The purpose of this work is to summarize cardiovascular magnetic resonance (CMR) research trends and highlights presented at the annual Society for Cardiovascular Magnetic Resonance (SCMR) scientific sessions over the past 20 years.Scientific programs from all SCMR Annual Scientific Sessions from 1998 to 2017 were obtained. SCMR Headquarters also provided data for the number and the country of origin of attendees and the number of accepted abstracts according to type. Data analysis included text analysis (key word extraction) and visualization by ‘word clouds’ representing the most frequently used words in session titles for 5-year intervals. In addition, session titles were sorted into 17 major subject categories to further evaluate research and clinical CMR trends over time.Analysis of SCMR annual scientific sessions locations, attendance, and number of accepted abstracts demonstrated substantial growth of CMR research and clinical applications. As an international field of study, significant growth of CMR was documented by a strong increase in SCMR scientific session attendance  and number of international participants . ‘Word clouds’ based evaluation of research trends illustrated a shift from early focus on ‘MRI technique feasibility’ to new established techniques (e.g. late gadolinium enhancement) and their clinical applications and translation  and more recently novel techniques and quantitative CMR imaging . Nearly every topic category demonstrated an increase in the number of sessions over the 20-year period with ‘Clinical Practice’ leading all categories. Our analysis identified three growth areas ‘Congenital’, ‘Clinical Practice’, and ‘Structure/function/flow’.The analysis of the SCMR historical archives demonstrates a healthy and internationally active field of study which continues to undergo substantial growth and expansion into new and emerging CMR topics and clinical application areas. On February 3, 2017, the Society for Cardiovascular Magnetic Resonance (SCMR) celebrated its 20th Annual Scientific Sessions in Washington D.C. Over the past 20 years, the field of cardiovascular magnetic resonance (CMR) has witnessed major advancements in data acquisition speed, image quality and development of novel imaging techniques , applicaOn the direction of the SCMR Executive Committee, the SCMR Science Committee sought to evaluate research trends in CMR by evaluating session titles from SCMR Annual Scientific Sessions Programs over the past 20 years. Our goal was to track the number of abstracts and scientific contributions, analyze the evolution of research trends and hot topics, and identify the changes in main clinical focus areas and application areas over the past 20 years.Scientific programs from all SCMR Annual Scientific Sessions from 1998 to 2017 were obtained from the SCMR Headquarters Office and SCMR members. Digital program files were available for 2000–2017, while programs of the 1998 and 1999 annual scientific sessions were only available in paper form. SCMR Headquarters also provided data for number of attendees, country of origin of attendees (only available for 2004–2017) and number of accepted abstracts according to type (available for 1998–2018): oral, poster, walking poster, e-poster, moderated poster, and pre-conference workshop. In addition, the ratio of attendance / (number of accepted abstracts) was calculated.voyant-tools.org. The tool was used to visualize research and clinical trends by creating ‘word clouds’ representing the most frequently used key words in session titles in 5-year intervals. Common key words found in many session titles such as ‘MRI’, ‘CMR’, ‘cardiac’, and ‘MR’ were excluded from the analysis. To further evaluate research and clinical CMR trends over time, session titles were analyzed and subsequently manually sorted into 17 major subject categories. Title counts were grouped into four-year time periods: 1998–2001, 2002–2005, 2006–2009, 2010–2013, 2014–2017. The evolution of these major subject categories was sub-divided into “super growth” (an absolute increase of ≥ 8 sessions from the first time period to the last), and “strong growth” (an absolute increase of ≥ 4 sessions from the first time period to the last). In addition, new categories were defined as those that did not have any sessions in the first time period.Session titles were abstracted from all programs and collated by year. Digital text analysis and visualization was performed using The dynamics and substantial growth of CMR research and applications are reflected in the evolution of SCMR annual scientific sessions locations and duration Table , scientiSignificant growth of CMR research and clinical applications is corroborated by the consistent and strong increase of SCMR scientific session attendance and abstracts which document a > 500% growth in attendance (270 attendees in 1999 to 1406 in 2017) and a > 700% increase in the number of accepted abstracts (98 in 1998 to 701 in 2018). A more detailed breakdown of annual scientific sessions abstracts  according to type is shown in Fig. Table Word clouds summarizing the results of key word extraction from SCMR annual scientific sessions titles are shown in Fig. The number of sessions within all major subject categories over the past 20 years are depicted in Fig. New categories (those that did not have any sessions in the first time period) include Electrophysiology, Tissue Characterization, Analysis/Post-processing, Interventional, and Clinical Application to Special Groups Fig. . This laCase sessions also saw significant growth in number and sophistication. From 1998 to 2001 there was a single case session offered, “Clinical Case Review Session: Bring Your Own”. From 2014 to 2017, there were 39 case sessions offered, including a live interventional CMR heart catheterization case presented by Children’s National Medical Center at the most recent SCMR annual scientific sessions in 2017. The first SCMR live case  was a unique experience for the SCMR audience and a milestone in the history of the SCMR annual scientific sessions. SCMR attendees were provided with the opportunity to watch a clinical CMR catheterization program live in operation and recognize potential benefits of interventional CMR for pediatric and adult patients.The results of our analysis of SCMR annual scientific sessions attendance, number and type of abstracts, as well as CMR research and application trends clearly demonstrated a healthy and internationally active field of study which continues to undergo substantial growth and expansion utilizing new and emerging CMR techniques to answer a broadening array of clinical questions. Changes in annual scientific sessions location and annual scientific sessions duration summarized in Table Nearly every topic category demonstrated an increase in the number of sessions from the first time period to the last. Clinical Practice led all categories in four of the five time periods. The top three growth areas were Congenital, Clinical Practice, and Structure/function/flow. In many sessions, growth mirrored the development of new imaging techniques or therapies. Tissue characterization has seen substantial growth since mapping techniques have become widely available. The advent of percutaneous valve techniques has coincided with the emergence of sessions dedicated to valve disease. Arrhythmias and CMR used to be mutually exclusive terms, but with real time techniques and recognition of the utility of CMR for defining the substrate for arrhythmias this area has blossomed. The “super growth” in the congenital category is not surprising, given the increasing role of CMR in this growing patient population. The category “Clinical Application to Special Groups” illustrates the growing application of CMR beyond traditional atherosclerotic coronary and vascular disease.We’ve seen the programs evolve from very broad sessions with a focus on development and validation, to a wide breadth of sessions that build upon the past and focus increasingly on specific applications to patient scenarios and groups where CMR might impact clinical care and practice guidelines. In this context, a continued collaboration between non-clinician PhD scientists and engineers and physician researchers and clinicians coupled with interactions with other clinically oriented societies will be critical for the continued success of CMR. The evolution of sessions at the SCMR annual scientific sessions mirrors the growth and maturation of the science and clinical practice of CMR over the past 20 years.


