 900nM of locus-specific primer, and 200nM of 3’ L1Hs probe was used. In all other 3’ junction ddPCR assays, 900nM of 3’ L1Hs primer, 4.5 μM of locus-specific primer, and 200nM of 3’ L1Hs probe was used. Droplet generation was performed as per the manufacturer’s instructions. Cycling conditions were 95°C for 10 min, followed by 40 cycles of 94°C for 30 seconds and 64°C for one minute, and then a final 10-min incubation at 98°C. Droplet reading was performed on a QX200 ddPCR droplet reader , and analysis was done using QuantaSoft Analysis software .The 3’ junction ddPCR assays were performed in 20-μL reactions using ddPCR Supermix for Probes (No dUTP)  and 200 ng Genomic DNA from the following cell lines was used: GM01630, GM01631 and GM01632 , Flp-In-293 , HeLa , LoVo , HCT116D (HCT116 derivative with a Flp-In site integrated kindly provided by J. Issa ; denotedFor mixing experiments, cell line genomic DNA positive for a particular L1 insertion was mixed via tenfold dilutions with cell line genomic DNA negative for that particular L1 insertion. Following mixing, dilutions were added at 150 ng to 200 ng per ddPCR reaction as described above.


Brain-derived neurotrophic factor (BDNF) regulates a variety of biological processes predominantly via binding to the transmembrane receptor tyrosine kinase TrkB. It is a potential therapeutic target in numerous neurological, mental and metabolic disorders. However, the lack of efficient means to deliver BDNF into the body imposes an insurmountable hurdle to its clinical application. To address this challenge, we initiated a cell-based drug screening to search for small molecules that act as the TrkB agonist. 7,8-Dihydroxyflavone  is our first reported small molecular TrkB agonist, which has now been extensively validated in various biochemical and cellular systems. Though binding to the extracellular domain of TrkB, 7,8-DHF triggers TrkB dimerization to induce the downstream signaling. Notably, 7,8-DHF is orally bioactive that can penetrate the brain blood barrier (BBB) to exert its neurotrophic activities in the central nervous system. Numerous reports suggest 7,8-DHF processes promising therapeutic efficacy in various animal disease models that are related to deficient BDNF signaling. In this review, we summarize our current knowledge on the binding activity and specificity, structure-activity relationship, pharmacokinetic and metabolism, and the pre-clinical efficacy of 7,8-DHF against some human diseases. Neurotrophins (NT) are growth factors that regulate the development and maintenance of the peripheral and the central nervous systems . It is aBDNF is of particular therapeutic interest because of its neurotrophic actions on a number of neuronal populations including sensory neurons ; motor To search for small molecules that mimic the biological functions of BDNF, we developed a cell-based TrkB receptor-dependent survival assay system, and used it to screen a chemical library via counter screening. The positive hits were then subjected to TrkB activation analysis in primary neurons and receptor binding assays. Finally, we identified two lead compounds: 7,8-dihydroxyflavone and deoxygedunin , 27, whiIn order to identify small molecules that mimic the neurotrophic activities of BDNF, we developed a cell-based survival assay using a cell permeable fluorescent dye MR(DERD)2, which produces red signal upon caspase-3 cleavage in apoptotic cells. TrkB-lacking SN56 cells  and its derived cell line T48 (which is stably transfected with TrkB) were utilized in our assay. We cultured the cells in 96-well plates and pre-incubated the cells with compounds from a library for 30 min, followed by staurosporine (STS) treatment for 9 h. MR(DEVD)2 was introduced to the cells 1 h before examination under fluorescent microscope. The apoptotic cells could be detected by the red signal, while the live cells had no signal. Using this caspase-activated fluorescent dye as a visual assay, we screened thousands of compounds from the Spectrum Collection library. Sixty-six compounds were found to selectively protect T48, but not SN56 cells, from STS-initiated apoptosis, indicating that these compounds might act either directly through TrkB receptor or its downstream signaling effectors. These positive hits were further analyzed on primary hippocampal neurons for TrkB activation and neuronal survival. 7,8-DHF is one of the positive compounds that specifically activate TrkB, but not TrkA or TrkC, at a concentration of 250 nM. It is also a bioavailable chemical that can pass through the BBB to provoke TrkB and its downstream PI3K/Akt and MAPK activation in mouse brain  upon intraperitoneal or oral administration. In addition to cortical and hippocampal neurons, 7,8-DHF also protects other cell types including the RGC  and PC12 cells from excitotoxic and oxidative stress-induced apoptosis and cell death –30. Fitt3H]-labeled 7,8-DHF and purified recombinant TrkB ECD (extracellular domain) proteins. We showed that 7,8-DHF has a Kd of ~320 nM toward TrkB with a binding ratio of 1:1 (ligand versus receptor). Similarly, Biocore Surface Plasmon Resonance (SPR) and fluorescent quenching assay support the notion that 7,8-DHF directly binds to TrkB ECD with Kd about 15.4 nM. As the positive control, BDNF displays a Kd of approximately 1.7 nM. These assays also demonstrated that 7,8-DHF but not 5,7-DHF  interacts with TrkB but not TrkA [To demonstrate that 7,8-DHF indeed is a TrkB specific agonist, we performed in vitro filter binding assay with [not TrkA , a findinot TrkA . UtiliziInternalization of the neurotrophin–Trk complex plays a critical role in signal transduction that initiates cell body responses to target-derived neurotrophins. The neurotrophin–Trk complex is internalized through clathrin-mediated endocytosis, leading to the formation of signaling endosomes , 35. UsiBDNF treatment elicits TrkB receptor ubiquitination and degradation –39. Our Flavonoids are a large group of polyphenolic compounds containing a basic flavan nucleus with two aromatic rings (the A and the B rings) interconnected by a three-carbon-atom heterocyclic ring (the C ring). Flavonoids are divided into several big categories including flavone, flavonol, flavanone, flavanonol, flavans, anthocyanidins and isoflavonoids. 5,7-dihydroxylation is commonly found on the A ring, but 7-hydroxy ring is common in the isoflavonoids subgroups. The B ring generally has 4′-, 3′,4′- or a 3′,4′5′-hydroxylation pattern. Rare flavonoids like 7,8-DHF lack B-ring oxygenation. Flavonoids are the largest and the most diverse class of plant secondary metabolites. These compounds are naturally present in vegetables, fruits, and beverages. Bioflavonoids have been known for a long time to exert diverse biological effects. In particular, they are antioxidants and preventive agents against cancer . AccumulThe widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds  mean that many animals, including humans, ingest significant quantities in their diet. Therefore, we tested a number of commercially available flavonoids for their TrkB agonistic activities. Our preliminary structural-activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. We also found that the 8-hydroxy group in A ring is essential for the TrkB stimulatory effect, as 5,7-DHF, 5,6-DHF and 5,6,7-THF could not activate TrkB. The dihydroxy groups in B ring displays relatively higher TrkB agonistic activity when compared to compounds with dihydroxy groups in A ring. None of the single hydroxy flavone derivatives exhibited notable TrkB stimulatory effect and no trihydroxy flavones or dimethoxy flavones demonstrated any substantial effect .The presence of 4′-position amino group enhances the agonistic effect of 7,8-DHF , which cTo optimize the lead compound and conduct more comprehensive SAR studies, we synthesized dozens of 7,8-DHF derivatives via medicinal chemistry. The first generation of the optimized derivative is 4′-dimethylamino-7,8-DHF, which