Separability of Human Motor Memories during reaching adaptation with force cues.

Judging by the breadth of our motor repertoire during daily activities, it is clear that learning different tasks is a hallmark of the human motor system. However, for reaching adaptation to different force fields, the conditions under which this is possible in laboratory settings have remained a challenging question. Previous work has shown that independent movement representations or goals enabled dual adaptation. Considering the importance of force feedback during limb control, here we hypothesised that independent cues delivered by means of background loads could support simultaneous adaptation to various velocity-dependent force fields, for identical kinematic plan and movement goal. We demonstrate in a series of experiments that indeed healthy adults can adapt to opposite force fields, independently of the direction of the background force cue. However, when the cue and force field were in the same direction but differed by heir magnitude, the formation of different motor representations was still observed but the associated mechanism was subject to increased interference. Finally, we highlight that this paradigm allows dissociating trial-by-trial adaptation from online feedback adaptation, as these two mechanisms are associated with different time scales that can be identified reliably and reproduced in a computational model.

Composition and decomposition of visuomotor maps during manual tracking.

Adapting hand movements to changes in our body or the environment is essential for skilled motor behavior, as is the ability to flexibly combine experience gathered in separate contexts. However, it has been shown that when adapting hand movements to two different visuomotor perturbations in succession, interference effects can occur. Here, we investigate whether these interference effects compromise our ability to adapt to the superposition of the two perturbations. Participants tracked with a joystick, a visual target that followed a smooth but an unpredictable trajectory. Four separate groups of participants (total n = 83) completed one block of 50 trials under each of three mappings: one in which the cursor was rotated by 90° (ROTATION), one in which the cursor mimicked the behavior of a mass-spring system (SPRING), and one in which the SPRING and ROTATION mappings were superimposed (SPROT). The order of the blocks differed across groups. Although interference effects were found when switching between SPRING and ROTATION, participants who performed these blocks first performed better in SPROT than participants who had no prior experience with SPRING and ROTATION (i.e., composition). Moreover, participants who started with SPROT exhibited better performance under SPRING and ROTATION than participants who had no prior experience with each of these mappings (i.e., decomposition). Additional analyses confirmed that these effects resulted from components of learning that were specific to the rotational and spring perturbations. These results show that interference effects do not preclude the ability to compose/decompose various forms of visuomotor adaptation.NEW & NOTEWORTHY The ability to compose/decompose task representations is critical for both cognitive and behavioral flexibility. Here, we show that this ability extends to two forms of visuomotor adaptation in which humans have to perform visually guided hand movements. Despite the presence of interference effects when switching between visuomotor maps, we show that participants are able to flexibly compose or decompose knowledge acquired in previous sessions. These results further demonstrate the flexibility of sensorimotor adaptation in humans.

Chimerism and tolerance: past, present and future strategies to prolong renal allograft survival.

PURPOSE OF REVIEW: Immunological factors are a major cause of kidney allograft loss. Calcineurin inhibitors (CNIs) have improved short-term kidney allograft survival; however, they in turn contribute to long-term kidney allograft loss from chronic CNI nephrotoxicity. Tolerance induction in transplantation can avoid the long-term adverse effects of immunosuppressive medications. This review aims to critically discuss recent efforts in inducing transplantation tolerance. RECENT FINDINGS: Tolerance induction mediated by chimerism has shown some promise in minimizing or even complete withdrawal of immunosuppressive treatments in kidney allograft recipients. There has been a number of approaches as varied as the number of centres conducting these trials. However, they can be grouped into those mediated by transient microchimerism and those facilitated by more stable macro or full donor chimerism. The success rates in terms of long-term drug-free graft survival has been limited in microchimerism-mediated tolerance induction approaches. Mixed macrochimerism of less than 50% donor may be unstable with mostly the recipient's native immune system overpowering the donor chimeric status.Tolerance induction leading to chimerism has been limited to living donor kidney transplantation and additional long-term outcomes are required. Furthermore, immune monitoring after tolerance induction has faced a limitation in studying due to a lack of sufficient study participants and appropriate study controls. SUMMARY: Tolerance induction is one of several strategies used to prolong kidney allograft survival, but it has not been routinely utilized in clinical practice. However, future applications from the trials to clinical practice remain limited to living donor kidney transplantation. Once further data regarding tolerance inductions exist and practicality becomes widely accepted, tolerance induction may shift the paradigm in the field of kidney transplantation to achieve the best possible outcome of 'One Organ for Life'.

Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus.

BACKGROUND AND AIMS: As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS: We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSIONS: This study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

How optimal is bimanual tracking? The key role of hand coordination in space.

When coordinating two hands to achieve a common goal, the nervous system has to assign responsibility to each hand. Optimal control theory suggests that this problem is solved by minimizing costs such as the variability of movement and effort. However, the natural tendency to produce similar movements during bimanual tasks has been somewhat ignored by this approach. We consider a task in which participants were asked to track a moving target by means of a single cursor controlled simultaneously by the two hands. Two types of hand-cursor mappings were tested: one in which the cursor position resulted from the average location of two hands (Mean) and one in which horizontal and vertical positions of the cursor were driven separately by each hand (Split). As expected, unimanual tracking performance was better with the dominant hand than with the more variable nondominant hand. More interestingly, instead of exploiting this effect by increasing the use of the dominant hand, the contributions from both hands remained symmetrical during bimanual cooperative tasks. Indeed, for both mappings, and even after 6min of practice, the right and left hands remained strongly correlated, performing similar movements in extrinsic space. Persistence of this bimanual coupling demonstrates that participants prefer to maintain similar movements at the expense of unnecessary movements (in the Split task) and of increased noise from the nondominant hand (in the Mean task). Altogether, the findings suggest that bimanual tracking exploits hand coordination in space rather than minimizing motor costs associated with variability and effort.NEW & NOTEWORTHY When two hands are coordinated to achieve a common goal, optimal control theory proposes that the brain assigns responsibility to each hand by minimizing movement variability and effort. Nevertheless, we show that participants perform bimanual tracking using similar contributions from the dominant and nondominant hands, despite unnecessary movements and a less accurate nondominant hand. Our findings suggest that bimanual tracking exploits hand coordination in space rather than minimizing motor costs associated with variability and effort.

Outstanding questions in transplantation: Tolerance.

In 2017, the American Society of Transplantation (AST) launched the Outstanding Questions in Transplantation Research forum to stimulate a community-wide discussion of how the field is evolving and to help identify areas where a better dialogue between clinicians and researchers could result in great advancements. Tolerance emerged as a topic of great interest to the AST community. This minireview provides an overview of clinical transplantation tolerance. Historical background followed by a review of the current status of attempts to establish tolerance in the clinic, highlighting the dynamic online discussion surrounding this important topic from the AST Transplantation Research forum, is provided.

Eye movements do not play an important role in the adaptation of hand tracking to a visuomotor rotation.

Adapting hand movements to changes in our body or the environment is essential for skilled motor behavior. Although eye movements are known to assist hand movement control, how eye movements might contribute to the adaptation of hand movements remains largely unexplored. To determine to what extent eye movements contribute to visuomotor adaptation of hand tracking, participants were asked to track a visual target that followed an unpredictable trajectory with a cursor using a joystick. During blocks of trials, participants were either allowed to look wherever they liked or required to fixate a cross at the center of the screen. Eye movements were tracked to ensure gaze fixation as well as to examine free gaze behavior. The cursor initially responded normally to the joystick, but after several trials, the direction in which it responded was rotated by 90°. Although fixating the eyes had a detrimental influence on hand tracking performance, participants exhibited a rather similar time course of adaptation to rotated visual feedback in the gaze-fixed and gaze-free conditions. More importantly, there was extensive transfer of adaptation between the gaze-fixed and gaze-free conditions. We conclude that although eye movements are relevant for the online control of hand tracking, they do not play an important role in the visuomotor adaptation of such tracking. These results suggest that participants do not adapt by changing the mapping between eye and hand movements, but rather by changing the mapping between hand movements and the cursor's motion independently of eye movements. NEW & NOTEWORTHY Eye movements assist hand movements in everyday activities, but their contribution to visuomotor adaptation remains largely unknown. We compared adaptation of hand tracking under free gaze and fixed gaze. Although our results confirm that following the target with the eyes increases the accuracy of hand movements, they unexpectedly demonstrate that gaze fixation does not hinder adaptation. These results suggest that eye movements have distinct contributions for online control and visuomotor adaptation of hand movements.