We report the electrical characterization and field emission properties of  Over the past decade, graphene and graphene-like materials have attracted a lot of attention. Due to its two-dimensional 2D) nature and several extraordinary properties, such as high mobility and current carrying capability, chemical stability, and mechanical robustness, graphene in particular has been the most commonly chosen material for new electronic devices ,2. HowevD nature ications ,8,9,10.Similarly to graphene, ubstrate ; howeverubstrate . MoS2 prf layers , even thm2V−1s−1 . Indeed,o >107)  and low /decade) ; moreoveachieved . Additio7  and loachieved  and spinachieved  have bee devices . In this paper, we characterize the transport properties of bilayer exposure  and tendexposure ; thus, tField emission (FE) is a quantum mechanical phenomenon in which electrons, extracted from a conductor or a semiconductor surface upon application of an intense electric field, flow in vacuum from a cathode to an anode. Classic field emission theory was developed by Fowler and Nordheim  for planTo date, FE from d (ETVA) . It has ructures ,40,41. Here, we measure FE current from the flat part of aterials . We highThe We used the silicon substrate as a common back gate and metal leads, patterned by standard electron beam lithography and a lift-off process, as drain and source. The metal leads are made of  S atoms . The twoIn the following, the transistor characterization refers to contacts 4 (drain) and 5 (source), as marked in Electrical measurements were performed using a Keithley 4200 SCS  connected to a Janis ST-500  probe station at room temperature and pressure of Field emission measurements were carried out at a pressure Considering that the presence of impurities and precursor residues could alter the emission process from  of MoO3 .  Ids−Vds a were meThe transfer curve discloses an n-type behavior with normally on channel at Remarkably, the prevailing on-state over a wide We also evaluate the field-effect mobility from the slope of the transfer characteristic (black curve) via the following formula:1 nFcm−2 . The obtm2V−1s−1 ,33,46,47m2V−1s−1 , which iFE experimentation on a selected flake, shown in Considering that the om edges , but it es [V/μm .In For a given distance, the current remains at the floor noise up to a threshold voltage, corresponding to what we define as the FE turn-on voltage; above this threshold it starts rising exponentially up to =5.25 eV ); and β al setup . FinallyThe Fowler–Nordheim behavior of the field emission current is usually checked by the linearity of the so-called FN plot of The FN plot of our measurements is reported in  sources ,33,52,53ing area . The seemingly low value of the amplification factor—less than Finally, we can evaluate the turn-on field from the voltage values at which the current emerges from the noise floor of material . The appubstrate , creates 4.45 eV ,57,58 anWe have presented the electrical transport characterization of field-effect transistors with


APOE) and ‘523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the APOE ε4-TOMM40 ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. APOE genotypes were determined by polymorphisms of rs429358 and rs7412. TOMM40 ‘523 genotypes were defined by the poly-T repeat length of rs10524523 . Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-ε4 carriers and almost all (94.2%) of the ε4 carriers had ‘523-L. The classification was highly concordant. Each ε4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for TOMM40 ‘523-L. In African Americans, nearly none (1.1%) of the non-ε4 carriers had ‘523-L, but only 47.8% of the ε4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between ε4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the ε4-‘523-L haplotype had stronger effect on risk of AD dementia than other ε4-‘523 haplotypes.Patterns of linkage between the ε4 allele of Apolipoprotein E ( APOE) ε4 is by far the most replicated risk allele for late onset Alzheimer’s disease (AD). Compared with Caucasians, the allele frequency of ε4 is higher among African Americans but its effect on the disease susceptibility appears weaker[APOE and neighboring genes. For instance, it has been reported that among Caribbean Hispanic ε4 carriers, subjects with the HpaI+ variant in the downstream APOC1 gene are more likely to have AD, but the same association is not observed among African Americans[APOE and a poly-T variant in another adjacent gene, Translocase of Outer Mitochondria Membrane (TOMM40) ‘523, together provide better precision in estimating the age of AD onset[TOMM40. Depending on the poly-T repeat length, individual ‘523 alleles can be grouped into 3 classes: Short (‘523-S: Poly-T repeat ≤ 19), Long (‘523-L: 20 ≤ poly-T repeat ≤ 29), and Very Long (‘523-VL: poly-T repeat ≥ 30)[APOE and TOMM40 ‘523 haplotypes differ between Caucasian and African Americans[Apolipoprotein E (rs weaker–3. This eat ≥ 30). Geneticeat ≥ 30), 8. NotaTOMM40 ‘523 in linkage with APOE ε4 between older Caucasian and African Americans, and examined their relationship with incident AD dementia. Since APOE ε4 and TOMM40 ‘523-L are in strong linkage disequilibrium (LD) among Caucasians, it is expected that the two alleles will demonstrate a similar effect on AD dementia in this population. By contrast, the heterogeneity of the ε4-‘523 haplotypes among African Americans allows us to investigate the role of the ε4-‘523-L haplotype in relation to AD susceptibility.In this study, using data from a large sample of prospective longitudinal studies of aging, we compared the distributions of Participants came from three community-based longitudinal cohort studies of diverse participants, the Religious Orders Study (ROS), the RusAt the time of this study, 1,948 Caucasian participants free of AD dementia at baseline had completed at least 1 follow-up clinical evaluation. Genotyping data were available on 1,886 (96.8%) of the participants. Considering the conflicting effects between the ε2 and ε4 alleles on AD dementia, ε2/4 carriers (N = 38) were excluded. As the result, statistical analyses were conducted in the remaining 1,848 Caucasian participants. The mean age at baseline was 78.4 years . 71.2% were females and the mean years of education was 16.3 . The average length of follow-up for the Caucasian participants was 8 years .Separately, genotyping data were available on 568 (98.8%) of the 575 African American participants who were dementia free at baseline and had completed at least 1 follow-up evaluation. We excluded 28 ε2/4 carriers and focused the analyses on the remaining 540 African Americans. For the African American participants, the mean baseline age was 73.4 years . 77.6% were females and the mean education was 14.8 years . The average length of follow-up was 5.9 years .APOE genotypes were determined by the two polymorphisms of rs429358 (codon 112) and rs7412 (codon 158) at exon 4 of the APOE gene. The TOMM40 ‘523 genotypes were determined by the polymorphism rs10524523 at intron 6 of the TOMM40 gene . Based on the the poly-T repeat length, each ‘523 allele was categorized into Short (‘523-S), Long (‘523-L) and Very Long (“523-VL), as previously defined[TOMM40 ‘523.DNA was extracted from peripheral blood mononuclear cells (PBMC) or post-mortem brain tissue. Genotyping was performed by Polymorphic DNA Technologies , blinded to all clinical data. The Distinct from the exclusive linkage between ε4 and ‘523-L in Caucasian Americans, other ‘523 alleles, ‘523-S in particular, have been reported in linkage with ε4 among African Americans. We therefore obtained strand specific (phased) haplotype data in a subset of African American ε3/4 heterozygotes in an effort to further explore how the strand specific ε4-‘523 haplotype variations differ in relation to AD dementia.Participants underwent a detailed cognitive testing and a uniform structured clinical evaluation each year. Cognitive assessment results were reviewed by a neuropsychologist for signs of impairment in various domains. Participants were examined by a clinician. After reviewing all available data, an annual diagnosis was made by the clinician. Diagnosis of AD follows the recommendation of the joint working group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and the t and Chi-square tests described demographic and genetic differences between Caucasian and African Americans. Primary analyses were stratified by race. Cohen's κ coefficients[APOE ε4 and TOMM40 ‘523-L genotypes. Cox proportional hazards models examined the associations of genetic variants with incident AD dementia. In these models, the outcome variable was time in years to incident AD dementia (event time). Time was right-censored at death or last clinical evaluation for participants who were never diagnosed with AD dementia. We first examined the ε4 effect by fitting a model including terms for ε3/4 heterozygous and ε4/4 homozygous. The dose effect was assessed by estimating the difference between the effect of ε4/4 and twice the effect of ε3/4. Next, we repeated the model for ‘523-L in lieu of ε4. Both models were adjusted for baseline age, sex, and education. Finally, by leveraging phased haplotype data from 83 African American ε3/4 heterozygotes, we applied Cox proportional hazards model to evaluate the associations of strand specific ε4-‘523 haplotype variations with incident AD dementia.Student fficients evaluatea priori at the nominal level of α = 0.05.All the analyses were conducted using SAS/STAT programs . Statistical significance was determined ps <0.001). Percent female participants were higher among African Americans (p = 0.003). On average, Caucasian Americans were followed 2 years longer than African Americans (p<0.001). During the follow-ups, 27.8% of Caucasian Americans and 10.4% of African Americans were diagnosed with AD dementia.Characteristics of study participants were summarized in p<0.001), of which 27.6% were ε3/4 heterozygous and 5.4% were ε4/4 homozygous. The ‘523-L allele was present in 21.9% of the Caucasian Americans, comparable to the percentage of ε4. Of the ‘523-L carriers, approximately half (10.2%) were ‘523 S/L, another half were L/VL (10.1%), and only a small number of ‘523-L carriers were L/L homozygous (1.6%). The presence of the ‘523 L allele was lower among the African Americans , of which a majority were of S/L genotype (10.9%), followed by L/VL (4.3%) and L/L (1.3%).The ε4 allele was present in 22.6% of the Caucasian Americans, of which 21.1% were ε3/4 heterozygous and 1.5% were ε4/4 homozygous. The presence of ε4 was higher among the African Americans  and the ε4/4 homozygotes had quadrupled risk  (p = 0.632), supporting a dose effect of ε4 on AD susceptibility.Consistent with the linkage between ε4 and ‘523-L, nearly none (0.8%) of the Caucasian non-ε4 carriers had ‘523-L, whereas 94.2% of the Caucasian ε4 carriers had ‘523-L . The clap<0.001) . The difTOMM40 ‘523-L in Caucasian Americans (ps<0.001). The dose effect of the ‘523-L allele was also evident, and the estimated effect of the 523-L homozygosity was equivalent to twice the effect of the 523-L heterozygosity (p = 0.859).Almost identical effect size and effect pattern were observed for mericans . The hazThe linkage between ε4 and ‘523-L was much weaker in African Americans, with the two variants being less concordant . Specifically, while 1.1% of the non-ε4 carriers had ‘523-L, only 47.8% of the ε4 carriers had ‘523-L .p = 0.195) (p<0.001). The lack of dosage effect for APOE ε4 in African Americans may be due to small sample size, and the test that assessed the difference between the effect of ε4/4 and twice the effect of ε3/4 was inconclusive. Notably, The effect pattern of TOMM40 ‘523-L on AD dementia differed distinctively from that of APOE ε4 (p = 0.011), but we did not detect a significant association for ‘523-L homozygosity (p = 0.650).The Cox proportional hazards model shows that while the ε3/4 heterozygotes among African Americans had higher risk for AD dementia, the estimated hazard ratio was not significant (= 0.195) . By cont APOE ε4 . The ‘52p = 0.009). The risk for the ε4 carriers in absence of ‘523-L allele was weaker and not significant .Since almost all of the non-ε4 African Americans did not carry ‘523-L allele and approximately half of the ε4 carriers had ‘523-L allele, we further split the ε4 carriers into those with and without the ‘523-L allele. 