possesses higher agonistic effect on TrkB than the parental compound 7,8-DHF with longer in vivo activity. Because catechol group containing compounds usually possess poor pharmacokinetic profiles, as a part of our effort to optimize the lead compound 4′-dimethylamino-7,8-DHF, we synthesized numerous bioisoteres of this compound to enhance its biological or physical properties. Replacing the 7,8-dihydroxy groups with imidazole or urea ring in A-ring elevates the TrkB agonistic activity than the lead compound. Since the 4′-dimethylamino group is prone to demethylation during metabolism, we replaced the dimethylamino group with a pyrrolidino or mono-methylamino group to address this potential issue. Several rounds of organic synthesis of 7,8-DHF derivatives have been performed and we have obtained a couple of synthetic benzo-imidazole derivatives displaying EC50 of about 5–10 nM in primary neurons (unpublished data). Their in vivo pharmacokinetic (PK) profiles and oral bioavailability are now under investigation.7,8-DHF treatment did not induce any apparent toxicity in mice. In one of our studies, we compared the pathological changes induced by 7,8-DHF after feeding C57BL/6 mice at 5 mg/kg for 3 weeks. No adverse pathological change was detectable in the drug-treated kidney, liver, lung, muscle, spleen, cortex, hippocampus, heart, intestine and testis . In addi50 >25 μM. CYP inhibition and induction assays reveal that 7,8-DHF has no time-dependent inhibition nor induction on major CYP enzymes. Concur with this result, 12 months chronic treatment or high dose acute treatment with 7,8-DHF suggests that 7,8-DHF is non-toxic to the rodents.To study the 7,8-DHF’s PK profiles, we have performed a panel of in vitro ADMET assays. We found that 7,8-DHF is stable in liver microsomal assay but labile in hepatocytes, indicating that 7,8-DHF might be readily subjected to secondary modification-conjugation. Caco-2 permeability assay, parallel artificial membrane permeability assay (PAMPA) and PAMPA-BBB assays demonstrate that 7,8-DHF possess reasonable absorption rate and is able to penetrate BBB . MDR1-MDIn vivo PK study shows that plasma 7,8-DHF concentration peaks at 10 min with 70 ng/ml, and brain 7,8-DHF also climaxes at 10 min with concentration of 50 ng/g of brain. 7,8-DHF in plasma can still be detected after 8 h (5 ng/ml) after administration. In contrast, only 7 ng/g of 7,8-DHF can be found in brain at 4 h and it is below the quantitative limit at 6 h . Among t1/2 more than 2 h in mouse circulation after oral administration [Catechol containing compounds usually have short in vivo half-life and are prone to be cleared in the circulation system after oxidation, glucoronidation, sulfation or methylation. For instance, Apomorphine is a catechol-containing non-narcotic morphine derivative that acts as a potent dopaminergic agonist. Its metabolism occurs through several enzymatic pathways, including N-demethylation, sulfation, glucuronidation, and catechol-O-methyltransferase as well as by nonenzymatic oxidation . L-DOPA stration . Conceivmax of 1554.9 ng/ml, Tmax of 0.28 h and T1/2 for PO of 2.32 h. Noticeably, 7,8-DHF plasma concentration released from R7  is much higher than orally administrating the same dose of parent 7,8-DHF. The oral bioavailability is increased from 4.6 %  to 84.2 % (R7). Accordingly, the brain exposure for 7,8-DHF is significantly increased by R7 than the parent compound upon oral administration of comparable dosage (unpublished data). TrkB and its downstream p-Akt/p-MAPK signalings are potently activated upon oral administration of R7, which is tightly correlating with 7,8-DHF concentrations in the animal brain. R7-provoked TrkB activation also fits well with the in vivo PK data, underscoring that the released 7,8-DHF from R7 prodrug triggers a long-lasting TrkB signalings in the mouse brain. This prodrug is now under preclinical IND-enabling study for the indication of Alzheimer’s disease.To improve the poor PK profiles intrinsic to catechol-containing molecules, we synthesized numerous prodrugs by modifying 7,8-dihydroxy groups with esters, carbamates or phosphates to improve the oral bioavailability and brain exposure of 7,8-DHF. Currently, an optimal prodrug R7 has been found with favorable in vitro ADMET  characteristics. R7 exhibits approximately 18 % oral bioavailability with CBDNF gene has been shown as a novel potential therapeutic in diverse models related to AD [There is mounting evidence that 7,8-DHF mimics the physiological activities of BDNF and exhibits promising therapeutic efficacy toward various neurological diseases including Parkinson’s disease (PD) , Huntinged to AD . BDNF aled to AD . Thus, tReduced acetylcholine neurotransmission due to loss of neurons in the basal forebrain and depletion of choline acetyltransferase are observed in AD pathology. Currently, there are two types of medication to treat AD: cholinesterase inhibitors and NMDA antagonist. However, these drugs can only delay the inevitable symptomatic progression of the disease without eliminating the main neuropathological hallmarks of the disease (i.e. formation of senile plaques and neurofibrillary tangles) nor rescuing the neuronal loss. 7,8-DHF potently stimulates hippocampal progenitor neurogenesis. For instance, oral administration of 7,8-DHF (5 mg/kg) in wild-type C57BL/6 J mice for a few weeks strongly induces neurogenesis . IntrapeObesity is a metabolic disorder with increasing prevalence worldwide. According to the World Health Organization (WHO), more than 39 % (~1.9 billion) of adults are overweight. Of these, over 600 million (~13 %) are obese in 2014. These numbers have been doubled since 1980. Therefore, developing effective pharmacotherapy to control excess body weight gain is a hot research direction nowadays.ex vivo. These data points to the fact that BDNF is a contraction-inducible protein in skeletal muscle that is capable of enhancing lipid oxidation via activation of AMPK. Thus, BDNF appears to be an active player in both neurobiology and peripheral metabolism [In addition to the neurotrophic activities, BDNF/TrkB signaling also plays a critical role in food intake and body weight control. In rodents, pharmacological treatments with BDNF induce a reduction of food intake, whereas genetic models with reduced BDNF/TrkB signaling display hyperphagia and obesity , 68. Rectabolism .Because BDNF has anti-obesity activity by suppressing food intake, we thus initiated a test to see if 7,8-DHF can be used to prevent the development of obesity. We investigated the effect of 7,8-DHF  on mouse body weight gain under chow diet or high-fat diet (HFD) feeding for 6 months . To our 7,8-DHF is a broadly validated small molecule that imitates the biological functions of BDNF via directly binding to the TrkB ECD to trigger TrkB receptor dimerization and autophosphorylation . It simuFurther investigations on the biochemical and mechanistic natures of 7,8-DHF are also necessary to boost its applications. For instance, the precise molecular details of how 7,8-DHF induces TrkB dimerization and activation are still unclear. For instance, how could 7,8-DHF mimic so many aspects of the physiological activities of the macromolecule BDNF, given that 7,8-DHF is only 254 dalton, which is 1 % of polypeptide hormone BDNF in size? Further, the tyrosine phosphorylated residues on TrkB intracellular domain and their relative abundance are different after BDNF and 7,8-DHF stimulations . What do7,8-dihydroxyflavone is a promising small molecular BDNF mimetic compound, which fully mimics the physiological actions of BDNF from neuronal survival, synpatogenesis, axonal regeneration etc. Notably, it is orally bioactive and is safe for chronic treatment. It has been extensively validated in various BDNFimplicated disease models. Hence, it acts as a good lead compound for further medicinal modification for optimizing its therapeutic efficacy toward various BDNF-mediated human disorders.


