TGF-ß Tumor Suppression through a Lethal EMT.

TGF-ß signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-ß mediator Smad4. We show that TGF-ß induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-ß-sensitive PDA cells, EMT becomes lethal by converting TGF-ß-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-ß. TGF-ß-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-ß tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.

Contextual determinants of TGFß action in development, immunity and cancer.

Few cell signals match the impact of the transforming growth factor-ß (TGFß) family in metazoan biology. TGFß cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions and various congenital diseases. The effects of the TGFß family are mediated by a combinatorial set of ligands and receptors and by a common set of receptor-activated mothers against decapentaplegic homologue (SMAD) transcription factors, yet the effects can differ dramatically depending on the cell type and the conditions. Recent progress has illuminated a model of TGFß action in which SMADs bind genome-wide in partnership with lineage-determining transcription factors and additionally integrate inputs from other pathways and the chromatin to trigger specific cellular responses. These new insights clarify the operating logic of the TGFß pathway in physiology and disease.

Publisher Correction: Contextual determinants of TGFß action in development, immunity and cancer.

In the section 'Combinatorial ligand perception' of the original article, DMP1 was incorrectly used in place of BMP. This has now been corrected in the HTML and PDF versions of the article.

Publisher Correction: TGF-ß orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

TGF-ß orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer1-4. EMTs are driven by SNAIL, ZEB and TWIST transcription factors5,6 together with microRNAs that balance this regulatory network7,8. Transforming growth factor ß (TGF-ß) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-ß signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer4,11. TGF-ß depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12-19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector20,21, as a key partner of TGF-ß-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-ß-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-ß-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-ß pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.

Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation.

BACKGROUND & AIMS: Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS: We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS: We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.

Serial Dependence in Perception.

Much evidence has shown that perception is biased towards previously presented similar stimuli, an effect recently termed serial dependence. Serial dependence affects nearly every aspect of perception, often causing gross perceptual distortions, especially for weak and ambiguous stimuli. Despite unwanted side-effects, empirical evidence and Bayesian modeling show that serial dependence acts to improve efficiency and is generally beneficial to the system. Consistent with models of predictive coding, the Bayesian priors of serial dependence are generated at high levels of cortical analysis, incorporating much perceptual experience, but feed back to lower sensory areas. These feedback loops may drive oscillations in the alpha range, linked strongly with serial dependence. The discovery of top-down predictive perceptual processes is not new, but the new, more quantitative approach characterizing serial dependence promises to lead to a deeper understanding of predictive perceptual processes and their underlying neural mechanisms.

Right Ventriculoarterial Coupling Surrogates and Long-Term Survival in LVAD Recipients: Results of the ASSIST-ICD Multicentric Registry.

BACKGROUND: Prediction of outcomes remains an unmet need in candidates for LVADs. The development of right-heart failure portends an excess in mortality rates, but imaging parameters of right ventricular systolic function have failed to demonstrate a prognostic role. By integrating pulmonary pressure, right ventriculoarterial coupling could fill this gap. METHODS: The ASSIST-ICD registry was used to test right ventriculoarterial coupling as a surrogate parameter at implantation for the prediction of all-cause mortality. RESULTS: The ratio of the tricuspid annular-plane systolic excursion over the estimated systolic pulmonary pressure (TAPSE/sPAP) was not associated with long-term survival in univariate analysis (P = 0.89), nor was the pulmonary artery pulsatility index (PAPi) (P = 0.13). Conversely, the ratio of the right atrial pressure over the pulmonary capillary wedge pressure (RAP/PCWP) was associated with all-cause mortality (P < 0.01). After taking tricuspid regurgitation severity, LVAD indication, LVAD model, age, blood urea nitrogen levels, and pulmonary vascular resistance into account, RAP/PCWP remained associated with survival (HR 1.35 [1.10 - 1.65]; P < 0.01). CONCLUSION: Among pre-implant RVAC surrogates, only RAP/PCWP was associated with long-term all-cause mortality in LVAD recipients. This association was independent of established risk factors.

Unnecessary antibiotic use in men who have sex with men (MSM) with anogenital symptoms attending a sexual health clinic: a retrospective analysis.