8.4% of the 358 African American non-ε4 carriers were diagnosed with AD dementia, and this percentage increased to 10.8% and 17.7% respectively for the ε4 carriers without (N = 93) and with the ‘523-L allele (N = 85). Results from the Cox proportional hazards model show that, compared with the non- ε4 carriers, African Americans ε4 carriers with the ‘523-L alleles had over twice the risk for incident AD dementia , results were consistent with those using the full dataset. In Caucasians, there was a high concordance between ε4 and ‘523-L (Cohen’s κ = 0.94). Nearly none (0.6%) of the non-ε4 carriers and almost all (92.4%) of the ε4 carriers had ‘523-L. The effect size and effect pattern on incident AD dementia were similar between ε4 and ‘523-L  than those with either ε4-‘523-S or ε4-‘523-VL haplotypes .In an exploratory analysis, we examined phased ε4-‘523 haplotype variations in 83 African American ε3/4 heterozygotes . In thisAPOE ε4 and the neighboring TOMM40 ‘523 variant in a large sample of community based older Caucasian and African Americans, and we interrogated their associations with incident AD dementia. Several observations were made.In this study, we examined the haplotypes between TOMM40 ‘523 genotypes  that are exclusive to the non- ε4 carriers may further differentiate age of onset for late onset AD[We confirmed the linkage between ε4 and ‘523-L in Caucasians Americans. This linkage is highly concordant, such that almost all the ε4 carriers had presence of the ‘523-L allele and almost all the non-ε4 carriers were absent of the ‘523-L allele. When modeled for the associations with incident AD dementia, ε4 and ‘523-L share very similar effect size and effect pattern as expected. In both cases, every single allele doubles the risk for AD dementia and the dose effect is evident. The two ‘523-L heterozygosities (‘523 S/L and ‘523 L/VL) show the same strength in association with incident AD dementia. This strong linkage between ε4 and ‘523-L among Caucasian Americans probably accounts for the lack of association of the poly-T repeat length with age of AD onset in a previous report. Some ev onset AD, but the onset AD, 18.APOE ε4 on the risk of AD dementia in Caucasians can differ across studies due to a variety of reasons ranging from population or sample differences to phenotypic variation. A previous study reported an odds ratio of 2.7 for ε3/4 and 12.5 for ε4/4, relative to ε3/3[It is noted that the effect size of e to ε3/3–21. FinaTOMM40 ‘523 genotypes differ distinctively between African and Caucasian Americans. There was an enrichment of '523-S allele in African Americans. In particular, the percent '523-S/S carriers in African Americans was more than doubled compared with Caucasian Americans. This result is consistent with an earlier report that the ‘523-S allele is more prevalent in African Americans than whites or Hispanics[We observed that the frequencies of Hispanics.APOE ε4 and AD dementia in African Americans.We also observed that the strong linkage between ε4 and ‘523-L haplotype was absent in African Americans. While nearly none of the non-ε4 carriers had the ‘523-L allele, only less than half of the ε4 carriers had ‘523-L. Consequently we could examine the effect patterns of haplotype variations on incident AD dementia. In fact, data at both genotypic and allelic level suggest that ε4-‘523-L haplotype among African Americans has a stronger effect on the susceptibility of AD dementia than other ε4-‘523 haplotypes. This finding helps further elucidate the relationship between APOE locus. The cis ε4 haplotype difference due to population stratification is not new. One earlier study reported an APOE ε4 and APOC1 HpaI+ haplotype that differs in frequency between ADs and controls, and such difference is only observed in Caribbean Hispanics, but not in African Americans[TOMM40 ‘523—APOE haplotypes among African Americans may well be just another example. Indeed, while the ε4-TOMM40 ‘523-L haplotype predominates in Caucasians, two additional haplotypes have been reported in Yorubans. The linkage between ε4 and multiple ‘523 alleles in African Americans represents a genetic crossover between Caucasian and Western African populations[TOMM40 ‘523 haplotypes, the two originated from the Western African population are less potent than the ε4- TOMM40 ‘523-L haplotype in affecting the susceptibility of AD. Since genetic risk factors in admixed populations including African Americans are highly dependent on ancestral background, future work is warranted to identify local ancestry in the APOE-TOMM40 region and to investigate its implication in the risk of AD.The reports on ε4 and AD in African Americans have been inconsistent, 23–26. pulations. Data frAPOE gene is involved in amyloid deposition, a neuropathologic hallmark of AD, via amyloid-β clearance [APOE ε2, ε3, and ε4 alleles encode three protein isoforms  which show differential response for amyloid-β kinetics. In mouse models, apoE4 increases amyloid-β deposition relative to apoE2 or apoE3[APOE ε4 carriers have more severe burden of amyloid plaques[TOMM40 ‘523 variant affects AD pathophysiology is an area of active research[TOMM40 ‘523, most likely exert their effects by altering gene transcription efficiency, the timing of transcription, transcript stability, transcript splicing, or possibly by changing patterns of epigenomic modification[TOMM40 ‘523 affects the expression levels of APOE and TOMM40 mRNAs in the temporal and occipital cortexes of late onset AD patients and normal controls[TOMM40 poly-T variation on transcription regulation was recapitulated in a cell-based luciferase reporting system[TOMM40 poly-T variants. Bekris et al. described a complex transcriptional regulatory region for TOMM40 and APOE expression that extends throughout both genes and is influenced by multiple polymorphisms including the TOMM40 poly-T locus[Extensive evidence suggests that the learance , 32. The or apoE3, 34. In d plaques, 36, andd plaques, 38. The research. Structuification. There iification–49. It h controls, and theng system. Gene exTOMM40 ‘523 haplotype variations on the risk of incident AD dementia among African Americans. Our data came from a diverse group of community based older persons who were free of AD at enrollment and followed longitudinally for incident events. The prospective nature of the design avoids potential bias due to prevalent AD. Uniform and structured decision rules for AD diagnosis were applied across all three studies. Limitations of this study are also noted. These are voluntary cohorts and participants are older and have higher education than the general population. The findings await replications from other studies.To our knowledge this is the first study that investigated the effect of ε4- S1 FileTable A. APOE ε4 and TOMM40 ‘523-L with AD dementia in Caucasian Americans (matched sample) Table B. APOE ε4 and TOMM40 ‘523-L with AD dementia in African Americans (matched sample).(DOCX)Click here for additional data file.


Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course. Polymorphisms and environmentally induced epigenetic variations seem to determine individual susceptibility to the development of lung fibrosis.n = 23) with IPF receiving antifibrotic therapy (n = 27) and healthy subjects (HS) (n = 27). We analyzed serum levels of five cfnucleosomes including bound HMGB1 (nucleosomes adducted to high-mobility growth protein B1), mH2A1.1 (nucleosomes containing the histone variant mH2A1.1), 5mC (nucleosomes associated with methylated DNA), and H3K9Ac and H3K27Ac (nucleosomes associated with histone H3 acetylated at lysine 9 or 27 residue).We have studied circulating epitopes on cell-free nucleosomes (cfnucleosomes) in 50 IPF patients. We have compared untreated IPF . Moreover, we found differences in epigenetic profiles between untreated IPF patients and those receiving anti-fibrotic therapy with mH2A1.1 and 5mC being significantly lower in untreated than in treated patients . Combination of four cfnucleosomes  allow to discriminate IPF vs HS with a good coefficient of determination (R2 = 0.681). The AUC for the ROC curve computed by this logistic regression was 0.93 (p < 0.001) with 91% sensitivity at 80% specificity.Our findings showed that serum levels of bound HMGB1, mH2A1.1, 5mC, H3K9Ac, and H3K27Ac were significantly lower in IPF patients than in HS  might have potential as biomarkers for diagnosis and treatment response. These results deserve further validation in longitudinal cohorts. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course –3. Post-Nucleosomes are the basic unit of chromatin consisting in a 147-bp DNA strand wrapped around a core of eight histone protein cores. During cellular damage such as apoptosis or necrosis, chromatin is fragmented into oligo- or mono-nucleosomes which are released into the blood stream , 12. Durn = 23) and patients with treated IPF ). The diagnosis of (definite) IPF was made according to the international recommendations of the ATS [n = 18) or nintedanib (n = 9)). HS were recruited from Liège university hospital by advertising in the waiting room. None showed any symptoms of a respiratory disease, and all had normal spirometric values with predicted forced expired volume in one second (FEV1) > 80% and FEV1/FVC ratio > 70%. Patients treated with histone deacetylase activators like theophylline were also excluded.Patients were recruited from the ambulatory care polyclinics of both Liège University Hospital and Erasme University Hospital (Brussels). Patients were divided into two groups: patients with untreated IPF .Venous blood was collected at enrolment in Vacutainer tubes (for serum sampling) from an antecubital site. Ten nucleosome epitopes, corresponding to nucleosomes associated methylated DNA (5-methylcytosine (5mC)); nucleosomes associated with histone modifications H3K9Ac, H3K27Ac, H4PanAc, H3K9me3, H4K20me3, H3K4Me2, or pH2AX; nucleosomes containing the histone variant mH2A1.1; and nucleosomes adducted to high-mobility growth protein B1 (HMGB1), were analyzed in the serum of IPF patients and controls.Epitopes on cfnucleosome levels were measured using Nu.Q™ enzyme-linked immunosorbent assays (ELISA)  performed according to the manufacturer’s instructions , 17. In U test in case of statistical significances. Area under the receiver operating characteristic (ROC) curves and sensitivities at defined specificities were calculated to test the performance of the biomarkers for differential diagnosis. Binary multiple logistic regressions were used to validate the statistical significance of the cfnucleosome biomarkers and to