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.

Gaze behavior during visuomotor tracking with complex hand-cursor dynamics.

The ability to track a moving target with the hand has been extensively studied, but few studies have characterized gaze behavior during this task. Here we investigate gaze behavior when participants learn a new mapping between hand and cursor motion, such that the cursor represented the position of a virtual mass attached to the grasped handle via a virtual spring. Depending on the experimental condition, haptic feedback consistent with mass-spring dynamics could also be provided. For comparison a simple one-to-one hand-cursor mapping was also tested. We hypothesized that gaze would be drawn, at times, to the cursor in the mass-spring conditions, especially in the absence of haptic feedback. As expected hand tracking performance was less accurate under the spring mapping, but gaze behavior was virtually unaffected by the spring mapping, regardless of whether haptic feedback was provided. Specifically, relative gaze position between target and cursor, rate of saccades, and gain of smooth pursuit were similar under both mappings and both haptic feedback conditions. We conclude that even when participants are exposed to a challenging hand-cursor mapping, gaze is primarily concerned about ongoing target motion suggesting that peripheral vision is sufficient to monitor cursor position and to update hand movement control.

Limited Contribution of Primary Motor Cortex in Eye-Hand Coordination: A TMS Study.

The ability to track a moving target with the eye is substantially improved when the target is self-moved compared with when it is moved by an external agent. To account for this observation, it has been postulated that the oculomotor system has access to hand efference copy, thereby allowing to predict the motion of the visual target. Along this scheme, we tested the effect of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when human participants (50% females) are asked to track with their eyes a visual target whose horizontal motion is driven by their grip force. We reasoned that, if the output of M1 is used by the oculomotor system to keep track of the target, on top of inducing short latency disturbance of grip force, single-pulse TMS should also quickly disrupt ongoing eye motion. For comparison purposes, the effect of TMS over M1 was monitored when subjects tracked an externally moved target (while keeping their hand at rest or not). In both cases, results showed no alterations in smooth pursuit, meaning that its velocity was unaffected within the 25-125 ms epoch that followed TMS. Overall, our results imply that the output of M1 has limited contribution in driving the eye motion during our eye-hand coordination task. This study suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1.SIGNIFICANCE STATEMENT The ability to coordinate eye and hand actions is central in everyday activity. However, the neural mechanisms underlying this coordination remain to be clarified. A leading hypothesis is that the oculomotor system has access to hand motor signals. Here we explored this possibility by means of transcranial magnetic stimulation (TMS) over the hand area of the primary motor cortex (M1) when humans tracked with the eyes a visual target that was moved by the hand. As expected, ongoing hand action was perturbed 25-30 ms after TMS, but our results fail to show any disruption of eye motion, smooth pursuit velocity being unaffected. This work suggests that, if hand motor signals are accessed by the oculomotor system, this is upstream of M1.

Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.

Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late sirolimus conversion and 12 on tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12, and 24 months post randomization, with T-cell subpopulations analyzed by flow cytometry and T-cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24 months post randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4(+)25(+++)Foxp3(+) regulatory T cells. While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients. Thus, chronic immune alterations are induced after sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

Relationship between education and age-related cognitive decline: a review of recent research.

