H2 inhalation therapy in patients with moderate COVID-19 (H2COVID): a prospective ascending-dose phase I clinical trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04633980.

The effect of hyperoxia on muscle sympathetic nerve activity: a systematic review and meta-analysis.

PURPOSE: We conducted a meta-analysis to determine the effect of hyperoxia on muscle sympathetic nerve activity in healthy individuals and those with cardio-metabolic diseases. METHODS: A comprehensive search of electronic databases was performed until August 2022. All study designs (except reviews) were included: population (humans; apparently healthy or with at least one chronic disease); exposures (muscle sympathetic nerve activity during hyperoxia or hyperbaria); comparators (hyperoxia or hyperbaria vs. normoxia); and outcomes (muscle sympathetic nerve activity, heart rate, blood pressure, minute ventilation). Forty-nine studies were ultimately included in the meta-analysis. RESULTS: In healthy individuals, hyperoxia had no effect on sympathetic burst frequency (mean difference [MD] - 1.07 bursts/min; 95% confidence interval [CI] - 2.17, 0.04bursts/min; P = 0.06), burst incidence (MD 0.27 bursts/100 heartbeats [hb]; 95% CI - 2.10, 2.64 bursts/100 hb; P = 0.82), burst amplitude (P = 0.85), or total activity (P = 0.31). In those with chronic diseases, hyperoxia decreased burst frequency (MD - 5.57 bursts/min; 95% CI - 7.48, - 3.67 bursts/min; P < 0.001) and burst incidence (MD - 4.44 bursts/100 hb; 95% CI - 7.94, - 0.94 bursts/100 hb; P = 0.01), but had no effect on burst amplitude (P = 0.36) or total activity (P = 0.90). Our meta-regression analyses identified an inverse relationship between normoxic burst frequency and change in burst frequency with hyperoxia. In both groups, hyperoxia decreased heart rate but had no effect on any measure of blood pressure. CONCLUSION: Hyperoxia does not change sympathetic activity in healthy humans. Conversely, in those with chronic diseases, hyperoxia decreases sympathetic activity. Regardless of disease status, resting sympathetic burst frequency predicts the degree of change in burst frequency, with larger decreases for those with higher resting activity.

Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.

BACKGROUND: Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. METHOD: In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. RESULTS: Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. CONCLUSION: This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.

JNK regulates ciliogenesis through the interflagellar transport complex and actin networks.

The c-Jun N-terminal kinase (JNK) regulates various important physiological processes. Although the JNK pathway has been under intense investigation for over 20 yr, its complexity is still perplexing, with multiple protein partners underlying the diversity of its activity. We show that JNK is associated with the basal bodies in both primary and motile cilia. Loss of JNK disrupts basal body migration and docking and leads to severe ciliogenesis defects. JNK's involvement in ciliogenesis stems from a dual role in the regulation of the actin networks of multiciliated cells (MCCs) and the establishment of the intraflagellar transport-B core complex. JNK signaling is also critical for the maintenance of the actin networks and ciliary function in mature MCCs. JNK is implicated in the development of diabetes, neurodegeneration, and liver disease, all of which have been linked to ciliary dysfunction. Our work uncovers a novel role of JNK in ciliogenesis and ciliary function that could have important implications for JNK's role in the disease.

Psychosis brain subtypes validated in first-episode cohorts and related to illness remission: results from the PHENOM consortium.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups-a 'lower brain volume' subgroup (SG1) and an 'higher striatal volume' subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership ('None'), and mixed SG1 + SG2 subgroups ('Mixed'). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of 'lower brain volume' in SG1 and 'higher striatal volume' (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

The apical ciliary adhesion complex is established at the basal foot of motile cilia and depends on the microtubule network.

The Ciliary Adhesion (CA) complex forms in close association with the basal bodies of cilia during the early stages of ciliogenesis and is responsible for mediating complex interactions with the actin networks of multiciliated cells (MCCs). However, its precise localization with respect to basal body accessory structures and the interactions that lead to its establishment in MCCs are not well understood. Here, we studied the distribution of the CA proteins using super-resolution imaging and possible interactions with the microtubule network. The results of this study reveal that the apical CA complex forms at the distal end of the basal foot and depends on microtubules. Our data also raise the possibility that CAs may have additional roles in the regulation of the organization of the microtubule network of MCCs.