evaluate their capacity to predict disease. p values < 0.05 were considered as statistically significant.All the statistical analyses were performed with the SPSS Statistics 24 software (IBM). For the different clinical groups, the mean value of duplicate measurements was used. Samples with a coefficient of variation (%CV) above 20% between its duplicates were repeated. The mean values were taken into consideration for the statistical analysis only if it reached the criteria: CV < 20. The distribution of the marker levels is given as median, interquartile, and total ranges. Comparisons of cfnucleosomes between the groups were performed by Kruskall-Wallis followed by Mann-Whitney The demographic functional and treatment characteristics are given in Table Epigenetic profiles of cfnucleosomes in subjects with untreated IPF, treated IPF, or HS were investigated using ELISA-based Nu.Q™ assays. Ten epigenetic features of serum cfnucleosomes were analyzed. The receiver operator characteristic (ROC) curves for each nucleosome assay in the untreated IPF group vs HS were established (data not shown). The area under the curve (AUC) for the individual ROC curves varied from 0.54 to 0.85 Table .Table 2SOf note, diagnostic sensitivity at 80% specificity for the five best nucleosome biomarkers ranged from 61 to 86% Table . Remarkap < 0.05 and p < 0.01, respectively) .Correlation studies between lung function indices and cfnucleosomes showed a positive correlation between DLCO/VA (%pred) and H3K27Ac or H3K9Ac (p < 0.001) combination of four cfnucleosomes: HMGB1, 5mC, H3K9Ac, and H3K27Ac with good coefficient of determination (R2 = 0.681). In this combination, each individual predictor was already highly statistically significant. The AUC for the ROC curve computed by this logistic regression was 0.93 (p < 0.001) with 91% sensitivity at 80% specificity for the discrimination of IPF patients vs HS . Pearson correlation analysis between age and levels of cfnucleosome modifications showed only a marginal correlation between the two parameters .In addition, we assessed if an increase in the diagnostic value could be observed by combining levels of cfnucleosome modifications. Statistical significance was calculated for several combinations using binary logistic regressions and the best combination was selected. This study revealed a highly statistically significant  and histone deacetylases (HDAC). Disruption of this balance either by an increase of HDAC or a decrease of HAT or both has been claimed to be involved in the pathophysiologic process of IPF . Given tMethylation is known to be deregulated in IPF . IPF-assLikewise, we identified a significant reduction in the level of the cfnucleosome carrying the histone variant mH2A1.1 in untreated IPF while those patients receiving anti-fibrotic drugs had levels similar to HS.Thinking beyond a single biomarker, we have assessed the value of combining several cfnucleosome modifications. After performing specific logistic regression comparing HS to untreated IPF, we found that a model of four Nu.Q™ cfnucleosome biomarkers , reached an AUC of 0.93 in a ROC curve analysis (80% specificity and 91% sensitivity), which holds promise for use in clinical practice.In conclusion, we have identified new blood-based cfnucleosome markers in untreated IPF patients. Intriguingly, some of those biomarkers tend to normalize in the patients receiving anti-fibrotic treatment. We believe these cfnucleosomes may have potential as diagnostic and treatment response tools. This observation warrants further validation in larger longitudinal cohorts to confirm their value as biomarkers in IPF.


A red phosphorus‐graphene nanosheet hybrid is reported as an anode material for lithium‐ion batteries. Graphene nanosheets form a sea‐like, highly electronically conductive matrix, where the island‐like phosphorus particles are dispersed. Benefiting from this structure and properties of phosphorus, the hybrid delivers high initial capacity and exhibits promising retention at 60 °C. Lithium‐alloy anode materials for lithium‐ion batteries (LIBs), such as Si,3P when used as a Li‐ion battery anode.−1, which is almost seven times higher than that of graphite. Phosphorus has three main allotropes: white, black and red. White phosphorus is poison and chemically not stable, which cannot be used as anode materials. Black phosphorus is thermodynamically and chemically most stable one and has higher conductivity than red phosphorus. However, its synthesis is difficult and requires high temperature and high pressure, which leads to the lowest commercial value among the three forms. Different from white and black phosphorus, red phosphorus is chemically stable, abundant, low‐cost and eco‐friendly, which make it promising for high‐energy LIBs. Despite these advantages, similar to other intermetallic alloy, two intrinsic issues of red phosphorus are the main hurdles for its application for LIBs. Firstly, it has a very low electronic conductivity (1 × 10−10 S cm−1), which makes electrochemical redox reactions difficult.Recently, phosphorus (P) was found to electrochemically lithiate and form Li4P3 via high‐energy ball‐milling, which delivers a capacity of 500 ∼ 700 mAhg−1.] Despite this encouraging progress, the current research on phosphorus‐based Li‐ion anodes is still limited in the following ways. First, either too much inactive additive was introduced to these phosphorus‐based hybrids, such as P/carbon black (30 wt% carbon black), or the content of the low‐capacity additives in the hybrid is too high, such as in the P/graphite hybrid (75 wt% graphite) and P‐Sn alloy (58 wt% Sn). This dramatically reduces the capacity and thereby the energy density of whole electrode. Second, most publications focus on the electrochemical performance at room temperature, while the study of cells operated at aggressive conditions, such as at high temperature (>50 °C) is rare to date, which is necessitated for the real application. Third, only limited cycling (≤100 cycles) has been reported, which is far from the practical application that needs longer cycles.Various carbon materials have been utilized to modify phosphorus and enhance the overall conductivity of the electrodes. These phosphorus/carbon composites, including P/carbon black (7:3),3P and graphene during the lithiation/delithiation process. Moreover, P‐O‐C bond is found in the hybrid material, and helps to maintain contact between the phosphorus and graphene. This structure and inter‐component bonding enable the P‐G hybrid anode to achieve a high initial capacity of 2517 mAhg−1 at room temperature, with 60% capacity retention after 300 cycles at 0.1 C (1C = 2600 mAhg−1) rate and good rate performance. At the elevated temperature of 60 °C, performance of the hybrid anode is also found to be excellent, showing 74% capacity retention after 200 cycles at a higher rate of 0.2 C.Herein, we report a red phosphorus‐graphene nanosheet (P‐G) hybrid as anode for lithium‐ion batteries, prepared via ball milling low‐cost commercial red phosphorus and graphene stacks. The graphene stacks are exfoliated into nanosheets and hybridize with phosphorus particles to form a 3D integrated network, which significantly improves the conductivityFigureThe synthesis process of the P‐G hybrid is schematically summarized in FigureRaw red phosphorus, graphene stacks, a mixture of phosphorus and graphene stacks (P/G mixture) and the ball‐milled P‐G hybrid were investigated by the X‐ray diffraction (XRD) technique . The starting red phosphorus powder has a medium‐range ordered structure based on its three broad diffraction peaks located at 2θ values of 15.0°, 31.6°, and 45.4°.The morphology of P‐G hybrid was investigated by electron microscopy. A transmission electron microscopy (TEM) image of graphene stacks and a scanning electron microscopy (SEM) image of raw phosphorus before ball‐milling are presented in Figure S3a and S3b, Supporting Information, respectively. It is clearly found that graphene stacks have multilayer stacked structure with a micro‐sized plane, and the raw phosphorus particles are above 50 μm in size. An SEM image of the ball‐milled P‐G hybrid is shown in Figure −1 and 1080 cm−1 in raw phosphorus sample are assigned to the P = O and P‐O‐P bonds, respectively, due to the presence of oxide on the commercial phosphorous particles.−1; this peak is assigned to P‐O‐C asymmetric stretching.[[qv: 2a]] This chemical bonding strongly binds the phosphorus to the graphene, promoting intimate P‐G contact and increasing the durability of the structure.Fourier transform infrared spectroscopy (FTIR) was used to investigate the potential of the chemical bonding between phosphorus and graphene nanosheets, as shown in Figure +. Cyclic voltammetry (CV) of the P‐G hybrid is shown in FigurexP (x=1–3) intermediates. The third peak, appearing between 0.2 V and 0.01 V, is believed to originate from lithium intercalation into graphene nanosheets.xP phase to LiyP (1 ≤ y < x ≤ 3) intermediates and finally to P.In order to investigate the electrochemical properties of the P‐G hybrid, CR2016‐coin cells were made in an argon‐filled glove box with the P‐G hybrid as the working electrode and lithium foil as the counter electrode. All cells were tested between 0.01 V and 2.0 V vs. Li/LiexP x=1– intermedst cycle to 200th cycle are illustrated in Figure −1 based on the mass of P, respectively, giving an initial coulombic efficiency of ca. 84%, corresponding to 96.7% phosphorus utilization compared with the theoretical specific capacity of phosphorus. The irreversible capacity of the first cycle is mainly attributed to the formation of an SEI layer on the electrode surface[[qv: 1b]],−1 based on the mass of P (898 mAhg−1 based on P‐G), having retained 60% of its capacity with respect to the second cycle capacity of 2137 mAhg−1 based on P. As graphene stacks were exfoliated into graphene nanosheets, the stable cycling capacity of the graphene nanosheet is expected to be low−1 based on P (756 mAhg−1 based on P‐G). When the rate was restored to 0.2 C after 50 cycles, the specific capacity returned to 1676 mAhg−1 based on P (1173 mAhg−1 based on P‐G), which is close to the 1691 mAhg−1 based on P of 3rd cycle. This indicates that the electrode cycling was reversible even at high current densities.The voltage profiles of P‐G hybrid from 1FigureIn order to understand the reason for the superior cyclability and rate capability of the P‐G hybrid, the energy‐filtered TEM (EFTEM) and the corresponding element mapping of P‐G hybrid after 150 cycles were detected and shown in st cycle and at 0.2 C at elevated temperature (60 °C) for the following cycles. Ball‐milled phosphorus‐carbon black (P‐CB) hybrid was used as a control sample. The electrochemical properties of the P‐G and P‐CB hybrid at 60 °C are illustrated in Figure−1 based on the mass of P, with high initial columbic efficiency of ca. 83.0%. After 200 cycles, P‐G hybrid at elevated temperature delivered capacity of 1623 mAhg−1 based on P, 1136 mAhg−1 based on P‐G, with a retention of 73% with respect to the second cycle capacity of 2222 mAhg−1 based on P. The coulombic efficiency of P‐G hybrid at 60 °C . Therefore, the electrochemical performance of lithium‐ion battery at elevated temperature >50 °C) is of great importance for real application. Even though many groups report the electrochemical properties of phosphorus at room temperature, their behavior at elevated temperature (>50 °C) is rarely studied up to now. In order to investigate