OBJECTIVES: To quantify the amount of unnecessary antibiotics, in particular ceftriaxone, given to men who have sex with men (MSM) with anogenital symptoms as part of presumptive management in an urban sexual health clinic and examine factors associated with unnecessary ceftriaxone. METHODS: This is a retrospective cross-sectional analysis of electronic records from all visits involving MSM reporting symptoms of bacterial sexually transmitted infection (STI) and who received presumptive antibiotics at Sydney Sexual Health Centre. The following variables were extracted: demographic and sexual behaviour data, presenting symptoms, prior STI diagnoses, use of anoscopy, use of point-of-care microscopy, prescriptions of antibiotics and subsequent nucleic acid amplification testing (NAAT) results for chlamydia and gonorrhoea in all anatomical sites (urethra, pharynx and rectum). We defined unnecessary antibiotic as an agent prescribed to treat an STI organism that was subsequently not detected. RESULTS: Among 1061 visits in this analysis, 41.8% yielded negative NAAT results for both chlamydia and gonorrhoea in all anatomical sites. There were 44.3% of visits which had positive gonorrhoea NAAT result in at least one anatomical site. There were 187 courses of ceftriaxone prescribed in patients who tested negative for gonorrhoea in all anatomical sites and therefore were unnecessary. Unnecessary ceftriaxone prescribing occurred in 50.2% of visits with anorectal symptoms, 19.6% of scrotal symptoms and 7.3% of urethral symptoms. Microscopy was associated with significantly less unnecessary ceftriaxone in urethral but not anorectal or scrotal presentations. In multivariable analysis, the following factors were associated with a higher likelihood of unnecessary ceftriaxone use: anorectal symptoms, scrotal symptoms, gonorrhoea in the preceding year, contact of a bacterial STI and living with HIV. CONCLUSIONS: This study highlights the significant amount of unnecessary ceftriaxone used for STI symptoms in MSM. A new pathway incorporating rapid point-of-care molecular testing in symptomatic patients may improve the precision of antibiotic prescribing and reduce unnecessary use.

Analysis of plant and fungal transcripts from resistant and susceptible phenotypes of Leptospermum scoparium challenged by Austropuccinia psidii.

Austropuccinia psidii is the causal pathogen of myrtle rust disease of Myrtaceae. To gain understanding of the initial infection process, gene expression in germinating Austropuccinia psidii urediniospores and in Leptospermum scoparium inoculated leaves were investigated via analyses of RNAseq samples taken 24 and 48 hours post inoculation (hpi). Principal component analyses of transformed transcript count data revealed differential gene expression between the uninoculated L. scoparium control plants that correlated with the three plant leaf resistance phenotypes (immunity, hypersensitive response and susceptibility). Gene expression in the immune resistant plants did not significantly change in response to fungal inoculation, while susceptible plants showed differential expression of genes in response to fungal challenge. A putative disease resistance gene, jg24539.t1, was identified in the L. scoparium hypersensitive response phenotype family. Expression of this gene may be associated with the phenotype and could be important for further understanding the plant hypersensitive response to A. psidii challenge. Differential expression of pathogen genes was found between samples taken 24 and 48 hpi, but there were no significant differences in pathogen gene expression that were associated with the three different plant leaf resistance phenotypes. There was a significant decrease in the abundance of fungal transcripts encoding three putative effectors and a putative carbohydrate-active enzyme between 24 and 48 hpi, suggesting that the encoded proteins are important during the initial phase of infection. These transcripts, or their translated proteins, may be potential targets to impede the early phases of fungal infection by this wide-host range obligate biotrophic basidiomycete.

Investigating cross-orientation inhibition with continuous tracking.