FMR protein: Evidence of an emerging role in retinal aging?

Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1-/y compared to their WT littermates. Indeed, up to now, only young or adult mice (<6 months) were investigated and have shown a specific retinal phenotype. Herein, we demonstrated that Fmr1-/y mice do not present the aging effect on retinal function observed in WT littermates since ERG a- and b-waves amplitudes as well as oscillatory potentials amplitudes were not collapsed with age (12/18 months old). Absence of FMRP and its consequences seem to protect the retina against aging effect, rising a pivotal role of FMRP in retinal aging process.

Adherens junctions stimulate and spatially guide integrin activation and extracellular matrix deposition.

Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We show that cadherin clustering stimulates and spatially guides integrin activation. Adherens junction (AJ)-associated integrin activation depends on locally generated tension and does not require extracellular matrix ligands. It leads to the creation of primed integrin clusters, which spatially determine where focal adhesions will form if ligands are present and where ligands will be deposited. AJs that display integrin activation are targeted by microtubules facilitating their disassembly via caveolin-based endocytosis, showing that integrin activation impacts the stability of the core cadherin complex. Thus, the interplay between cadherins and integrins is more intimate than what was once believed and is rooted in the capacity of active integrins to be stabilized via AJ-generated tension. Altogether, our data establish a mechanism of cross-regulation between cadherins and integrins.

Distinct spatiotemporal contribution of morphogenetic events and mechanical tissue coupling during Xenopus neural tube closure.

Neural tube closure (NTC) is a fundamental process during vertebrate development and is indispensable for the formation of the central nervous system. Here, using Xenopus laevis embryos, live imaging, single-cell tracking, optogenetics and loss-of-function experiments, we examine the roles of convergent extension and apical constriction, and define the role of the surface ectoderm during NTC. We show that NTC is a two-stage process with distinct spatiotemporal contributions of convergent extension and apical constriction at each stage. Convergent extension takes place during the first stage and is spatially restricted at the posterior tissue, whereas apical constriction occurs during the second stage throughout the neural plate. We also show that the surface ectoderm is mechanically coupled with the neural plate and its movement during NTC is driven by neural plate morphogenesis. Finally, we show that an increase in surface ectoderm resistive forces is detrimental for neural plate morphogenesis.

A systematic review of relationships and sex education outcomes for students with intellectual disability reported in the international literature.

BACKGROUND: Little is known about how to evaluate relationships and sex education (RSE) delivered to students with intellectual disability and what stakeholders perceive are important outcomes. The present study aimed to systematically review existing studies on outcomes of RSE, as the first step in the development of a core outcome set (COS) for students with intellectual disability. METHOD: A systematic literature process included two stages: (1) searching for studies reporting on RSE outcomes for students with intellectual disability and (2) studies reporting on measurement properties (e.g. validity, reliability and responsiveness) of standardised instruments identified in stage 1. RESULTS: A total of 135 RSE outcomes were extracted from 42 studies: 43 outcomes for students in secondary education and 92 outcomes for students in further education. No RSE outcomes were reported for primary education. Outcomes referred to the human body, hygiene, relationships, sexuality, sex and its consequences, inappropriate and appropriate social and sexual behaviour, keeping safe, emotional vocabulary and positive self-esteem. Outcomes were predominantly knowledge-based, rather than relating to skills and attitudes development. Students with intellectual disability, parents and teachers perceive different RSE outcomes meaningful. Five instruments were used to measure the outcomes, but none have established psychometric properties with this population. CONCLUSIONS: The comprehensive list of RSE outcomes for students with intellectual disability will be used to inform the next steps of a Core Outcome Set needed for RSE evaluations in research and education settings. There is an urgent need to develop standardised instruments validated for students with intellectual disability.

Stratification of patients admitted for SARS-CoV2 infection: prognostic scores in the first and second wave of the pandemic.