Here, we assess the application of various surface modification methods on monolayer graphene sheets grown by chemical vapour deposition to obtain a uniform and pinhole-free ALD HfO2 film with a substantially small CET at a wafer scale. The effects of various surface modifications, such as N-methyl-2-pyrrolidone treatment and introduction of sputtered ZnO and e-beam-evaporated Hf seed layers on monolayer graphene, and the subsequent HfO2 film formation under identical ALD process parameters were systematically evaluated. The nucleation layer provided by the Hf seed layer (which transforms to the HfO2 layer during ALD) resulted in the uniform and conformal deposition of the HfO2 film without damaging the graphene, which is suitable for downscaling the CET. After verifying the feasibility of scaling down the HfO2 thickness to achieve a CET of ~1.5 nm from an array of top-gated metal-oxide-graphene field-effect transistors, we fabricated graphene heterojunction tunnelling transistors with a record-low subthreshold swing value of <60 mV/dec on an 8″ glass wafer.The downscaling of the capacitance equivalent oxide thickness (CET) of a gate dielectric film with a high dielectric constant, such as atomic layer deposited (ALD) HfO However, the crucial inherent limitation of ALD is that the uniform and high-quality film formation is determined by the condition of the exposed surface because the process kinetics is entirely based on the interaction and chemical adsorption of the precursors on the substrate surfacek dielectric films102 plasma11151718192021k dielectric films (mostly Al2O3 and HfO2), which are acceptable for device fabrication. However, to achieve high-performance graphene-based FETs, ultimately, the capacitance equivalent oxide thickness (CET) of a gate dielectric film needs to be downscaled using a HfO2 film with a higher k value than Al2O3, while maintaining a substantially low leakage current. In addition, for large-scale device integration, the CET downscaling is to be realised on graphene grown by chemical vapour deposition (CVD), which is most relevant to large-scale device fabrication.Atomic layer deposition (ALD), which is free of plasma damage and offers precise nanoscale thickness control with outstanding film quality and uniformityRecently, we introduced GSM-TFETs as a novel graphene-semiconductor hybrid device for high- performance and low-power electronics2 film thickness on CVD-grown monolayer graphene and demonstrate the fabrication of high-performance GSM-TFETs with a substantially small CET at the wafer scale. For this, several surface passivation methods, including N-methyl-2-pyrrolidone (NMP) treatment and the introduction of ultrathin sputtered ZnO and e-beam-evaporated Hf seed layers, were evaluated. Through a systematic comparison of the effects of these surface treatments on the subsequent growth of thermal ALD HfO2 films by various characterization techniques, we selected the most promising process of preparing high-quality HfO2 films on the monolayer graphene. Based on this screening process, we obtained scaled HfO2 films of excellent gate dielectric quality with a CET of ~1.5 nm in the MOG-FET structure. Finally, GSM-TFETs with the scaled HfO2 gate dielectric films showing SS values less than ~60 mV/dec were fabricated on an 8″ wafer.In this paper, we report the scaling of the ALD HfO2 films using three different methods i.e. surface treatment using NMP, introduction of ~3-nm-thick seed layers, including sputtered ZnO and e-beam-evaporated Hf films. Here, to demonstrate the influence of the organic solvent residue on graphene, NMP was used for the wet treatment, which was performed on a 2D MoS2 sheet with surface conditions  similar to graphene18171820212/Si substrates) are also included. After preparing all the samples, the ALD was carried out using tetrakis-(ethylmethylamino) hafnium (TEMAHf) and H2O as precursors. We chose a relatively high deposition temperature of 200 °C, which is the lowest temperature within the stable ALD regime of HfO2 with a stable deposition rate  and transmission electron microscopy (TEM), respectively (the sample structures are shown on the right side of 2 film directly deposited on SiO2 without graphene showed a thickness of around 20 nm (as measured by TEM), and conformal deposition without pinholes was observed, as shown in 2 film was deposited on monolayered graphene transferred onto the SiO2 substrate, island growth behaviour appeared, as shown in k films on CVD-grown graphene consisting of a small number of surface nucleation sites such as grain-boundaries, vacancies, and organic residues132 film on graphene, suggesting that the surface properties of graphene may have been altered and a more facile nucleation of the subsequent HfO2 film may have been induced. However, the surface of the HfO2 film became rough with many pinholes (probably because of the unconnected boundaries between the islands), which may eventually provide high leakage current paths across the dielectric film.The surface morphology and cross sectional microstructure of the HfO2 films without boundaries and pinholes were achieved when either sputtered ZnO or e-beam-evaporated Hf served as the seed layer on graphene (see 2/ZnO/graphene and HfO2/Hf/graphene on SiO2) exhibited surface morphologies similar to that of the HfO2 film directly grown on the SiO2/Si substrate. HfO2 films with locally irregular topologies appeared randomly, which could possibly be attributed to the generation of process-induced nanoparticles on the graphene   see . The mea2 films deposited on the graphene surface before and after applying the various surface modification processes, characterizations including X-ray diffractometry (XRD), medium energy ion scattering spectroscopy (MEIS), and X-ray reflectometry (XRR) were carried out. 2 films on different substrates. It is well known that ALD typically produces an amorphous HfO2 film on Si in the ALD regime and crystallization begins at temperatures >500 °C2 films grown on the modified graphene surfaces were amorphous and did not show any diffraction peaks. To compare the quality of the ALD HfO2 films on the various modified graphene surfaces, MEIS was carried out and the spectra were used for simulations to estimate the HfO2 film density [ρ(HfO2)], as summarized in 2 film deposited on SiO2 was ~9.6 g/cm3, which is close to the value shown by bulk HfO22 film was