We investigated cross-orientation inhibition with the recently developed continuous tracking technique. We designed an experiment where participants tracked the horizontal motion of a narrow vertical grating. The target was superimposed on one of three different backgrounds, in separate sessions: a uniform gray background or a sinusoidal grating oriented either parallel or orthogonal to the target. Both mask and target where phase reversed. We cross-correlated target and mouse movements and compared the peaks and lags of response with the different masks. Our results are in agreement with previous findings on cross-orientation inhibition: The orthogonal mask had a weak effect on the peaks and lags of correlation as a function of target contrast, consistently with a divisive effect of the mask, while the parallel mask acted subtractively on the response. Interestingly, lags of correlation decreased approximately linearly with contrast, with decrements of the order of 100 ms, even at 10 times the detection threshold, confirming that it is possible to investigate behavioral differences above threshold using the continuous tracking paradigm.

Telemedicine in Vascular Surgery During COVID-19 Pandemic: A Systematic Review and Narrative Synthesis.

BACKGROUND: The COVID-19 pandemic resulted in seismic changes to healthcare service delivery. The use of telemedicine was widely adopted during the pandemic, although its value in the safe care of vascular patients is unknown. METHODS: A systematic review was undertaken to identify studies that described outcomes or patient/clinician views of telemedicine (telephone or video) services in vascular surgery during or after the pandemic. Two reviewers independently searched medical databases, selected studies, extracted data, and undertook a narrative synthesis. RESULTS: Twelve studies were included. Most studies reported increased telemedicine use during the pandemic. Most patients (80.6%-100%) were satisfied with telephone or video consultation. More than 90% of the patients felt that telemedicine was a good substitute during the pandemic to avoid travelling and reduce transmission risk. Three studies showed patients had a strong preference for continuing telemedicine consultations postpandemic. Two studies evaluating patients with arterial ulceration and venous diseases reported no significant difference in clinical outcome between patients reviewed face-to-face and those seen remotely. One study showed clinicians preferred face-to-face consultations. No study conducted cost analysis. CONCLUSIONS: Patients and clinicians viewed telemedicine favorably as an alternative to face-to-face clinics during the pandemic and included studies did not identify any safety concerns. Its role postpandemic is not clearly defined, although these data suggest a significant proportion of patients would appreciate, and be suitable for, such consultations in the future.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Systematic review of groin wound surgical site infection incidence after arterial intervention.

The objectives were to determine the surgical site infection incidence (including superficial/deep) fter arterial intervention through non-infected groin incisions and identify variables associated with incidence. MEDLINE, EMBASE and CENTRAL databases were searched for randomised controlled trials and observational studies of adults undergoing arterial intervention through a groin incision and reported surgical site infection. Infection incidence was examined in subgroups, variables were subjected to meta-regression. One hundred seventeen studies reporting 65 138 groin incisions in 42 347 patients were included. Overall surgical site infection incidence per incision was 8.1% (1730/21 431): 6.3% (804/12 786) were superficial and 1.9% (241/12 863) were deep. Superficial infection incidence was higher in randomised controlled trials (15.8% [278/1762]) compared with observational studies (4.8% [526/11 024]); deep infection incidence was similar (1.7% (30/1762) and 1.9% (211/11 101) respectively). Aneurysmal pathology (ß = -10.229, P < .001) and retrospective observational design (ß = -1.118, P = .002) were associated with lower infection incidence. Surgical site infection being a primary outcome was associated with a higher incidence of surgical site infections (ß = 3.429, P = .017). The three-fold higher incidence of superficial surgical site infection reported in randomised controlled trials may be because of a more robust clinical review of patients. These results should be considered when benchmarking practice and could inform future trial design.

Patient Satisfaction with Tele- and Video-Consultation in the COVID-19 Era - A Survey of Vascular Surgical Patients.