To test the prognostic performance of different scores, both specifically designed for patients with COVID-19 and generic, in predicting in-hospital mortality and the need for mechanical ventilation (MV). We retrospectively collected clinical data of patients admitted to the Emergency Department of the University Hospital AOU Careggi, Florence, Italy, between February 2020 and January 2021, with a confirmed infection by SARS-CoV2. We calculated the following scores: Sequential Organ Failure Assessment (SOFA) score, CALL score, 4C Mortality score, QUICK score, CURB-65 and MuLBSTA score. The end-points were in-hospital mortality and the need for MV. We included 1208 patients, mean age 60 ± 17 years, 57% male sex. Compared to survivors, non-survivors showed significantly higher values of all the prognostic scores (4C: 13 [10-15] vs 8 [4-10]; CALL: 11 [10-12] vs 9 [7-11]; QUICK: 4 [1-6] vs 0 [0-3]; SOFA: 5 [4-6] vs 4 [4-5]; CURB: 2 [1-3] vs 1 [0-1]; MuLBSTA: 11 [9-13] vs 9 [7-11], all p < 0.001). Discriminative ability evaluated by the Receiver Operating Curve analysis showed the following values of the Area under the Curve: 0.83 for 4C, 0.74 for CALL, 0.70 for QUICK, 0.68 for SOFA, 0.76 for CURB and 0.64 for MuLBSTA. The mortality rate significantly increased in increasing quartiles of 4C and CALL score (respectively, 2, 8, 24 and 54% for the 4C score and 1, 17, 33 and 68% for the CALL score, both p < 0.001). 4C and CALL score allowed an early and good prognostic stratification of patients admitted for pneumonia induced by SARS-CoV2.

Multisubject Task-Related fMRI Data Processing via a Two-Stage Generalized Canonical Correlation Analysis.

Functional magnetic resonance imaging (fMRI) is one of the most popular methods for studying the human brain. Task-related fMRI data processing aims to determine which brain areas are activated when a specific task is performed and is usually based on the Blood Oxygen Level Dependent (BOLD) signal. The background BOLD signal also reflects systematic fluctuations in regional brain activity which are attributed to the existence of resting-state brain networks. We propose a new fMRI data generating model which takes into consideration the existence of common task-related and resting-state components. We first estimate the common task-related temporal component, via two successive stages of generalized canonical correlation analysis and, then, we estimate the common task-related spatial component, leading to a task-related activation map. The experimental tests of our method with synthetic data reveal that we are able to obtain very accurate temporal and spatial estimates even at very low Signal to Noise Ratio (SNR), which is usually the case in fMRI data processing. The tests with real-world fMRI data show significant advantages over standard procedures based on General Linear Models (GLMs).

Somitic mesoderm morphogenesis is necessary for neural tube closure during Xenopus development.

Neural tube closure is a fundamental process during vertebrate embryogenesis, which leads to the formation of the central nervous system. Defective neural tube closure leads to neural tube defects which are some of the most common human birth defects. While the intrinsic morphogenetic events shaping the neuroepithelium have been studied extensively, how tissues mechanically coupled with the neural plate influence neural tube closure remains poorly understood. Here, using Xenopus laevis embryos, live imaging in combination with loss of function experiments and morphometric analysis of fixed samples we explore the reciprocal mechanical communication between the neural plate and the somitic mesoderm and its impact on tissue morphogenesis. We show that although somitic mesoderm convergent extension occurs independently from neural plate morphogenesis neural tube closure depends on somitic mesoderm morphogenesis. Specifically, impaired somitic mesoderm remodelling results in defective apical constriction within the neuroepithelium and failure of neural tube closure. Last, our data reveal that mild abnormalities in somitic mesoderm and neural plate morphogenesis have a synergistic effect during neurulation, leading to severe neural tube closure defects. Overall, our data reveal that defective morphogenesis of tissues mechanically coupled with the neural plate can not only drastically exacerbate mild neural tube defects that may arise from abnormalities within the neural tissue but can also elicit neural tube defects even when the neural plate is itself free of inherent defects.

Improving the Sensitivity of Task-Related Functional Magnetic Resonance Imaging Data Using Generalized Canonical Correlation Analysis.