deposited on pristine and NMP-treated graphene, the measured density decreased to ~8.7 g/cm3, presumably because of the incomplete HfO2 film growth, as shown by the SEM and TEM analyses  showing the most conformal HfO2 growth with a high film density . Low-q XRR is a useful technique to estimate i) the layer thickness, ii) surface and interface roughness values, and iii) vertical surface density gradient and layer density of a multilayered structure2 films were uniformly stacked on the graphene substrates with sharp interfaces. To obtain further details, least squares fitting of the reflectivity data was also carried out, as shown in 2/ZnO/graphene/SiO2 sample, the estimated thickness of the HfO2/ZnO stacked layer was around 17.7 nm, including the 14.0-nm-thick HfO2 and 3.7-nm-thick ZnO layers (see Rgraphene = ~2.5 nm) than that of the overlying ZnO layer (RZnO = ~0.76 nm). This increased interface roughness could be attributed to the mechanical deformation of graphene caused by the plasma-induced damage generated during the sputtering of the ZnO seed layer, which in turn formed a nearly uniform ZnO layer anchored on graphene. It is also possible that the ZnO/graphene nanocomposite layer leads to the requirement of a longer incubation time for the ALD of HfO2 because of the local appearance of an inert surface of graphene incorporated in the ZnO seed layer. The densities of each layer in the HfO2/ZnO/graphene/SiO2 structure obtained from the XRR measurements were ρ(HfO2) = 9.6 g/cm3, ρ(ZnO) = 4.6 g/cm3, ρ(graphene) = 2.2 g/cm3, and ρ(SiO2) = 2.7 g/cm3, which are in a reasonable agreement with the bulk values [ρo(HfO2) = 9.68 g/cm3ρo(ZnO) = 4.4 ~ 4.9 g/cm3ρo(graphene/graphite) = 2.2 g/cm3ρo(SiO2) = 2.2 g/cm32 density matches well with the MEIS-derived value listed in 2/ZnO/graphene/SiO2 sample can be uniformly stacked as a separate layer forming a sharp interface with the overlying ALD HfO2 film; however, the underlying graphene layer is geometrically deformed (damaged) because of the subsequent ZnO sputtering.To further compare the integrity of the HfOfer low-q XRR was yers see , which ayers see . The sim2/Hf/graphene/SiO2 sample, the least squares fitting was performed by assuming the seed layer as either a metallic Hf layer (fitting curve in red) or a HfO2 layer (fitting curve in green), as shown in 2, which verifies that the deposited Hf seed layer was mostly converted to HfO2. The thickness, density, and roughness values of the HfO2 and graphene layers were extracted from the best fit curve and are summarized in 2 film , G (~1587.8 cm−1), and 2D (~2694.6 cm−1) peaks. Both the shape of the 2D peak and its higher intensity (I2D) than the G peak (IG) with a low intensity D peak confirm that the synthesised graphene is a monolayer and is of high quality2 films were deposited on the pristine, NMP-treated, and Hf-seeded graphene monolayers, the Raman spectra were quite similar to that of the sample without any surface treatment, except for the appearance of additional peak features as shoulders on the G peak [denoted as Y and D′ peaks in 2 film was only achieved by the introduction of the ZnO and Hf seed layers. However, in the case of the ZnO-seeded sample, all the graphene-related Raman features were completely removed, as shown in Raman spectroscopy is one of the most widely used techniques for assessing the quality of graphene and its possible interaction with adjacent layers. In this study, we carried out Raman spectroscopy on the various samples at room temperature to analyse the effects of surface passivation and the subsequent ALD of HfOgraphene . The mai2/Hf seed layer and the graphene layer. First, a D′ peak  and Y peak  appear as shoulders on the G peak, as shown in −1) and widening (>22 cm−1) in comparison to the peak shown by pristine graphene on SiO2, as shown in 2/Hf-seed layer and the graphene layer. The 2D peak shift and widening can be attributed to either carrier density modulation induced by a charge transfer or the introduction of mechanical strain by an additional seed layerP2D) is larger than the G peak shift (ΔPG), the strain effect is dominantP2D < ΔPG, the charge carrier density modulation effect is the main factor causing the peak shiftP2D (~13.5 cm−1) is much larger than ΔPG (~5.5 cm−1), suggesting a strong strain effect caused by the adjacent layers, specifically the Hf seed layer (see Pheating < 2 cm−1) is much smaller than the shifts observed in this studyThe following additional observations were made from the Raman spectra, leading to information on the interface between the HfOayer see . Note th2 was covered on the graphene surface. The Y peak was absent in the Raman spectra obtained from HfO2 on SiO2 without graphene (the bottom-most in 2 on graphene reached a maximum (Hf-seeded sample); therefore, we can postulate that this feature is closely related to the amount of interface between HfO2 and graphene and probably, the number of bonds between Hf and graphene . The detailed fabrication process steps are described in the experimental methods section. As illustrated in 2/Si wafer in a top-gated geometry and the gate length and channel width were fixed at 5 μm and 10 μm, respectively. The TEM analysis of the cross section of the FET sample prepared via focused ion beam milling indicated the presence of an ~5-nm-thick gate dielectric (HfO2) layer between the graphene and gate metal stack, as shown in In summary, analyses of the HfO2 with and without the Hf seed layer. The as-transferred pristine graphene showed an average sheet resistance of ~1.05 kΩ/□. After the ALD of HfO2 directly on the transferred graphene, the value increased to ~1.51 kΩ/□ and the standard deviation almost doubled. We are unable to provide a definite explanation for this at the moment; however, we speculate that this observation can be attributed to the direct exposure of the monolayered graphene to the highly oxidizing ambient encountered in the ALD. On the contrary, when the graphene layer was pre-coated with the e-beam evaporated Hf seed layer, the increase in the sheet resistance of graphene was much smaller  with a similar standard deviation even after the ALD of HfO2. This indicates that the introduction of the ultrathin Hf seed layer is also beneficial towards maintaining the intrinsic quality of the graphene. We note that the MOG FETs built on SiO2 (100 nm)/Si in back-gated configuration before and after Hf deposition were also measured  versus gate bias (VG) curve is shown in k dielectrics on monolayered graphene, which can be used as a suitable building block for the fabrication of high-performance graphene tunnelling transistors.The dielectric quality of the formed ~5-nm-thick HfO2 gate dielectric film into GSM-TFETs on an 8″ glass wafer. The GSM-TFET consists of vertical tunnelling junctions with graphene, InGaZnO (IGZO), and Mo electrode functioning as the work function tunable source, tunnelling barrier, and drain electrode, respectively, as shown in 6 were achieved at drain voltage (VD) = 0.5 VVD, VG needs to be downscaled. 