The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age-related cognitive decline. This review paper addresses the potential link between education and age-related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow-up period of 7.6 years; each contained a population-based, non-demented sample. In the majority of studies, results showed that education did not moderate age-associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age-related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future.

Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients.

UNLABELLED: Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ≈ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. CONCLUSIONS: TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal.

BDNF and COMT polymorphisms have a limited association with episodic memory performance or engagement in complex cognitive activity in healthy older adults.

Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and individual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation.

Genomic biomarkers correlate with HLA-identical renal transplant tolerance.

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLA-identical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4(+)CD25(high)CD127(-)FOXP3(+) regulatory T cells and CD19(+)IgD/M(+)CD27(-) B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.

Differentiation of regulatory myeloid and T-cells from adult human hematopoietic stem cells after allogeneic stimulation.

Introduction: Donor hematopoietic stem cell (DHSC) infusions are increasingly being studied in transplant patients for tolerance induction. Methods: To analyze the fate of infused DHSCs in patients, we developed an in vitro culture system utilizing CD34+DHSCs stimulated with irradiated allogeneic cells in cytokine supplemented medium long-term. Results: Flow cytometric analyses revealed loss of the CD34 marker and an increase in CD33+ myeloid and CD3+ T-cell proportion by 10.4% and 72.7%, respectively, after 21 days in culture. T-cells primarily expressed TcR-αß and were of both CD4+ and CD8+ subsets. Approximately 80% of CD3+ T cells lacked expression of the co-stimulatory receptor CD28. The CD4+ compartment was predominated by CD4+CD25+CD127-FOXP3+ Tregs (>50% CD4+CD127- compartment) with <1% of all leukocytes exhibiting a CD4+CD127+ phenotype. Molecular analyses for T-cell receptor excision circles showed recent and increased numbers of TcR rearrangements in generated T cells over time suggesting de novo differentiation from DHSCs. CD33+ myeloid cells mostly expressed HLA-DR, but lacked expression of co-stimulatory receptors CD80 and CD83. When studied as modulators in primary mixed lymphocyte reactions where the cells used to stimulate the DHSC were used as responders, the DHSC-lines and their purified CD8+, CD4+, CD33+ and linage negative subsets inhibited the responses in a dose-dependent and non-specific fashion. The CD8+ cell-mediated inhibition was due to direct lysis of responder cells. Discussion: Extrapolation of these results into the clinical situation would suggest that DHSC infusions into transplant recipients may generate multiple subsets of donor "chimeric" cells and promote recipient Treg development that could regulate the anti-donor immune response in the periphery. These studies have also indicated that T cell maturation can occur in vitro in response to allogeneic stimulation without the pre-requisite of a thymic-like environment or NOTCH signaling stimulatory cell line.

Single-cell coating with biomimetic extracellular nanofiber matrices.

Cell therapies offer great promise in the treatment of diseases and tissue regeneration, but their clinical use has many challenges including survival, optimal performance in their intended function, or localization at sites where they are needed for effective outcomes. We report here on a method to coat a biodegradable matrix of biomimetic nanofibers on single cells that could have specific functions ranging from cell signaling to targeting and helping cells survive when used for therapies. The fibers are composed of peptide amphiphile (PA) molecules that self-assemble into supramolecular nanoscale filaments. The PA nanofibers were able to create a mesh-like coating for a wide range of cell lineages with nearly 100 % efficiency, without interrupting the natural cellular phenotype or functions. The targeting abilities of this system were assessed in vitro using human primary regulatory T (hTreg) cells coated with PAs displaying a vascular cell adhesion protein 1 (VCAM-1) targeting motif. This approach provides a biocompatible method for single-cell coating that does not negatively alter cellular phenotype, binding capacity, or immunosuppressive functionality, with potential utility across a broad spectrum of cell therapies. STATEMENT OF SIGNIFICANCE: Cell therapies hold great promise in the treatment of diseases and tissue regeneration, but their clinical use has been limited by cell survival, targeting, and function. We report here a method to coat single cells with a biodegradable matrix of biomimetic nanofibers composed of peptide amphiphile (PA) molecules. The nanofibers were able to coat cells, such as human primary regulatory T cells, with nearly 100 % efficiency, without interrupting the natural cellular phenotype or functions. The approach provides a biocompatible method for single-cell coating that does not negatively alter cellular phenotype, binding capacity, or immunosuppressive functionality, with potential utility across a broad spectrum of cell therapies.