General Linear Modeling (GLM) is the most commonly used method for signal detection in Functional Magnetic Resonance Imaging (fMRI) experiments, despite its main limitation of not taking into consideration common spatial dependencies between voxels. Multivariate analysis methods, such as Generalized Canonical Correlation Analysis (gCCA), have been increasingly employed in fMRI data analysis, due to their ability to overcome this limitation. This study, evaluates the improvement of sensitivity of the GLM, by applying gCCA to fMRI data after standard preprocessing steps. Data from a block-design fMRI experiment was used, where 25 healthy volunteers completed two action observation tasks at 1.5T. Whole brain analysis results indicated that the application of gCCA resulted in significantly higher intensity of activation in several regions in both tasks and helped reveal activation in the primary somatosensory and ventral premotor area, theoretically known to become engaged during action observation. In subject-level ROI analyses, gCCA improved the signal to noise ratio in the averaged timeseries in each preselected ROI, and resulted in increased extent of activation, although peak intensity was considerably higher in just two of them. In conclusion, gCCA is a promising method for improving the sensitivity of conventional statistical modeling in task related fMRI experiments.

Numerical simulation data of building integrated solar thermal collectors under diverse conditions.

This dataset presents the thermal performance of building-integrated flat solar collectors with a uniform and multiple riser structure. The input data of the numerical model were obtained with the use of the PVGIS tool. Solar radiation and ambient temperature values at slopes 0°, 45°, and 90° were extracted and used as boundary conditions. Numerical calculations were carried using Finite Element (FE) analysis. Three-dimensional transient models were developed to calculate the investigated configurations' thermal performance based on the environmental temperature, the solar radiation, and the inclination angle. The numerical model was validated with the use of an experimental data set showing a good agreement between the two models with RMSE of 5%. Data of hourly heat flux through the building masonry with the building-integrated solar collector and the average fluid temperature of each system is presented.

Antitumor Activity against Human Colorectal Adenocarcinoma of Silver Nanoparticles: Influence of [Ag]/[PVP] Ratio.

Silver nanoparticles (AgNPs) not only have shown remarkable results as antimicrobial and antiviral agents but also as antitumor agents. This work reports the complete characterization of five polyvinylpyrrolidone-coated AgNP (PVP-AgNP) formulations, their cytotoxic activity against human colon tumor cells (HCT-15), their cytotoxic effect on primary mouse cultures, and their lethal dose on BALB/c mice. The evaluated AgNP formulations have a composition within the ranges Ag: 1.14-1.32% w/w, PVP: 19.6-24.5% and H2O: 74.2-79.2% with predominant spherical shape within an average size range of 16-30 nm according to transmission electron microscopy (TEM). All formulations assessed increase mitochondrial ROS concentration and induce apoptosis as the leading death pathway on HCT-15 cells. Except for AgNP1, the growth inhibition potency of AgNP formulations of human colon tumor cancer cells (HCT-15) is 34.5 times higher than carboplatin, one of the first-line chemotherapy agents. Nevertheless, 5-10% of necrotic events, even at the lower concentration evaluated, were observed. The cytotoxic selectivity was confirmed by evaluating the cytotoxic effect on aorta, spleen, heart, liver, and kidney primary cultures from BALB/c mice. Despite the cytotoxic effects observed in vitro, the lethal dose and histopathological analysis showed the low toxicity of these formulations (all of them on Category 4 of the Globally Harmonized System of Classification and Labelling of Chemicals) and minor damage observed on analyzed organs. The results provide an additional example of the rational design of safety nanomaterials with antitumor potency and urge further experiments to complete the preclinical studies for these AgNP formulations.

Numerical data on heat flux of a novel controlled-temperature double skin façade.

Hourly heat flux for variant boundary conditions of a novel controlled-temperature double skin façade (DSF) building element in a two- dimensional time- dependent study was determined. The building element is subjected to boundary conditions, characterizing different orientations (azimuth 0°, 90°, 180°, 270°) and climatic conditions of the four seasons. This data article provides detailed numerical data on the hourly heat flux, temperatures attained at the exterior and within the building element for six different geometries and for the variant boundary conditions under study. The external boundary conditions were determined with the use of the PVGIS tool, corrected in accordance to the sol-air temperature equation. The numerical simulation studies were performed with the use of the computational fluid dynamics (CFD) tool Comsol Multiphysics [2].

Climate mitigation in the Mediterranean Europe: An assessment of regional and city-level plans.