2 film, which controls the work function of graphene, is well defined between the gate electrode and graphene. The drain current density (JD) versus VD characteristics  is modulated exponentially by the change in t is the thickness of the barrier and Φ). Therefore, a high on/off ratio is achieved by the modulation of the electric field across the junctions, and more specifically, by the reduced barrier height.Based on the discussion in our previous reportJD versus VG characteristics for various VD values at forward bias. We obtained an average SS value of 60 mV/dec for up to four orders of magnitude of current modulation ranging from JD = 10−13 A/μm2 to 10−9 A/μm2, and a minimum swing of 25 mV/dec was obtained for one order of magnitude of current modulation ranging from 10−13 A/μm2 to 10−12 A/μm2 at |VD| < 0.5 V. The threshold VG ranged from −0.55 V to −0.45 V as VD was varied from −0.4 V to −0.1 V. In forward bias, the observation of a shifted VG is natural because each VD compensates for the built-in potential corresponding to a different energy barrier such that for an increased VD, the threshold voltage appears at a lower VG. Therefore, the work function of graphene should be increased to turn the device off. Nevertheless, a value of 25 mV/dec is a record-low value among field-effect devices consisting of graphene or transition metal dichalcogenides, and their heterostructures and the less-than-60 mV/dec value directly proves the carefully designed tunnelling barrier and its successful operation. On the other hand, under reverse bias, we observed an average SS of 60 mV/dec for up to three orders of magnitude of current modulation ranging from J = 10−12 A/μm2 to 10−9 A/μm2 and a minimum swing of 30 mV/dec for one order of magnitude of current modulation ranging from 7 × 10−12 A/μm2 to 7 × 10−11 A/μm2 at VD < 0.5 V. In reverse bias, the threshold VG change with various VD is comparable to that in forward bias. Note that both in forward and reverse biases, VD and VG can be less than 0.5 V, which can enable low-power consumption in logic circuitry. Despite the relatively low on-current of 3 × 10−7 A/μm2, this is the first proof-of-concept demonstration of a device with 2D materials showing SS values <60 mV/dec and there is much room for further improvement. First, the device fabricated here has a relatively large tunnelling thickness of 20 nm compared to 5–10 nm used for most TFETs and the current can be expected to exponentially enhance with further thickness scaling. Moreover, thorough interface control between each layer at the vertical tunnel junction can be applied to the fabrication process .Monolayered graphene was synthesized on copper (Cu)-evaporated 6″ Si wafer by CVD using hydrogen and methane. The sample was spin-coated with poly(methyl methacrylate) (PMMA) and then soft-baked to improve the adhesion of PMMA to graphene. Then, the Cu film was peeled off from the Si wafer and completely etched away in a Cu etchant. Finally, the separated graphene layer was transferred onto a 6″ Si wafer covered with a thermally grown SiO2 gas. The thickness of the two seed layers was fixed at approximately 3 nm. The ZnO seed layer was sputtered at an RF power of 100 W, while the Hf seed layer was e-beam-evaporated. After passivating the graphene surface, ALD of HfO2 was carried out at 200 °C by separately injecting TEMAHf and H2O vapour with N2 purging steps in-between. The deposition rate of the HfO2 films on a SiO2 (300 nm)/Si substrate was monitored to be roughly 0.07 nm/cycle  were patterned by photolithography and lift-off after deposition by e-beam evaporation. As the gate dielectric, ALD HfO2 was introduced on the e-beam evaporated Hf seed layer, which yielded a total dielectric (HfO2) thickness of ~5 nm including the transformed HfO2 seed layer formed during the ALD. Finally, a 100 nm Au/10 nm Cr top gate electrode was deposited and defined in a manner similar to the source/drain electrode formation. Metal pads (100 nm Au/10 nm Ti) were subsequently fabricated on each metal electrode for stable electrical measurement.For the fabrication of the top-gated FET devices using monolayered graphene at the wafer scale, a graphene monolayer was grown on a 6″ Cu/SiO2. The IGZO thin film was patterned using dilute HF etchant. A 100-nm-thick SiO2 layer was deposited by plasma-enhanced CVD at 200 °C and patterned by dry etching. The wafer-scale CVD graphene was then transferred to form the graphene–IGZO–metal junctions and patterned by O2 plasma. The graphene was then placed in contact with the source electrode . Finally, after forming the gate dielectric HfO2 (5–6 nm in thickness) on graphene, the gate electrode  was stacked to complete the device fabrication.The GSM-TFETs were fabricated on an 8″ glass wafer using standard semiconductor processes. First, the sputtered drain electrode  was defined by photolithography and dry etching. To deposit the amorphous IGZO thin film (10–20 nm in thickness), a target prepared by mixing GaO, InO, and ZnO powders was sputtered by RF plasma using Ar/O2 film was examined both by field-emission SEM  and TEM . The HfO2 films were characterized by XRD  and XRR  and a high-resolution goniometer (resolution = ± 0.0001°)). The graphene layers in the samples were also characterized by a Renishaw micro-Raman spectroscopy with an excitation wavelength of 514 nm. The electrical characteristics of the fabricated FET devices were measured using a Keithley 4200-SCS semiconductor parameter analyser in a N2 chamber probe station.The growth behaviour of the ALD HfOHow to cite this article: Jeong, S.-J. et al. Thickness scaling of atomic-layer-deposited HfO2 films and their application to wafer-scale graphene tunnelling transistors. Sci. Rep.6, 20907; doi: 10.1038/srep20907 (2016).