BACKGROUND: The COVID 19 pandemic has resulted in the increasing use of telemedicine due to the advantages of avoiding viral transmission. Evidence suggests that telemedicine, for certain conditions, may be as effective as face-to-face consultations; however, there is no research to date regarding vascular patients' acceptance or satisfaction with telemedicine during and after the COVID-19 pandemic. METHODS: A patient satisfaction interview was designed to survey three aspects of the service: patient acceptability of teleconsultations as a replacement to physical clinics; their views of teleconsultation during the pandemic; and the future role of teleconsultations postpandemic. Patients undergoing remote teleconsultation (either by telephone or video software), between April and June 2020 were suitable for inclusion. Patients were contacted by telephone in August 2020 to undertake the survey. Local "Research and Development" approval was obtained. RESULTS: A total of 333 patients had a consultation with a vascular consultant between April and June 2020, of which 178 were teleconsultations. Successful contact was made with 72 patients, of whom 68 agreed to participate; 10 patients had undergone video consultations, while the remainder had telephone consultations. Teleconsultations were widely viewed as acceptable, and over 90% of patients felt they were beneficial. 91% felt that not needing to travel for appointments was advantageous to them. The option of teleconsultation during the COVID pandemic was valued by 94% of the cohort. While all interviewees felt teleclinics should continue during the pandemic, the majority (74%) also wanted to use teleconsultations for clinic appointments after the pandemic. CONCLUSIONS: Telemedicine is viewed by vascular patients as generally acceptable and beneficial for use during the pandemic. The majority of patients wanted future telemedicine appointments postpandemic. Telemedicine services started as a result of the COVID-19 pandemic, which may have been viewed as a temporary measure, should be planned to continue long term.

The PReliMinAry (Pain Relief in Major Amputation) Survey.

OBJECTIVES: Major Lower Limb Amputation (MLLA) is associated with significant peri- and post-operative pain and has been identified as a research priority by patient and healthcare groups. The PReliMinAry survey was designed to evaluate existing MLLA analgesia strategies; identifying areas of equipoise and informing future research. METHODS: A targeted multi-national, multi-disciplinary survey was conducted via SurveyMonkey® (October 5, 2020-November 3, 2020) and advertised via social media and society email lists. The 10-questions explored 'pain-team' services, pre-operative neuroleptic medication, pre-incision peripheral nerve blocks and catheters, surgically placed nerve catheters, post-operative adjunctive regimens, future research engagement and equipoise. RESULTS: Seventy-six responses were received from 60 hospitals worldwide. Twelve hospitals(20%) had a dedicated MLLA pain team, 7(12%) had none. Most pain teams (n = 52; 87%) assessed pain with a 0-10 numerical rating scale. Over half of respondents "never" preloaded patients with oral neuroleptic agents(n= 42/76; 55%). Forty-seven hospitals(78%) utilized patient controlled opioid analgesia. Most hospitals are able to provide pre-incision loco-regional peripheral nerve blocks, nerve catheters and surgical nerve catheters (95%, 77%, and 90% respectively), but use was variable. Ultrasound(US) guided peripheral nerve catheters were "infrequently" or "never" used in 57% of hospitals, whilst 23% "infrequently" or "never" utilize surgically placed nerve catheters. CONCLUSIONS: The survey revealed a preference towards 'single-shot' nerve blocks and surgical catheters. A difference between the use of US guided nerve catheters and those surgically placed likely reflects the difference of literature evaluating these techniques. Most respondents felt there was equipoise surrounding future trials evaluating nerve blocks/catheters, but less so for surgical catheters.

Expansion of a single transposable element family is associated with genome-size increase and radiation in the genus Hydra.

Transposable elements are one of the major contributors to genome-size differences in metazoans. Despite this, relatively little is known about the evolutionary patterns of element expansions and the element families involved. Here we report a broad genomic sampling within the genus Hydra, a freshwater cnidarian at the focal point of diverse research in regeneration, symbiosis, biogeography, and aging. We find that the genome of Hydra is the result of an expansion event involving long interspersed nuclear elements and in particular a single family of the chicken repeat 1 (CR1) class. This expansion is unique to a subgroup of the genus Hydra, the brown hydras, and is absent in the green hydra, which has a repeat landscape similar to that of other cnidarians. These features of the genome make Hydra attractive for studies of transposon-driven genome expansions and speciation.

Management and outcomes of ventricular septal defects after acute myocardial infarction: A multicenter retrospective study.