the high temperature electrochemical properties, cells were tested at 0.1 C rate at room temperature for activation for the 10 °C is oDifferential capacity (dQ/dV) plots of the charge/discharge profiles of P‐G and P‐CB are shown in Figure −1 based on mass of P and excellent capacity retention within 300 cycles is achieved at room temperature. Even at elevated temperature of 60 °C, ca. 1623 mAhg−1 based on P with a retention of 73% after 200 cycles and high coulombic efficiency of 99.0% is achieved. Taking the facile and general method as well as the low cost starting materials into account, this P‐G hybrid is believed to be promising anode candidate for the next generation lithium‐ion battery.In summary, we successfully developed a phosphorus‐graphene nanosheet hybrid via simple ball milling low‐cost red phosphorus and graphene stacks. The graphene stacks are exfoliated into two‐dimensional large pieces of graphene nanosheets, which build up highly‐electronically‐conductive matrix. Large phosphorus particles are grounded to much smaller size and hybridize with graphene nanosheets to form a 3D integrated network. In addition, the content of graphene nanosheets has been optimized. Sufficient graphene nanosheets are required to build up 3D integrated network. Moreover, P‐O‐C chemical bonds, found between phosphorus and carbon in the hybrid, ensure an intrinsic electrical connection and a robust structure. As a result, high gravimetric specific capacity of 2362 mAhgPreparation of P‐G Hybrid, P‐CB Hybrid, P/G Mixture, and P/G Control Sample: The P‐G hybrid was prepared though a straightforward, industry‐accepted ball‐milling approach. The raw materials, commercial red phosphorus  and graphene stacks  were mixed together with a mass ratio of 7:3. The mixture was then ball‐milled for 1000 min at a speed of 400 rpm in a stainless steel jar under argon atmosphere. P‐CB hybrid was prepared following the same procedure using carbon black as a carbon source. The P/G mixture used for XRD test was prepared by directly mixing raw red phosphorus and raw graphene stacks. The P/G control sample for electrochemical test was prepared by hand milling the ball milled phosphorus and ball‐milled graphene stacks with the ratio of 7:3. The phosphorus and graphene stacks were separately ball‐milled for 1000 min at a speed of 400 rpm under argon atmosphere before hand‐mill mixing.Characterization: Powder XRD was collected on a Rigaku Miniflex II spectrometer with Cu Kα radiation. The morphology of the P‐G hybrid was investigated with scanning electron microscope (Nano630 FE‐SEM). TEM and EFTEM (JEOL 2010 LaB6) were used for microstructure investigation and elemental mapping. FTIR spectroscopy was performed as diffuse reflectance measurements with powder samples using a Bruker IFS 66/S FT‐IR spectrometer and Spectra‐Tech Collector II DRIFTS accessory; samples were diluted with KBr in approximately a 30:1 mass ratio.Electrochemical Measurement: Electrochemical performance was tested using 2016‐type coin cells, which were assembled in an argon‐filled dry glove box . The working electrodes were prepared by casting a slurry composed of 70 wt.% active material, 15 wt.% Super P carbon black, and 15 wt.% sodium carboxymethylcellulose (NaCMC) binder (2 wt.% in water) on copper foil, drying at 100 °C under vacuum overnight, and punching out disks 12 mm in diameter. The mass loading of electrodes was 0.8–1.5 mg cm−2. 1M LiPF6 in a mixture of ethylene carbonate (EC), diethyl carbonate (DEC) and fluoroethylene carbonate (FEC) (1:1:0.2 by volume). Galvanostatic charge/discharge tests were carried out on a LAND battery tester between 0.01 V and 2.0 V versus Li/Li+. Cyclic voltammetry (CV) was performed at a scan rate of 0.1 mVs−1 within the range of 0.01–2.0 V using a CHI 660D electrochemical workstation.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Identifying the true identity of a subject in the absence of external verification criteria  is an unresolved issue. Here, we report an experiment on the verification of fake identities, identified by means of their specific keystroke dynamics as analysed in their written response using a computer keyboard. Results indicate that keystroke analysis can distinguish liars from truth tellers with a high degree of accuracy - around 95% - thanks to the use of unexpected questions that efficiently facilitate the emergence of deception clues. It is known that terrorists cross borders using false passports or claiming false identities2. For example, one of the suicide bombers involved in the Brussels train-station attack on March 22, 2016 was travelling through Europe using the identity of an Italian football player3. In these scenarios, security measures mainly consist of cross-checks on the data declared by the suspects or in the verification of biometric features, such as fingerprints, hand geometry, and retina scans4. Nevertheless, terrorists are mostly unknown: they are not listed in any database, and the security services do not have any information by which to recognise them.Presently, one of the major issues related to identity and security is represented by the numerous and current threats of terrorist attacks6. Existing security systems for online authentication are now primarily based on passwords, while other biometric methods have been recently proposed7. These are based on human-computer interaction recording, such as systems for user authentication and identification via keystroke analysis or mouse dynamics8. In short, machines are trained to recognise the typical usage pattern of the keyboard/mouse of a specific user. However, these methods entail acquiring the writing or the mouse movement pattern of each user and storing it in a database queried upon every authentication.False identities in online services represent another unresolved issue. They expose people to the risk of being attacked and manipulatedet al. proposed a novel methodology which, using mouse dynamics in response to unexpected questions, identifies fakers of personal identities with a high degree of accuracy11. In brief, the authors developed a task in which they presented liars and truth tellers with questions related to their ID-card identities. Participants were asked to answer “yes” or “no” to questions by clicking the correct response on the computer screen with the mouse in accordance with the personal information on their ID card. Questions given to participants were of three types: control, expected and unexpected questions. The first set of questions was related to personal features about which no one could lie in a physical setting . Expected questions were questions about the information on the ID card (e.g. “were you born in 1990?”). Finally, unexpected questions were derived from the ID card information (e.g. “are you 26 years old?”). Unexpected questions may be retrieved directly by truth tellers, while liars would compute them on the fly, and this additional working-memory load shows itself in the increased number of errors and in mouse trajectories and kinematics.Recently, Monaro et al.11, we recorded the subjects’ typing pattern on the keyboard (keystroke dynamics). The main advantage of relying on keystroke dynamics is that, in contrast to mouse tracking, it can also be adopted in situations in which it is not possible to formulate close-ended “yes or no” questions, such as the online context (e.g. a website subscription form).However, the yes/no structure of the test requires preliminary crafting of the questions by the experimenter, and this may be problematic for the online application of the technique. In order to overcome such caveats, we will report here an experiment in which participants respond to similar questions entering their response in an edit box using the keyboard. In the present work, we asked unexpected questions of participants, but, innovatively with respect to Monaro In short, we will report data from an experiment that registered the keyboard dynamics when participants answered questions related to personal identity not requiring preliminary information about the examinee.12. The major involvement of memory load is revealed by the increased number of errors and longer response times15. In a similar way, some authors have argued that the writing pattern of an individual (i.e. keystroke dynamics) may provide a clue to recognising deception. Keystroke dynamics refers to detailed timing information regarding human typing rhythm: it describes exactly when each key is pressed and released while a person is typing at a computer keyboard, a mobile phone or a touchscreen panel16. Typing pattern analysis is an implicit-behaviour measure insofar as the user is not aware of it during interaction with the device17. The keystroke features most commonly extracted are latencies, for example, how long a key is held down (dwell Time), or the time between the release of one key and the pressing of the next (flight time)16. Grimes et al.18 proposed a model to explain the relationship between deception and keystroke dynamics.In order to identify liars and, more generally, the production of deceptive responses, several authors have studied the cognitive mechanisms involved in deception. There is a broad consensus in the literature that producing a lie is cognitively more complex than truth telling. It requires the inhibition of the true response and its substitution with a lie which, in turn, should be not easily verified as such19 or in chat interplay20. The results support the cognitive-load theory, confirming that deception is correlated with keystroke features. Up to now, however, no study in the literature has reported results on the identification of identity deception via keystroke pattern analysis.Few studies in the literature have applied keystroke dynamics to identify the production of false information. Moreover, all such studies have focussed on the identification of deception in online reviews21 and the Concealed Information Test (CIT)22. It has been shown that CIT and aIAT spot liars with an accuracy of 90%. However, their practical application is limited, as they require the use of the to-be-tested true information. In other words, CIT and aIAT can detect which one between two information is true and which is false, while in the real cases only one information, the one that the examinee declared, is available. Finally, both CIT and aIAT perform overt lie detection.To date, scientific lie-detection methods based on the cognitive mechanism of deception that may be used to unmask false identities are the autobiographical Implicit Association Test (aIAT)23. Covert lie detection refers to conditions under which the examinee is unaware that he or she is under the scrutiny of a scientifically based lie-detection technique. Such covert lie-detection techniques include thermal imaging lie detection24, the voice stress analyser25, mouse tracking11 and linguistic analysis26.Overt lie detection includes all techniques for which the examinee knowingly takes a lie-detection test. This category includes the polygraph, P300, fMRI, CIT, aIAT and othersThe technique that we present here falls under the category of covert lie-detection techniques. That is, the subject responded to questions by digitising, in an edit box, his or her responses as free text. There was no constraint or specific instruction to follow, for the response collection mimicked the typical online form. For research purposes, liars were instructed to respond with a fake identity, but, in