Multialkylated cyclopentanes (MACs), a class of synthetic hydrocarbon fluid have attracted intensive interest as possible space lubricants due to a series of unique physical and chemical properties. Here, we used graphene with high mechanical strength and chemical inertness as lubricant additive to explore its potential for space application. The effects of space irradiation on graphene and the tribological properties of graphene as lubricant additive were firstly investigated in detail under simulated space environment composed of high vacuum, high/low temperature and irradiation. Results demonstrate that graphene not only possesses outstanding anti–irradiation capacity but also significantly improves the space performance and tribological properties of MACs, which depends on the excellent physicochemical properties and high load-carrying ability of graphene as well as more effective separation of the sliding surfaces. The success of spacecraft missions depends on the accuracy and reliability of various drive mechanisms that in turn are dependent on the good lubrication with low friction and low wear, low mechanical noise and long-term durability. Hence lubricants play a crucial role in controlling friction and wear and ensuring the performance of these mechanisms. Multialkylated cyclopentanes (MACs) consisted of the di– and tri–substituted (2–octylodecyl) cyclopentane have been focused on the potential application for actual space drive mechanisms and microelectromechanical systems (MEMS) due to the good chemical inertness, excellent viscosity properties, low volatility, low pour points and high thermal stability1257−1K−1), extraordinary carrier mobility (up to 27000 cm2 V−1s−1), large theoretical specific surface area (2630 m2 g−1) and excellent mechanical properties 11121315161718192122Carbon nanomaterials are being considered for fundamental research and industrial application. Graphene has attracted tremendous attention for its unique physical and chemical properties including outstanding thermal conductivity  and LT (−100 °C), AO, UV and EL irradiation. In addition, the friction mechanism of graphene is also explored through scanning electron microscopy (SEM) and transmission electron microscopy (TEM).−1, in–plane vibration of sp2 carbon atoms), 2D band  and D band (introduction of defects) give information about clustering of the sp2 phase, the presence of sp2–sp3 hybridization and impurities, and so forth24−1, the blueshift of 2D band from 2670 to 2927 cm−1 due to foreign atoms, electron and hole doping15 atoms/cm2s could react with a small number of carbon atoms activated by bombardment of high–energy particles on both basal planes and edges of graphene, which results in the modification of the flat geometric structure of graphene due to the change of the bond lengths and anglesD/IG indicates the increased defects. Prolonged EL irradiation could lead to the appearance of vacancy– and interstitial–type defects, even the formation of carbon atomic chainsRaman spectroscopy has historically played an important role in probing structural and electronic characteristics of carbon based materials. The G band  and excitation of atoms (excitation effect)3233To visualize the morphology of graphene sheets before and after irradiation, SEM images are shown in TEM was employed to explore the morphology and structure of the graphene before and after irradiation. The size and shape of the original graphene is shown in 3638−1 are assigned to –C–O–C– and –CHO, a wide peak at 3380 cm−1 and a weak peak at 3626 cm−1 are due to the appearance of hydroxyl groupsTo investigate the effects of irradiation on the lubricants (MACs and MACs+G), the FTIR spectra of the lubricants before and after irradiation are shown in −4 Pa condition, we could observe that the friction curves of MACs+G were much more stable, and the average friction coefficient (Cof) was always lower (~0.2) than that of MACs (~0.3) before and after irradiation. 3) is much lower than that of the disc lubricated by MACs (~0.5 mm3). −4 Pa) and low temperature (−100 °C) with higher vacuum (6.5 × 10−5 Pa). The lubricants showed very smooth friction curves under –100 °C and 6.5 × 10–5 Pa condition, and the average Cof of MACs+G was lower and more stable than that of MACs. Graphene can improve to some extent the tribological behavior of MACs under 170 °C and 2.3 × 10−4 Pa. The friction results in high temperature and cryogenic conditions were different because the viscosity of the lubricant largely affected the tribological performance of the systems, which mainly depends on the film thickness and fluidity of the lubricant. When friction tests were conducted in the mild test conditions or running-in stage, the good tribological performance depended on a thin oil film between the tribological interfaceThe tribological properties of the lubricants after irradiation were systematically investigated under high vacuum condition. In order to obtain the direct evidence on antiwear ability of MACs+G before and after irradiation, −1 and weak 2D band at~2882 cm−1. The disappearance of D band and broadening of G band indicate that the graphene have tended to graphitization during friction process. XPS and Raman spectra of the wear tracks demonstrate that this tribological behavior is attributed to the easily shearing graphene–rich tribo–film on the rubbing surface which prevents the rubbing surfaces from coming into direct contact, enhances the load–bearing capacity, improves the friction and wear resistance.To further confirm the friction reducing and antiwear mechanism of MACs+G under simulated space environments, the wear tracks lubricated by MACs+G were investigated with XPS and Raman spectra and the corresponding worn particles were also analyzed with TEM. XPS and Raman spectra of wear tracks identify the components of the protective film and provide more direct evidence for the friction mechanism. As shown in TEM micrographs with EDS of the worn particles are shown in 44Space environment is one of the greatest challenges for the potential applications of lubricants and lubricant additives. The effects of irradiation on graphene are systematically evaluated under simulated space irradiation environment . Combined with these experimental results and analysis before and after irradiation as well as the literature reports293233Commercially obtained multilayer graphene ) was pressed into a thin sheet on the tinfoil with double–sided adhesive tape by 769YP–24Z tablet power press machine to conduct the space irradiation experiments. MACs was provided by Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences , its physical properties are shown in 2)472 in the upper atmosphere, its number density is about 8 × 107 atoms/cm3 at 400 Km altitude, and the AO flux orbit is 1014 ~ 1015 atoms/cm2s2s with impingement kinetic energy of 5 eV for 120 min at the sample position, the vacuum UV irradiation with energy levels of 800W/m2 in the range of 115–400 nm was carried out under high vacuum (10−5 Pa) for 120 min and the experiment of EL provided the high–intensity beam of electrons (500 μA/cm2) for 120 min. The basic principle of AO irradiation was described in ref. In low earth orbit (LEO), radiation can be categorized as electromagnetic irradiation like infrared, visible, ultraviolet, X ray and gamma ray, and particulate irradiation including cosmic rays, trapped electrons and protons, and solar flares. The solar UV irradiation in the range of 100–400 nm accounts for 8% of the solar wavelength range (0.115 μm up to 50 μm), so the intensity of UV is only about 8% of the total solar energy  with KBr were finely ground in an agate mortar with a pestle for 10 minutes, then the power was filled into a drillhole of 1 cm diameter inside a stainless steel gasket and was pressed between anvils by 769YP–24Z tablet power press machine under 12 MPa for 10 s. After that, the pressure was slowly released and the as-prepared sheet with thickness of 0.5 mm was measured by FTIR. The lubricants before and after irradiation were coated homogeneously on a KBr wafer by scraper with roughness of 0.1 μm to obtain their FTIR spectra. The chemical states of the C element of graphene before and after irradiation were analyzed by a PHI–5702 multifunctional X–ray photoelectron spectroscope (XPS) manufactured by American Institute of Physics Electronics Company using K–Alpha irradiation as the excitation source. The