BACKGROUND AND AIM: The mortality rate of patients with post-myocardial infarction (MI) ventricular septal defects (VSDs) is high, and the benefit of surgery is unclear. We aimed to investigate the management and outcomes of post-MI VSD over a 10-year period in a large cohort. METHODS: Data of patients with post-MI VSD admitted in three French university hospitals from 2008 to 2019 were examined. The characteristics of those who underwent surgery were compared with those who received medical treatment. Mortality risk factors, survival curves, and outcomes at 30 days and 1 year after treatment were determined. RESULTS: Of the 92 patients whose data were examined, 50 underwent surgery and 42 received exclusive medical treatment. All patients were critically ill. Overall, 76.1% of patients received inotropic support, and 63% received mechanical ventilation. Circulatory assistance, mainly via intra-aortic balloon pump and extra-corporeal membrane oxygenation, was provided to 46.7% patients, with 14.1% requiring a second assistance. The median time to surgery was 4 days. At 1 year, mortality was 46% in those who underwent surgery and 83.3% in those treated medically (p < .001). Survival curves at 1 and 3 months showed major differences, and the survival rate showed little change 30 days after treatment. Cardiogenic shock and cardiac arrest emerged as risk factors for mortality. CONCLUSIONS: In our retrospective, multicenter study, the mortality resulting from post-MI VSD did not seem to improve over the last decade. Although surgery carried considerable risks, it improved survival.

Ideal observer analysis for continuous tracking experiments.

Continuous tracking is a newly developed technique that allows fast and efficient data acquisition by asking participants to "track" a stimulus varying in some property (usually position in space). Tracking is a promising paradigm for the investigation of dynamic features of perception and could be particularly well suited for testing ecologically relevant situations difficult to study with classical psychophysical paradigms. The high rate of data collection may be useful in studies on clinical populations and children, who are unable to undergo long testing sessions. In this study, we designed tracking experiments with two novel stimulus features, numerosity and size, proving the feasibility of the technique outside standard object tracking. We went on to develop an ideal observer model that characterizes the results in terms of efficiency of conversion of stimulus strength into responses, and identification of early and late noise sources. Our ideal observer closely modeled results from human participants, providing a generalized framework for the interpretation of tracking data. The proposed model allows to use the tracking paradigm in various perceptual domains, and to study the divergence of human participants from ideal behavior.

JEDi: java essential dynamics inspector - a molecular trajectory analysis toolkit.

BACKGROUND: Principal component analysis (PCA) is commonly applied to the atomic trajectories of biopolymers to extract essential dynamics that describe biologically relevant motions. Although application of PCA is straightforward, specialized software to facilitate workflows and analysis of molecular dynamics simulation data to fully harness the power of PCA is lacking. The Java Essential Dynamics inspector (JEDi) software is a major upgrade from the previous JED software. RESULTS: Employing multi-threading, JEDi features a user-friendly interface to control rapid workflows for interrogating conformational motions of biopolymers at various spatial resolutions and within subregions, including multiple chain proteins. JEDi has options for Cartesian-based coordinates (cPCA) and internal distance pair coordinates (dpPCA) to construct covariance (Q), correlation (R), and partial correlation (P) matrices. Shrinkage and outlier thresholding are implemented for the accurate estimation of covariance. The effect of rare events is quantified using outlier and inlier filters. Applying sparsity thresholds in statistical models identifies latent correlated motions. Within a hierarchical approach, small-scale atomic motion is first calculated with a separate local cPCA calculation per residue to obtain eigenresidues. Then PCA on the eigenresidues yields rapid and accurate description of large-scale motions. Local cPCA on all residue pairs creates a map of all residue-residue dynamical couplings. Additionally, kernel PCA is implemented. JEDi output gives high quality PNG images by default, with options for text files that include aligned coordinates, several metrics that quantify mobility, PCA modes with their eigenvalues, and displacement vector projections onto the top principal modes. JEDi provides PyMol scripts together with PDB files to visualize individual cPCA modes and the essential dynamics occurring within user-selected time scales. Subspace comparisons performed on the most relevant eigenvectors using several statistical metrics quantify similarity/overlap of high dimensional vector spaces. Free energy landscapes are available for both cPCA and dpPCA. CONCLUSION: JEDi is a convenient toolkit that applies best practices in multivariate statistics for comparative studies on the essential dynamics of similar biopolymers. JEDi helps identify functional mechanisms through many integrated tools and visual aids for inspecting and quantifying similarity/differences in mobility and dynamic correlations.