a real setting, no hint is given to the subject that he or she is under the scrutiny of a credibility-assessment technique.The experiment aims to investigate whether there are differences in the writing patterns of a person who provides real personal information and a person who, on the contrary, provides intentionally false personal information. Half of participants were instructed to lie about their identity, while the remaining half entered their real information.et al.11, we used unexpected questions to increase the cognitive load . The use of unexpected questions has been shown to be effective in uncovering deception in investigative interviews27. In our experiment, expected questions are information typically reported on the ID card (e.g. month of birth), while unexpected questions are information that liars have to compute starting from the available expected information (e.g. the zodiac sign) and that truth tellers have, in contrast, readily available.In our experiment, similar to the experimental design in Monaro et al.18, we expect to detect a greater variability in liars’ typing patterns and, conversely, minor deviations from average values in truth tellers’ typing patterns.Given that lying taps further into working memory than truth telling, we expect keystroke dynamics to reflect this cognitive difference. We expect longer reaction times (RT) and more errors in liars relative to truth tellers, especially in response to unexpected questions, a type of question that requires a higher cognitive load. Moreover, in line with the model of Grimes https://truthorlie.math.unipd.it/new/, and the task code is publicly available at this link: https://github.com/SPRITZ-Research-Group/Covert_lie_detection_using_keyboard_dynamics. Data were stored via MySQL Ver 14:14 Database. Finally, data were analysed using R28 for preliminary descriptive statistical analysis and WEKA29 for developing the machine-learning (ML) models trained to classify whether the collected response was that of a truth teller or that of a liar. Data are publicly available at this link: https://github.com/SPRITZ-Research-Group/Covert_lie_detection_using_keyboard_dynamics, as is the R code used for preliminary descriptive statistical analysis and the description of the WEKA procedure followed to obtain the ML models. For the sake of clarity, ML refers to the study and construction of algorithms that can learn information from a set of data  and make predictions for a new set of data . ML is now the basis for a large number of applications, such as the self-driving cars, speech recognition (e.g. Siri), recommender systems, etc. It enables the training of one or more algorithms to predict outcomes without being explicitly programmed and only uses the information learned from the training set. Usually, ML models outperform traditional statistical models.The experiment was conducted in the laboratories of the School of Psychology at Padua University using a single laptop ASUS F552WE-SX039 15.6” in order to avoid possible device-specific variation. The experiment was run from a site built using PHP, HTML and JavaScript. Recording of keystrokes and intervals was programmed using JavaScript. Through the website, we collected the responses of 60 individuals who completed the edit box presented below . These 40 participants were used to preliminarily build an ML classification model (training set). When the model was built, a new group of 20 participants—6 males and 14 females—was recruited to test the classification model .All participants signed an informed-consent agreement. A photo of each participant’s face was taken and pasted on a standard Italian ID card together with the personal information of the participant. Debriefing at the end of the experiment was carried out.The experimental procedure was approved by the ethics committee for psychological research in the Padova University Psychology Department. The experiment was performed in accordance with relevant guidelines and regulations.et al.11. We had 20 participants to answer truthfully, while the others were instructed to lie about their identity according to a false autobiographical profile which was presented on the fake ID card displaying the participant’s real photo and false personal information. After the learning phase, participants were required to correctly recall the information presented on the ID card twice; they performed a mental-arithmetic task in between. This multistep procedure ensured the investigator that liars actually learned their assigned false personal information.The experimental procedure is similar to the one adopted by Monaro For both experimental groups, the task required answering 18 open-ended questions related to identity. Table Before starting the experiment, participants completed a warm-up block consisting of three questions. Data collected from the warm-up block were not further analysed.Control questions (n = 4): these included personal and physical information that was not possible to hide from the examiner in the face-to-face experimental setting . All participants, including liars, responded to these questions truthfully.Expected questions (n = 8): these were questions targeting information that appeared on the ID card. In the case of liars, the answers to these questions about their fake IDs were learned in the preliminary part of the experiment. Truth tellers responded truthfully to these questions while liars were required to lie and provide the information found on their fake ID.Unexpected questions (n = 6): unexpected questions were based on information strictly related to identity but not explicitly rehearsed in the preliminary phase by truth tellers or by liars. Truth tellers responded to these questions referring to their real identity, while liars responded referring to their assigned fake identity.The 18 questions, randomly presented to subjects, belonged to the following categories:The control, expected and unexpected questions shown to participants during the experiment are reported in Table Typical response length ranged between 1 and 4 words. The total duration of the task was about 10–15 minutes.Number of errors: this refers to the total number of errors committed by the person in answering the 18 questions. Specifically, error means the number of fields for which incorrect information was entered. Errors were calculated by checking each response given by the subject against the conceptually correct information. We only considered conceptual errors for three reasons. First, other types of errors, such as typing errors, were rarely detected because of the low number of words required by the responses. Second, when encountered, such errors were minimal, thereby not affecting the conceptual correctness of the answer. Third, an indirect measure of typing errors was already given by the use frequency of special characters, such as Del and Canc keys. An example reported as a conceptual error was the answer “Capricorn” when the corresponding date of birth of the learned profile was the December 2, 1988. Another example based on the same date of birth would be the answer “22” to a question related to age. Most conceptual errors were detected in unexpected questions, when the subjects, truth tellers or liars, were required to compute the unexpected information asked from the known data written on their own profile .30. GULPEASE is an index which takes into account the length of the sentence read.Prompted-firstdigit: this refers to the interval between the onset of the sentence on the computer screen and the first key pressed. This index was subsequently adjusted using a readability index for the Italian language (GULPEASE Index) in order to refine the reaction time by weighting the latency of the response to the question for the difficulty of reading the questionPrompted-enter: this refers to the total time from the stimulus onset to ENTER (pressed at the end of the response).Firstdigit-enter: this refers to the time between the first key and ENTER.Time before enter key: this refers to the time between last key and ENTER.Answer length: this refers to the number of characters of the response.Writing time: this refers to the average typing speed (firstdigit-enter/number of characters).Down time: this refers to the timestamp for pressing each key.Up time: this refers to the timestamp for releasing each key.Up and down time: this refers to the sum of down time and up time for each key.Press time: this refers to the duration between each key down and each key up.Flight time: this refers to the interleaving time between each key up and the next key down.Di-graphs: these refer to the sum of up time, down time or up and down time for two consecutive keys.Tri-graphs: these refer to the sum of up time, down time or up and down time for three consecutive keys.Frequency of use for special characters: this refers to the total number of key pressing for Shift, Del and Canc, Space and Arrows characters.For each response, the following data were collected and stored for analysis:We calculated a total of 62 attributes for each subject, averaging each variable over the 18 responses given by each subject. The complete list of the 62 attributes is reported in Supplementary Table The data set generated and analysed in the current study is available from the corresponding author upon reasonable request.https://github.com/SPRITZ-Research-Group/Covert_lie_detection_using_keyboard_dynamics.The datasets generated during and/or analysed during the current study are available in the “Covert_lie_detection_using_keyboard_dynamics” repository, 31. To avoid the multiple-testing problem, the Bonferroni correction was applied and the p-value was set to 0.0008. Furthermore, we calculated the Cohen’s d effect size. Results are presented in Table A first analysis was carried out by examining the statistical differences in the collected data for truth tellers and liars through independent t-test. We ran a Welch’s t-test (included in the R software ‘lsr’ package), which adjusts the number of degrees of freedom when the variances are not assumed to be equalWe analysed the error rate separately for control, expected and unexpected stimuli. The analysis yielded the results reported in Table 32. On the basis of these criteria, in a first-features selection step, we selected the predictors that show maximum correlation with the dependent variable. These predictors were as follows: number of errors (rpb = 0.85), prompted-firstdigit adjusted for the GULPEASE index (rpb = 0.71), prompted-firstdigit (rpb = 0.70), prompted-enter (rpb = 0.65), firstdigit-enter (rpb = 0.46), writing time (rpb = 0.50) and time before enter key down (rpb = 0.43). In a second step, we looked at the intercorrelation between these seven features. Two of the seven predictors (prompted-firstdigit and prompted-enter) showed a very high correlation value, respectively, with prompted-firstdigit adjusted GULPEASE (rpb = 0.99) and firstdigit-enter (rpb = 0.89). Hence, to avoid redundancy, these features have been excluded. The five final attributes of the feature selection considered for the purposes of classification are described, as are their correlations, in Table https://github.com/SPRITZ-Research-Group/Covert_lie_detection_using_keyboard_dynamics.It has been suggested that classifier accuracy is enhanced by selecting a subset of predictors which have maximum correlation with the dependent variable and minimal intercorrelation between features rpb = 