In Europe, regions in the Mediterranean area share common characteristics in terms of high sensitivity to climate change impacts. Does this translate into specificities regarding climate action that could arise from these Mediterranean characteristics? This paper sheds light on regional and local climate mitigation actions of the Mediterranean Europe, focusing on the plans to reduce greenhouse gases emissions in a representative sample of 51 regions and 73 cities across 9 Mediterranean countries (Croatia, Cyprus, France, Greece, Italy, Malta, Portugal, Slovenia, Spain). The study investigates: (i) the availability of local and regional mitigation plans, (ii) their goals in term of greenhouse gas emissions reduction targets on the short and medium-long term, and (iii) the impact of transnational climate networks on such local and regional climate mitigation planning. Results of this study indicate an uneven and fragmented planning, that shows a Mediterranean West-East divide, and a link with population size. However, overall, both regional and city action seem insufficiently ambitious with regards to meeting the Paris Agreement, at least at city level. While national frameworks are currently weak in influencing regional and local actions, transnational networks seem to be engaging factors for commitment (at city level) and ambitiousness (at regional level). The uneven and fragmented progress revealed by this study, does not align with the characteristics shared by investigated regions and cities in terms of environmental, socio-political, climatic and economic conditions. The results support the call of a common green deal at the Mediterranean level to further address specific Mediterranean challenges and related needs. This will allow to capitalise on available resources, generate local-specific knowledge, build capacities, and support Mediterranean regions and cities in preparing the next generation of more ambitious mitigation plans.

Sublingual vaccination and delivery systems.

Most infectious agents use mucosal tissues as entry portals, thus, mucosae are frequently defined as a first line of defense against pathogens. Mucosal protection generally operates through antibody-mediated and cytotoxic T-cell responses which can be triggered by mucosal vaccines. Sublingual vaccination provides many advantages such as systemic and mucosal responses (both locally and at remote mucosal sites), besides being a needle-free administration route with high patient compliance and limited adverse effects. Buccal mucosa complexity nonetheless represents a challenge for vaccine administration, hence, many efforts were recently deployed to improve vaccine components, mucoadhesion and/or penetration. Several innovative approaches indeed confirmed that a robust and protective immunity can be achieved by sublingual vaccines. This review will then specify the most recent delivery systems and improvements developed to increase sublingual vaccines efficiency. We will focus our description on the immune mechanisms involved and the requirements for optimal sublingual immunization and mucosal protection.

FAK displacement from focal adhesions: a promising strategy to target processes implicated in cancer progression and metastasis.

BACKGROUND: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed or activated in several advanced-stage solid cancers. It is known to play both kinase-dependent and -independent roles in promoting tumor progression and metastasis. Numerous inhibitors, targeting either the enzymatic or scaffolding activities of FAK have been generated, with varying degree of success. Here, we describe a novel approach to site-specifically target both kinase-dependent and -independent FAK functions at focal adhesions (FAs), the primary sites at which the kinase exerts its activity. METHODS: We took advantage of the well-characterized interactions between the paxillin LD motifs and the FAK FAT domain and generated a polypeptide (LD2-LD3-LD4) expected to compete with interactions with paxillin. Co-immunoprecipitation experiments were performed to examine the interaction between the LD2-LD3-LD4 polypeptide and FAK. The effects of LD2-LD3-LD4 in the localization and functions of FAK, as well as FA composition, were evaluated using quantitative immunofluorescence, cell fractionation, FA isolation and Western Blot analysis. Live cell imaging, as well as 2-D migration and cell invasion assays were used to examine the effects on FA turnover and tumor cell migration and invasion. RESULTS: Expression of the LD2-LD3-LD4 polypeptide prevents FAK localization at FAs, in a controlled and dose-dependent manner, by competing with endogenous paxillin for FAK binding. Importantly, the LD2-LD3-LD4 peptide did not otherwise affect FA composition or integrin activation. LD2-LD3-LD4 inhibited FAK-dependent downstream integrin signaling and, unlike existing inhibitors, also blocked FAK's scaffolding functions. We further show that LD2-LD3-LD4 expression markedly reduces FA turnover and inhibits tumor cell migration and invasion. Finally, we show that dimers of a single motif, linked through a flexible linker of the proper size, are sufficient for the displacement of FAK from FAs and for inhibition of tumor cell migration. This work raises the possibility of using a synthetic peptide as an antimetastatic agent, given that effective displacement of FAK from FAs only requires dimers of a single LD motif linked by a short flexible linker. CONCLUSION: In conclusion, these results suggest that FAK displacement from FAs is a promising new strategy to target critical processes implicated in cancer progression and metastasis. Video abstract.