binding energies of the target elements were determined at a pass energy of 29.3 eV, with a resolution of about ±0.3 eV, using the binding energy of oxygen (O1s: 531.0 eV) as the reference. Graphene was characterized using high–resolution TEM (FEI Tecnai F300) with an accelerating voltage of 300 kV. Small amount of graphene before and after irradiation was dispersed in ethanol in an ultrasonic bath for 20 min and deposited onto a holey carbon TEM grid. The morphology of graphene sheets before and after irradiation was observed using field–emission scanning electron microscopy . The pressed graphene sheets before and after irradiation were cut into a small piece with 3 mm ×3 mm and were attached to copper disk by conducting resin. We used an accelerating voltage of 5.0 kV with low/high magnification (×5000 and ×10000).Raman spectra of the graphene sheets before and after irradiation were first obtained by Renishaw inVia Raman microscope with 532 nm laser excitation to investigate the influence of AO, UV and EL irradiation. Fourier transform infrared (FTIR) spectra were recorded in the wavenumber range of 4000–500 cmThe friction tests were conducted on an in–house rotational ball–on–disk vacuum tribometer under simulated space environment including high vacuum, high/low temperature and irradiation. The fixed upper specimens were an AISI 52100 steel balls with standard 3 mm diameter, and the lower specimens were the stainless steel disks. For high/low temperature (170 °C and –100 °C) friction tests under high vacuum, the lower specimens were replaced by the steel disks . Before the friction tests, the lubricants were coated homogeneously on the steel disks. All the tests were conducted at rotational radius of 7.5 mm, sliding speed of 300 r/min, applied load of 5 N and duration of 60 min under high vacuum condition. The friction coefficients were monitored continuously as a function of time. Friction test under the same conditions was repeated three times in order to ensure repeatability. The wear volume of the lower specimens and the morphology of the wear tracks were measured using a MicroXAM–3D contact surface mapping microscope profilometer. The wear tracks lubricated by MACs+G with AO irradiation were also investigated with XPS and Raman spectroscopy. The lower specimen is cleaned ultrasonically several times in baths of acetone and is dried with pure nitrogen for surface analysis. In addition, after friction tests, some worn particles were picked up from the steel disk lubricated by MACs+G with AO irradiation, they were repeatedly centrifuged with the speed of 3000 rpm for 5 min using ethanol, and were rinsed in trichloromethane and ethanol to eliminate all the residual MACs. In the end, the worn particles were investigated by TEM to further confirm the friction mechanism of graphene.How to cite this article: Fan, X. and Wang, L. Graphene with outstanding anti-irradiation capacity as multialkylated cyclopentanes additive toward space application. Sci. Rep. 5, 12734; doi: 10.1038/srep12734 (2015).


A polymorphism (rs35705950) in the promoter region of the mucin MUC5B is associated with both familial and sporadic forms of idiopathic pulmonary fibrosis. (IPF) We hypothesize that this common MUC5B variant will impact the expression of cough, a frequent disabling symptom seen in subjects with IPF.We genotyped 136 subjects with IPF. All living subjects were provided with a Leicester Cough Questionnaire (LCQ) to measure cough severity. We assessed allele effects of the MUC5B polymorphism on the LCQ scores using SAS General Linear Models (GLM) in the patients with IPF.In the 68 of the total 136 IPF patients who returned the LCQ, MUC5B minor allele frequency (T) is consistent with prior published studies (31%). We found a significant independent effect of the T allele on the LCQ score (p = 0.002 for subjects with IPF). This effect is independent of other common causes of cough, including gastroesophogeal reflux disease and upper airway cough syndrome.Cough severity, a common disabling phenotypic component of IPF, is significantly associated with the presence of the minor allele of a MUC5B promoter polymorphism. This study highlights a possible genetic mechanism for phenotypic heterogeneity in pulmonary fibrosis. The Interstitial Lung Diseases (ILDs) are a heterogeneous group of lung diseases that result in progressive pulmonary functional decline and death. Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic ILD, with an estimated 100,000 Americans affected. Current theory suggests that fibrotic lung disease occurs when genetically susceptible individuals are exposed to environmental triggers. Recently, a common variant in the promoter region of the mucin 5B (MUC5B) gene [Cough is a prominent but not universal symptom in patients with IPF. Cough is estimated to be present in 84% of patients with IPF and is more prevalent in patients who have never smoked or have more advanced disease . IPF relThe etiology of cough attributed to IPF is not clear. There may be mechanical factors at play including destruction of the cough inhibitory fibers as the lung is distorted with the fibrotic process . StudiesSubjects were recruited from ongoing University of Utah ILD studies between 2005 and 2012. The diagnosis of IPF was established utilizing current diagnostic criteria ,8. This Subjects were given the Leicester Cough Questionnaire (LCQ) . This quComorbid conditions known to cause cough were determined by chart review and by personal interview when possible. These conditions include smoking status and history, use of ACE inhibitors, evidence of upper airway cough syndrome , history of sleep apnea, and gastroesophogeal reflux disease (GERD). In addition, spirometry measuring forced vital capacity (FVC) and Forced Expired Volume in one second (FEV1) and diffusion capacity (DLCO) was performed utilizing standard methodology .Genotyping was performed using a commercially available TaqMan assay; rs35705950 (MUC5b) according to the manufactures methods . Each 5 ul PCR reaction contained 20 ng of genomic DNA, primers, probes, TaqMan Universal PCR Master Mix . PCR was carried out under the following conditions: 50°C for 2 minutes to activate UNG, 95°C for 10 min, followed by 40 cycles of 92°C for 15 sec, and 60°C for 1 minute using a 384 well dual block ABI 9700. Fluorescent endpoints of the TaqMan reactions were measured using a 7900HT sequence detection instrument.T-test, and Fisher’s exact test were used to compare diagnostic subgroups within our sample for demographic characteristics and the rs35705950 minor allele frequencies. We used SAS General Linear Models (GLM) to test for association between the LCQ scale scores and MUC5B genotype within the IPF group, first employing a full model including all the secondary covariates listed above, in addition to age, gender, and IPF status. Any subject with a missing value on any predictor was not included in the analysis. From these analyses, we report allele effects on questionnaire scales independent of these other model effects, and also total variance (R2) explained by the model. We then employed a parsimonious model including only predictors that were significant in the full model. We compared total variance by the full model to variance explained by the parsimonious model to explore the relative contribution of the additional predictors and the potential loss of statistical power due to missing data across all the predictors in the full model.Chi-square test, A total of 136 subjects with IPF were genotyped for the MUC5B SNP rs35705950. At the time of our study, 45 subjects had already died. 68 living subjects returned the LCQ.Table Amongst the 68 patients with LCQ data, 71.64% of the subjects endorsed a history of GERD. All subjects with GERD reported treatment with proton pump inhibitors. A smaller percentage of patients reported a history of known UACS and were treated with a variety of therapies including nasal steroids and antihistamines, mostly on an intermittent basis. Only 35.82% of the patients reported a history of smoking. None were current smokers.The mean FVC and FEV1/FVC demonstrated restrictive disease as expected. The DLCO was reduced. This is summarized in Table The mean total LCQ score was 16.16 with a range of 7.16 – 21.0. A lower score reflects a more severe cough. In IPF subjects with available LCQ data, the T allele is observed with a frequency of 0.37. In the IPF subjects