0.6, writin29. Four different classifiers were trained via a 10-fold cross-validation procedure using data from the first 40 participants as a training set37. We selected four classifiers that differ based on their assumptions. Random forest operates by constructing a multitude of decision trees33. Logistic regression measures the relationship between the categorical dependent variable and one or more independent variables by estimating probabilities using a logistic function34. Support vector machine (SVM) is a non-probabilistic binary linear classifier which maps the space, so the examples of the separate categories are divided by a clear gap that is as wide as possible36. Logistic model tree (LMT) combines logistic regression and decision-tree learning37.Classifiers were run in WEKA, an ML softwareErrors: errors are a key attribute, as the results indicated that eliminating errors from predictors led to a decrease in classification accuracy around 80% for the cross-validation and around 68% for the test.Prompted-firstdigit: when this predictor is eliminated with its related variables (such as prompted-firstdigit and prompted-enter), the overall accuracy remains substantially high (around 90% for training and around 95% in the test). Furthermore, these results are similar for different classifiers.Firstdigit-enter, writing time and time before enter key down: when eliminating the firstdigit-enter variable using the predictors, the accuracy remains high . The same occurs when removing the writing time and time key before enter down.Finally, to evaluate the generalisation of the results for completely new data, models were tested on 20 new participants not previously used in the learning phase. Accuracies obtained by the classifiers during training and testing are reported in Table The accuracy obtained for each classifier and all classification metrics are reported, in greater detail, in Supplementary Table All these analyses were conducted taking into account the responses to all three types of questions . We specifically analysed control questions separately as both liars and truth tellers were required to respond truthfully to control questions. All classifiers yielded a classification around chance level for this type of question Writing time (firstdigit-enter/answer length)Prompted-firstdigit – prompted-enter (prompted-firstdigit minus prompted-enter)Writing time/prompted-firstdigit – prompted-enter [writing time/(prompted-firstdigit minus prompted-enter)]One could argue that keyboard dynamics are modulated by a number of different variables such as age, cultural level and typing skills. Hence, the analyses reported above were conducted on raw data using two groups of subjects similar in age, cultural level and typing skills. In order to render the results generalisable, it would be interesting to see whether similar results hold not only for raw data but also for normalised predictors. To overcome this limitation, we ran the classification models again using only normalised indices, less influenced by inter-individual and environmental variables. These indices were:Results from the five classifiers using the normalised predictors are reported in Table Errors to unexpected questions are diagnostic of lying, and the subjects should respond without errors in order to cheat the test, However, this seems impossible as subjects are already performing at their maximum level. There are no easy countermeasures to the number of errors; therefore, countermeasures are limited by keystroke dynamics.Parameters used to encode keystroke dynamics and correlate with the dependent variable are high in number, and only some were used in building the original model. It is unlikely that the cheater succeeds in implementing countermeasures that simultaneously remain under voluntary control all possible efficient predictors.Resistance to countermeasures is a central issue for all available lie-detection techniques. We did not directly test resistance to countermeasures in the present paper, but a number of reasons indicate that coaching subjects could be difficult, particularly as pertains to:To highlight these points, we have tested a new model that uses the following as predictors: (rpb = 0.85), prompted-firstdigit (rpb = 0.70), prompted-enter (rpb = 0.65), time before enter key flight (rpb = 0.43) and di-graph down time average (rpb = 0.38) . Results for the new set of predictors for the sample of 40 participants are as follows : Random Forest = 90%, Logistics = 92.5%, SVM = 95% and LMT = 97.5%. Results for the 20 participants of the validation sample were as follows: Random Forest = 90%, Logistics = 100%, SVM = 90% and LMT = 90%. Classification metrics are reported in Supplementary Table 38. Anomalies are data that have different patterns relative to normal instances. The detection of anomalies provides significant information and has applications in many fields. For example, the detection of anomalies is used in credit-card transactions, astronomical images or nuclear-plant functioning. Anomaly-detection techniques classify subjects after a training limited to the most frequent group, in our experiment the truth tellers39. At prediction, new instances with unknown class labels can either belong to the target class  or to a new class that was not available during training . This type of learning problem is known as one-class classification. Following this logic, we tested whether a one-class classifier38 can classify liars satisfactorily even if the model is trained only using data from truth tellers. This ML algorithm was trained using logistic regression on the data of the 20 original truth tellers and tested on the new group of 20 participants (10 liars and 10 truth tellers). The one-class algorithm correctly classified 85% of the instances; specifically, it correctly classified 70% of the truth tellers as the target and 100% of the liars as the outlier  or who completed the test using a smartphone or a tablet (n = 31); participants who did not speak Italian as first language (n = 3), to exclude the possibility that the response time was influenced by a poor knowledge of the language; participants who completed the experiment with the clear intention to sabotage it (n = 1); participants who took the task more than one time (n = 15); participants for whom the system did not record keystroke up time (n = 41).22, this figure (50%) could look somewhat high. However, in this study the 24% of participants were excluded because of non-compliance of the technical instructions that were given in the recruiting email (they were instructed about avoiding to use smartphones or tablet or using the non-supported browser Explorer given that it was not recording the up-times). One may presume that people who lack of motivation do not focus on all the instruction details before clicking the test link, increasing the rate of participants to be excluded.After filtering the participants using these criteria, 151 participants (86 liars and 65 truth tellers) were used for the final analysis. It should be noted that the dropout rate was around 50%. Given that we recruited subjects among trusted participants and that comparable online lie detection experiments have reported a dropout rate around 30%https://github.com/SPRITZ-Research-Group/Covert_lie_detection_using_keyboard_dynamics.The final group of 151 participants consisted of 41 males and 110 females . Data are publicly available at the following link: Data from the new 151 online-recruited participants were used to evaluate the models built with the original sample of 40 participants. The features entered in the models were those reported in Table A second model was evaluated using the alternative set of predictors mentioned above . The model was built on the original sample of 40 participants and tested on the 151 online-recruited participants. Results for the test set are as follows: Random Forest = 90%, Logistic = 90.1%, SVM = 90.1% and LMT = 90.7%. Classification metrics are reported in Supplementary Table Finally, running a 10-fold cross-validation on the 151 online-recruited participants  the accuracy of the four classifiers is in the range of 92–94%.These results confirm that the proposed technique can spot liars with high-level accuracy even when administered online.et al. in previous research11. Monaro et al.11 presented a technique based on unexpected questions that was effective in uncovering liars . While the authors required participants to respond using the mouse and analysed mouse trajectory, in this study, we required subjects to digit their responses in an edit box, a condition which mimics online form completion. Lie detection via keystroke dynamics is more suitable than mouse tracking for online contexts (e.g. to verify the authenticity of information typed by the user during an online subscription). Moreover, this setting allows for the use of covert lie detection, a lie-detection procedure in which the respondent is unaware of being tested for lies.The novelty of this work is in the mean that has been apply to spot liars, which extends the possible applications of the unexpected-questions technique proposed by Monaro It is one of the few techniques that can be used to implement covert lie detection.It does not require external instrumentation because only a computer and a keyboard are required.The number of predictors is high, rendering the development of effective countermeasures to lie detection difficult.The procedure proposed herein seems to have the following advantages:We conducted a proof-of-concept lie-detection experiment in which liars  are identified based on their anomalous typing style (i.e. keystroke dynamics). Questions about identity that were expected were mixed with unexpected questions. This approach confirmed that unexpected questions effectively increase liars’ cognitive and facilitate their differentiation from truth tellers. The predictor that most contributed to this classification was the number of errors made by liars, mainly when presented with these unexpected questions about identity. Furthermore, liars exhibited longer reaction times between the onset of the question and the start of their response in the edit box. This result shows that liars require more time to retrieve their response. The increase in time was not only limited to the onset of the response but was also observed in the time required to type the full response and in the time taken to confirm the response after the last letter was pressed. Liars take more time to verify their untruthful responses with respect to truth tellers offering true responses. In short, final rechecking of the response took more time for liars than truth tellers. Examples of the prototypical deceptive and truthful keystroke patterns are reported in Table 11 as well as other RT-based lie-detection techniques22. However, it is suitable for a broader range of applications, such as the web deception.To conclude, the technique of asking unexpected questions combined with keystroke pattern analysis may be an efficient instrument to spot fake identities with the possibility of easy application in the online context. The methodology that we proposed in this paper showed an accuracy similar to that obtained in other studies using the unexpected-questions techniqueAs anticipated in the previous section, the resistance to countermeasures was not directly tested in the present paper; it remains an open issue. The high number of predictors leads one to think