Steering cell migration by alternating blebs and actin-rich protrusions

Background High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. Results Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. Conclusions Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times

Targeting Treatment-Resistant Auditory Verbal Hallucinations in Schizophrenia with fMRI-Based Neurofeedback – Exploring Different Cases of Schizophrenia

Auditory verbal hallucinations (AVHs) are a hallmark of schizophrenia and can significantly impair patients' emotional, social, and occupational functioning. Despite progress in psychopharmacology, over 25% of schizophrenia patients suffer from treatment-resistant hallucinations. In the search for alternative treatment methods, neurofeedback (NF) emerges as a promising therapy tool. NF based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntarily change of the activity in a selected brain region - even in patients with schizophrenia. This study explored effects of NF on ongoing AVHs. The selected participants were trained in the self-regulation of activity in the anterior cingulate cortex (ACC), a key monitoring region involved in generation and intensity modulation of AVHs. Using rt-fMRI, three right-handed patients, suffering from schizophrenia and ongoing, treatment-resistant AVHs, learned control over ACC activity on three separate days. The effect of NF training on hallucinations' severity was assessed with the Auditory Vocal Hallucination Rating Scale (AVHRS) and on the affective state - with the Positive and Negative Affect Schedule (PANAS). All patients yielded significant upregulation of the ACC and reported subjective improvement in some aspects of AVHs (AVHRS) such as disturbance and suffering from the voices. In general, mood (PANAS) improved during NF training, though two patients reported worse mood after NF on the third day. ACC and reward system activity during NF learning and specific effects on mood and symptoms varied across the participants. None of them profited from the last training set in the prolonged three-session training. Moreover, individual differences emerged in brain networks activated with NF and in symptom changes, which were related to the patients' symptomatology and disease history. NF based on rt-fMRI seems a promising tool in therapy of AVHs. The patients, who suffered from continuous hallucinations for years, experienced symptom changes that may be attributed to the NF training. In order to assess the effectiveness of NF as a therapeutic method, this effect has to be studied systematically in larger groups; further, long-term effects need to be assessed. Particularly in schizophrenia, future NF studies should take into account the individual differences in reward processing, fatigue, and motivation to develop individualized training protocols

Endocytic reawakening of motility in jammed epithelia

Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination

Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes

Most migrating cells extrude their front by the force of actin polymerization. Polymerization requires an initial nucleation step, which is mediated by factors establishing either parallel filaments in the case of filopodia or branched filaments that form the branched lamellipodial network. Branches are considered essential for regular cell motility and are initiated by the Arp2/3 complex, which in turn is activated by nucleation-promoting factors of the WASP and WAVE families. Here we employed rapid amoeboid crawling leukocytes and found that deletion of the WAVE complex eliminated actin branching and thus lamellipodia formation. The cells were left with parallel filaments at the leading edge, which translated, depending on the differentiation status of the cell, into a unipolar pointed cell shape or cells with multiple filopodia. Remarkably, unipolar cells migrated with increased speed and enormous directional persistence, while they were unable to turn towards chemotactic gradients. Cells with multiple filopodia retained chemotactic activity but their migration was progressively impaired with increasing geometrical complexity of the extracellular environment. These findings establish that diversified leading edge protrusions serve as explorative structures while they slow down actual locomotion

Impact of a tailored program on the implementation of evidence-based recommendations for multimorbid patients with polypharmacy in primary care practices — results of a cluster-randomized controlled trial

Background: Multimorbid patients receiving polypharmacy represent a growing population at high risk for negative health outcomes. Tailoring is an approach of systematic intervention development taking account of previously identified determinants of practice. The aim of this study was to assess the effect of a tailored program to improve the implementation of three important processes of care for this patient group: (a) structured medication counseling including brown bag reviews, (b) the use of medication lists, and (c) structured medication reviews to reduce potentially inappropriate medication. Methods: We conducted a cluster-randomized controlled trial with a follow-up time of 9 months. Participants were general practitioners (GPs) organized in quality circles and participating in a GP-centered care contract of a German health insurance. Patients aged >50 years, suffering from at least 3 chronic diseases, receiving more than 4 drugs, and being at high risk for medication-related events according to the assessment of the treating GP were enrolled. The tailored program consisted of a workshop for GPs and health care assistants, educational materials and reminders for patients, and the elaboration of implementation action plans. The primary outcome was the change in the degree of implementation between baseline and follow-up, measured by a summary score of 10 indicators. The indicators were based on structured surveys with patients and GPs. Results: We analyzed the data of 21 GPs (10 - intervention group, 11 - control group) and 273 patients (130 - intervention group, 143 - control group). The increase in the degree of implementation was 4.2 percentage points (95% confidence interval: −0.3, 8.6) higher in the intervention group compared to the control group (p = 0.1). Two of the 10 indicators were significantly improved in the intervention group: medication counseling (p = 0.017) and brown bag review (p = 0.012). Secondary outcomes showed an effect on patients’ self-reported use of medication lists when buying drugs in the pharmacy (p = 0.03). Conclusions: The tailored program may improve implementation of medication counseling and brown bag review whereas the use of medication lists and medication reviews did not improve. No effect of the tailored program on the combined primary outcome could be substantiated. Due to limitations of the study, results have to be interpreted carefully. The factors facilitating and hindering successful implementation will be examined in a comprehensive process evaluation. Trial registration number ISRCTN34664024, assigned 14/08/201