for whom we do not have LCQ data, the T allele frequency was 0.33.Table In our cohort of 68 IPF patients, we replicate the reported association between the minor T allele of SNP rs35705950 in the MUC5B promoter region and ILD. Our data demonstrate a minor allele frequency (MAF) of 37% in the group with LCQ and 33% in the group without the LCQ, similar to previously published IPF data ,12. SeibWithin the subset of patients for whom we have data on cough severity, we found statistically significant association of the minor T allele with cough severity. This association is independent of effects of age, gender and other clinical variables . This lack of association with the FEV1/FVC ratio and DLCO suggests that concomitant emphysema or other obstructive disease does not account for any of the observed cough differences. There were an additional 68 patients who did not return the cough questionnaire. This is in part because 45 of these patients had died prior to the initiation of this study. It is notable that this group matches the questionnaire group in age, sex and genotype frequency. However, the pulmonary function was significantly lower, likely related to the late phase of their disease at the time of recruitment. The IPF subjects demographics are consistent with the current literature in that they were predominantly male and older in age. Of note, our population does have a smaller percentage of smokers than is typically reported. This reflects the population of Utah where smoking is less common.There are several possible mechanisms for our observation that MUC5B genetic variation is related to cough severity. MUC5B expression is upregulated in patients with IPF who carry the minor allele . The uprThe MUC5B polymorphism relationship to cough in IPF observed in our study may be consistent with recent findings by Seibold et al.  demonstrThe presence of the minor (T) allele has been associated with improved survival in IPF . This fiThis study has a number of limitations. The number of patients who responded to the questionnaire is relatively small, mostly reflective of the death of subjects who were accrued in earlier years prior to the current study with the cough questionnaire. For these subjects, descriptive information including sinus disease, acid reflux disease or estimates of cough severity on subjects are not uniformly available. Thus, although the genotype frequencies were similar in subjects with and without cough questionnaires, we do not know if this group’s cough severity has any relation to the T allele. A second limitation is that our measure of cough was a self-report rather than an objective cough count. This methodology may introduce some reporter bias. However, it should be noted that a well-accepted validated questionnaire was utilized. Our analysis of the comorbidities known to impact cough is suboptimal. Subjects were assigned a categorization of affectation by self-report and medical record review when available. In the case of GERD, current estimates that up to 90% of patients with idiopathic pulmonary fibrosis have GERD . Our repThe variable expression of cough in IPF patients is not predictable. Cough is a problematic symptom in many, but not all, patients with this disease. While well-known cough risk factors such as GERD or ACE inhibitors can sometimes be controlled, clinicians are often unsuccessful in mitigating this troubling symptom. Recently, use of thalidomide has been shown to decrease cough severity in IPF , but theOur findings represent a potentially important application of the role MUC5B plays in the phenotypic expression of IPF. Phenotypic heterogeneity is observed clinically in patients with IPF but the genetic components of this heterogeneity are not understood. As further genetic contributions to IPF are elucidated, it is important to determine the associations between genotypes and phenotypic expression. Our observation of the possible relationship between MUC5B and cough suggests a possible influence of this polymorphism and suggests that the presence of the minor allele in MUC5B may account for a specific phenotypic component of IPF.The authors declare that they have no competing interests.MBS was responsible overseeing all aspects of the study and is the guarantor of the manuscript. M.B.S, RKW, HC, and designed the research; MBS, MW, SW, PC and NS collected the data; HC and RW analyzed the data; RW performed the sequencing; MBS, RKW, HC, PC and KS wrote the paper. All authors read and approved the final manuscript.


We propose a graphene-based full valley- and spin-polarization device based on strained graphene with Rashba spin orbit coupling and magnetic barrier. The underlying mechanism is the coexistence of the valley and single spin band gaps in a certain Fermi energy. By aligning the Fermi energy in the valley and single spin band gaps, remarkable valley- and spin-polarization currents can be accessed. K and K’ points14678et al.1111The realization of stable single-layer carbon crystals, called graphene, has led to an intensive investigation of electronic properties of graphene1K and Although the single spin and valley polarizations in graphene have been extensively studied, the works, realizing simultaneously both spin and valley polarizations for graphene, are still fewx direction applied on the graphene and is homogeneous along the y axis. The elastic deformation can be treated as a perturbation to the hopping amplitudes and acts as a gauge potential δt parametrizes the strain by its effect on the nearest neighbor hopping, x axis, which can be generated by depositing ferromagnetic metal or superconducting materials on top of the dielectric layer, as is the way in semiconductor heterostructures19B is the strength of the local magnetic field, The graphene-based system under consideration includes the strain, RSOC and magnetic barrier, as depicted in K, here E and incident angle here W is the width of the graphene sample in the y direction. The valley, spin resolved and total conductance are defined ashere We also introduce valley and spin polarizations K valleys as function of the Fermi energy. As the incident energy increases, for EF < 10.2 meV. For K valley [K valley are forbidden wholly. Such transport property leads to that there are not only full valley polarization and high spin polarization but also obvious total conductance in the energy ranges EF < 10.2 meV, but the rather small conductance makes it impossible for either detection or applications. From   valley , the conK valley , the conK points in strained graphene with only magnetic barrier [K valley is wider than that of K electrons is distinct in amplitude from its counterpart for K and In this work, we propose and demonstrate that valley and spin filters can be simultaneously achieved in a strained graphene with RSOC and magnetic barrier. Such a remarkable result can be understood by the band structures in each region. For comparison, we first show the band structures near the  barrier  and only barrier . In Fig.So we study the band structure of strained graphene with both magnetic barrier and RSOC . It is sThe valley and single spin band gaps can be deceived by the extreme points of energy band  see in . In Fig.In conclusion, we have demonstrated that strained graphene with RSOC and magnetic barrier can generate valley- and spin-polarization currents. To observe such polarized current in the concerned structure, it is highly desirable to keep the system with valley gap and single spin band gap. The full valley-polarization current mainly appears in the valley gap and full spin-polarization one mostly occurs in the single spin band gap. The valley and single spin band gaps can be modulated by strain, RSOC and magnetic strength. In addition, under the strain and magnetic manipulation, the spin polarization can be switched by adjusting the strain and magnetization strengths. The full valley- and spin-polarization currents provide the desirable routines to construct spin/valley filter for graphene-based logic applications.2, where low energy physics are governed by massive Dirac fermion.Our results would be also applicable to other spin and valley coupled systems, such as monolayers of silicene and MoSHow to cite this article: Wu, Q.-P. et al. Full Valley and Spin Polarizations in Strained Graphene with Rashba Spin Orbit Coupling and Magnetic Barrier. Sci. Rep.6, 21590; doi: 10.1038/srep21590 (2016).