that it is possible to develop many models that take into account different features for the prediction. This makes it more difficult for the user to fully control the lie-detection machine via efficient, planned countermeasures. However, our study also shows that some features, such as the number of errors, play an important role in classification accuracy. To point out this issue, we plan to specifically test the technique’s resistance to countermeasures by instructing subjects to beat the lie-detection machine with explicit strategies.Before the experimental task, the subjects spent a few minutes learning the fake identity. In some real cases , the subject spent more time learning more the false identity in greater depth. However, it is also true that in other real cases (e.g. the user trying to subscribe to a website with a fake identity), people are not so well prepared. Since the method is based on asking unexpected questions, the time taken to learn the information is not crucial. Indeed, what is crucial to beat the test is to be prepared to respond with unexpected information. Future experiments will be directed at testing the accuracy of the method in the case of a subject who is aware of the underlying logic of the task in advance or who knows the possible unexpected questions in advance. Asking unexpected questions entails a complex crafting process that requires identifying what would be unexpected questions for the examinee. If an unexpected question is not really unexpected (as the subject may prepare him or herself in advance), it becomes an expected question and loses its efficacy. Though unexpected questions can be varied in content , another future direction could be to tune new strategies, different from unexpected questions, to increase liars’ cognitive load, thereby resulting in an alteration of keystroke dynamics.The experiment was conducted using students; hence, a replication with older and less-skilled subjects is required, for age and writing skills may mediate the effect of lying.Some of the unexpected questions included in the task rely on information that cannot be generalised to all cultures and ethnicities. An example is the unexpected question about the zodiac sign, which may be well-known personal information in some culture but not in others.Other limits of the present investigations include the following:In line with these limitations, future studies will address the collection of additional data from populations with different ages, skills and cultures.Supplementary Tables


Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling. Neuroprotective strategies have been developed to ameliorate brain damage by preservation or restoration of neurological functions. An extensively studied therapeutic strategy for the treatment of several brain diseases has been the administration of brain-derived neurotrophic factor (BDNF). This growth factor is central to the differentiation, maturation and survival of neurons. Despite its relative success in the laboratory, administration of neurotrophins did not produce the expected results in clinical trials. Thus, intrathecally administered BDNF in patients of amyotrophic lateral sclerosis (ALS) did not show significant effects on motor function and survival . A. ANTR. TAdditionally, under excitotoxic conditions, TrkB-FL activity is also impaired by phosphatase Shp-2 (Src homology-2 domain-containing phosphatase-2) dephosphorylation of residue Tyr515 h 36]. C. C36]. CExcitotoxicity contributes to neuronal death in acute disorders other than stroke, as well as many chronic diseases of the CNS . TherefoNeurotrophic signalling is severely impaired in AD. This progressive neurodegenerative disorder causes the most prevalent age-related dementia. It is characterized by the formation of senile plaques, which are extracellular deposits of misfolded amyloid β-peptide (Aβ), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein . PatientIn addition to BDNF, a decrease in the TrkB-FL receptor has been found in postmortem AD brains, specifically in the nucleus basalis , and froSeveral mechanisms activated by the Aβ peptide, acting at different levels of the BDNF/TrkB signalling pathway, result in neurotrophic deficiency in AD. One prominent effector of this deathly Aβ activity is calpain which is overstimulated in postmortem AD brains . ActivatOther important mechanisms contributing to the deficiency of BDNF/TrkB signalling in AD are the suppression of MAPK/ERK and PI3K/Akt pathways by sub-lethal concentrations of Aβ, without interference of TrkB-FL and PLCγ activation , and theGlued via Htt-associated protein 1 (HAP1) [This autosomal dominant neurodegenerative disorder is caused by a CAG expansion in the huntingtin (Htt) gene that results in elongation of the polyglutamine (polyQ) tract at the Htt N-terminus. Dysfunction and death of the medium-sized spiny neurons (MSNs) of the striatum is a primary pathological feature of this disease and main responsible for the motor, cognitive and psychiatric decline. It has been proposed that a deficiency of BDNF/TrkB signalling contributes to the selective vulnerability of MSNs in HD . Reduced1 (HAP1) ,97 or di1 (HAP1) . The exp1 (HAP1) . Thus, t1 (HAP1) . An addi1 (HAP1) , which aBdnf expression from promoter II [Bdnf by recruiting the methyl-CpG binding protein 2 (MeCP2) to promoter IV [The phosphorylation of wild-type Htt in Ser421 by Akt promotes the anterograde movement of vesicles , mediatemoter II  by sequemoter II . In contmoter II , leadingmoter II . Additiomoter IV , also semoter IV .NTR and TrkB-Shc [NTR but decreased TrkB-FL protein levels are observed in the striatum from HD patients at late disease stages [NTR since this gene is regulated by this transcription factor [In addition to altering BDNF levels and transport, mutant Htt also leads to reduced neurotrophic support by affecting the availability of neurotrophin receptors. Thus, in HD patients there is an imbalance in the striatal expression of TrkB-FL mRNA with respect to p75TrkB-Shc . Conseque stages ,110. Thee stages  could unn factor . In addin factor . Furthern factor  could ren factor ,115. Addn factor  and, theNTR signalling through PTEN (phosphatase and tensin homolog) resulting in suppression of Akt signalling [The deficiency in BDNF/TrkB downstream signalling observed in HD has been recently revealed to precede the defects in transport and expression of neurotrophin and receptors ,118. Thugnalling ,119. Likgnalling , highligThe most common neurodegenerative movement disorder, PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) along with defective intracellular accumulation of α-synuclein inclusions, the so-called Lewy bodies and Lewy neurites. Postmortem studies of PD patients reveal a reduction of BDNF mRNA and protein in the vulnerable region SNpc ,122 and Nevertheless, it is generally assumed that the impairment of neurotrophic signalling in PD is the consequence of the toxicity and prion-like propagation of misfolded α-synuclein . InteresFinally, mitochondrial dysfunction alters calcium homeostasis in PD leading to the overactivation of calpain  which thMalfunction of BDNF/TrkB also plays a role in the pathophysiology of psychiatric disorders although the available evidence is still limited. Among them, one of the better characterised diseases is depression. Several lines of evidence indicate that it may be associated with the inability of neuronal systems to exhibit adaptive plasticity, and highlight the reduction in neurotrophic signalling as one central disease mechanism (reviewed in reference ). StressBdnf promoters has been observed in psychotic subjects [Schizophrenia patients suffer impairments in perception, cognition and motivation that reflect, at least in part, deficits in dendritic spines . An essesubjects . Additiosubjects ,164 and subjects ,166, havsubjects .Other pathologies related to decreased BDNF/TrkB signalling are neurodegenerative diseases of the retina such as glaucoma, age-related macular degeneration, diabetic retinopathy or retinitis pigmentosa. For glaucoma, death of retinal ganglion cells (RGCs) resulting in optic nerve damage and irreversible blindness can be explained by a lack of neurotrophic support . The mosNTR levels [Finally, excessive activation of TrkB-FL has been unveiled as a molecular mechanism underlying the induction of epilepsy , which iR levels ,179. It R levels , and furThe disorders and pathological conditions induced or promoted by aberrant BDNF/TrkB signalling could be potentially treated by fine-tuned activation  or suppression  of this pathway. Particularly, in the case of neurological disorders, the recovery of neurotrophic signalling could be not only neuroprotective but also promote adult neurogenesis (reviewed in ) or synaDifferent strategies directed to increase the availability of BDNF have been evaluated. Several research groups have shown neuroprotective effects in disease models induced by treatment with recombinant BDNF. However, administration of this neurotrophin did not exhibit the expected results in clinical trials ,2 mostlyBdnf promoters, which do not respond to synaptic activity and may contribute to cognitive decline [An interesting alternative to BDNF administration is the enhancement of endogenous neurotrophin production. For example, physical exercise evokes a significant increase of BDNF levels in rat hippocampus and cerebral cortex  which is decline . Since m decline . These r decline ,197.Another strategy has consisted in the development of small-size TrkB agonists alternative to BDNF, or BDNF mimetics, such as 7,8-dihydroxyflavone , an stable molecule able to efficiently cross the BBB after oral administration . 7,8-DHF2+ levels and restores BDNF-induced intracellular signalling [In any case, the efficiency of treatments enhancing or mimicking BDNF actions, or those directed to TrkB transactivation, could be dramatically limited if the receptor stability and function were aberrant, as is frequently the case in neurological and psychiatric disorders. Therefore, we necessarily need to devise therapeutic compounds that recover TrkB receptor and downstream signalling to be used in combination with drugs acting upstream. This is particularly important in the case of diseases with an excitotoxic component due to calpain and metalloproteinase/γ-secretase activation. As mentioned, isoforms TrkB-FL and TrkB-T1 are RIP substrates and release a receptor ectodomain that acts as a BDNF scavenger and significantly alters BDNF/TrkB signalling . Additiognalling .One of the more innovative ideas for the modulation of BDNF/TrkB downstream signalling pathways is shuttle-mediated drug delivery by conjugation of the therapeutic molecules to cell-penetrating peptides (CPPs) capable to cross the BBB and the cell membrane (reviewed by ). Thus, In this article, we have reviewed evidence demonstrating that dysregulation of neurotrophic signalling is common to most neurological disorders, including stroke and neurodegenerative diseases, and that alterations are produced at different levels of this route. Altogether, the presented data highlight the importance of this key pathway for the treatment of neurological disorders and show the necessity of approaching the development of therapies in a more integral way. The enhancement of the BDNF/TrkB signalling pathways will certainly require the combination of BDNF targets with those addressing the aberrant expression and function of TrkB receptors and downstream effectors.