Physical activity levels, ownership of goods promoting sedentary behaviour and risk of myocardial infarction: results of the INTERHEART study.

AIMS: To evaluate the association between occupational and leisure-time physical activity (PA), ownership of goods promoting sedentary behaviour, and the risk of myocardial infarction (MI) in different socio-economic populations of the world. Studies in developed countries have found low PA as a risk factor for cardiovascular disease; however, the protective effect of occupational PA is less certain. Moreover, ownership of goods promoting sedentary behaviour may be associated with an increased risk. METHODS: In INTERHEART, a case-control study of 10 043 cases of first MI and 14 217 controls who did not report previous angina or physical disability completed a questionnaire on work and leisure-time PA. RESULTS: Subjects whose occupation involved either light [multivariable-adjusted odds ratio (OR) 0.78, confidence interval (CI) 0.71-0.86] or moderate (OR 0.89, CI 0.80-0.99) PA were at a lower risk of MI, whereas those who did heavy physical labour were not (OR 1.02, CI 0.88-1.19), compared with sedentary subjects. Mild exercise (OR 0.87, CI 0.81-0.93) as well as moderate or strenuous exercise (OR 0.76, CI 0.69-0.82) was protective. The effect of PA was observed across countries with low, middle, and high income. Subjects who owned both a car and a television (TV) (multivariable-adjusted OR 1.27, CI 1.05-1.54) were at higher risk of MI compared with those who owned neither. CONCLUSION: Leisure-time PA and mild-to-moderate occupational PA, but not heavy physical labour, were associated with a reduced risk, while ownership of a car and TV was associated with an increased risk of MI across all economic regions.

CD4+CD25+FOXP3+ regulatory T cells: a potential "armor" to shield "transplanted allografts" in the war against ischemia reperfusion injury.

Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4+CD25+FOXP3+ regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.

Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients.

BACKGROUND: Thirty-seven patients have received a living-donor kidney transplant in a phase 2 study designed to induce tolerance with facilitated allogeneic hematopoietic stem cell transplant. The study protocol is based on tolerogenic CD8 + /T-cell receptor - facilitating cells (FCR001; also including hematopoietic stem cells and αß-T-cell receptor + T cells) and low-dose, nonmyeloablative conditioning. Persistent chimerism allowing full immunosuppression (IS) withdrawal was achieved in 26 patients (time off IS 36-123 mo). METHODS: We evaluated biomarkers of tolerance through urinary cell mRNA profiling and immunocompetence to respond to vaccination in these patients. We also assessed kidney function and metabolic parameters compared with standard-of-care patients on IS. RESULTS: Persistently chimeric patients retained chimerism after removal of IS and remained rejection free without donor HLA-specific antibody development. The presence of donor chimerism at >50% correlated with a signature of tolerance in urinary cell mRNA profiles, with a uniquely elevated increase in the ratio of cytotoxic T lymphocyte-associated protein 4 to granzyme B mRNA. Tolerance was associated with protection from recurrence of immune-mediated causes of kidney disease. Tolerant participants were safely vaccinated, developed protective immune responses, and did not lose chimerism after vaccination. When compared with kidney transplant recipients treated with standard IS, tolerant participants showed stable kidney function and reduced medication use for hypertension and hyperlipidemia. CONCLUSIONS: These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients.