Liquid-like condensates mediate competition between actin branching and bundling.

Cellular remodeling of actin networks underlies cell motility during key morphological events, from embryogenesis to metastasis. In these transformations, there is an inherent competition between actin branching and bundling, because steric clashes among branches create a mechanical barrier to bundling. Recently, liquid-like condensates consisting purely of proteins involved in either branching or bundling of the cytoskeleton have been found to catalyze their respective functions. Yet in the cell, proteins that drive branching and bundling are present simultaneously. In this complex environment, which factors determine whether a condensate drives filaments to branch or become bundled? To answer this question, we added the branched actin nucleator, Arp2/3, to condensates composed of VASP, an actin bundling protein. At low actin to VASP ratios, branching activity, mediated by Arp2/3, robustly inhibited VASP-mediated bundling of filaments, in agreement with agent-based simulations. In contrast, as the actin to VASP ratio increased, addition of Arp2/3 led to formation of aster-shaped structures, in which bundled filaments emerged from a branched actin core, analogous to filopodia emerging from a branched lamellipodial network. These results demonstrate that multi-component, liquid-like condensates can modulate the inherent competition between bundled and branched actin morphologies, leading to organized, higher-order structures, similar to those found in motile cells.

Morphological control of bundled actin networks subject to fixed-mass depletion.

Depletion interactions are thought to significantly contribute to the organization of intracellular structures in the crowded cytosol. The strength of depletion interactions depends on physical parameters such as the depletant number density and the depletant size ratio. Cells are known to dynamically regulate these two parameters by varying the copy number of proteins of a wide distribution of sizes. However, mammalian cells are also known to keep the total protein mass density remarkably constant, to within 0.5% throughout the cell cycle. We thus ask how the strength of depletion interactions varies when the total depletant mass is held fixed, a.k.a. fixed-mass depletion. We answer this question via scaling arguments, as well as by studying depletion effects on networks of reconstituted semiflexible actin in silico and in vitro. We examine the maximum strength of the depletion interaction potential U∗ as a function of q, the size ratio between the depletant and the matter being depleted. We uncover a scaling relation U∗ ∼ qζ for two cases: fixed volume fraction φ and fixed mass density ρ. For fixed volume fraction, we report ζ < 0. For the fixed mass density case, we report ζ > 0, which suggests that the depletion interaction strength increases as the depletant size ratio is increased. To test this prediction, we prepared our filament networks at fixed mass concentrations with varying sizes of the depletant molecule poly(ethylene glycol) (PEG). We characterize the depletion interaction strength in our simulations via the mesh size. In experiments, we observe two distinct actin network morphologies, which we call weakly bundled and strongly bundled. We identify a mass concentration where different PEG depletant sizes lead to weakly bundled or strongly bundled morphologies. For these conditions, we find that the mesh size and intra-bundle spacing between filaments across the different morphologies do not show significant differences, while the dynamic light scattering relaxation time and storage modulus between the two states do show significant differences. Our results demonstrate the ability to tune actin network morphology and mechanics by controlling depletant size and give insights into depletion interaction mechanisms under the fixed-depletant-mass constraint relevant to living cells.

A qualitative exploration of the experiences of Aboriginal and Torres Strait Islander people using a real-time video-based telehealth service for diabetes-related foot disease.

INTRODUCTION: Diabetes-related foot disease (DFD) is one of the most prevalent causes of global hospitalisation and morbidity, and it accounts for up to 75% of lower-extremity amputations globally. The 5-year mortality rate following any amputation ranges from 53% to 100%. Early identification of wounds and multidisciplinary management can reduce amputation rates by 39-56%. Rural and remote communities and Indigenous populations are disproportionately affected by DFD. This is reflected in amputation rates, which are much higher for Indigenous than for non-Indigenous Australians and for those in very remote areas than for those in major cities or inner regional areas. The large geographical spread of the population in Australia is a substantial barrier for those providing or accessing health services, particularly multidisciplinary and specialist services, which undoubtedly contributes to poorer DFD outcomes in rural and remote communities. METHODS: A real-time, video-based telehealth service for DFD management was established at the Royal Adelaide Hospital Vascular Services clinic to improve access to specialist services for rural and remote Aboriginal and Torres Strait Islander communities. An exploratory qualitative study that utilised one-on-one, semi-structured interviews was conducted with 11 participants who identified as Aboriginal and who had participated in the telehealth foot service. Interviews were transcribed, de-identified and analysed using thematic analysis, using an inductive approach. RESULTS: Four interrelated themes emerged. 'Practical benefits of staying home' describes the reduced burden of travel and advantages of having local healthcare providers and support people at consultations. 'Access to specialists and facilities' highlights how some participants felt that there was a lack of appropriate facilities in their area and appreciated the improved access telehealth provided. 'Feeling reassured that a specialist has seen their feet' reflects the positive impact on wellbeing that participants experienced when their feet were seen by specialist health staff. 'Facilitates communication' describes how participants felt included in consultations and how seeing a person on screen assisted conversation. CONCLUSION: The advantages of real-time, video-based telehealth go beyond reduced travel burden and improved access to specialist care. This model of care may facilitate relationship-building, patient wellbeing, and feelings of trust and safety for Aboriginal and Torres Strait Islander DFD patients.

Longitudinal Relationship Between Posttraumatic Stress Symptoms and Physical Symptoms in Military Veterans.

OBJECTIVE: This study aimed to assess the temporal relationship of posttraumatic stress disorder (PTSD) symptoms and physical symptoms in a non-treatment-seeking deployed military sample. METHODS: Data were from a longitudinal study of Australian Defence Force personnel deployed to the Middle East Area of Operations between 2010 and 2012 ( n = 1871). Predeployment assessment was conducted 4 months before deployment (T1). Of these, 1324 (70.8% retention rate) participated in assessment within 4 months after deployment (T2), and 1122 (60.0%) completed the third time point at 4 years after deployment (T3). PTSD symptoms were assessed with the posttraumatic stress checklist and physical symptoms with a 67-item self-report Health Symptom Checklist. To explore directional influences between symptoms over time, longitudinal cross-lagged association between the modeled latent factors for PTSD symptoms and physical symptoms was estimated using structural equation modeling. RESULTS: From T1 to T2, there was a significant bidirectional effect with higher physical symptom count at T1 predicting higher PTSD symptom severity at T2 ( ß = 0.17, p < .001) and higher PTSD symptom severity at T1 predicting higher physical symptom count at T2 ( ß = 0.13, p < .001). The effect of T2 on T3 was unidirectional. PTSD symptom severity at T2 had no effect on physical symptom count at T3, but physical symptom count at T2 predicted an increase in PTSD symptom severity at T3 ( ß = 0.11, p = .013). CONCLUSIONS: Considering early physical symptoms and their physiological underpinnings after traumatic exposures could help identify those at risk of later PTSD.

Improving communication and teamwork during labor: A feasibility, acceptability, and safety study.

BACKGROUND: TeamBirth was designed to promote best practices in shared decision making (SDM) among care teams for people giving birth. Although leading health organizations recommend SDM to address gaps in quality of care, these recommendations are not consistently implemented in labor and delivery. METHODS: We conducted a mixed-methods trial of TeamBirth among eligible laboring patients and all clinicians (nurses, midwives, and obstetricians) at four high-volume hospitals during April 2018 to September 2019. We used patient and clinician surveys, abstracted clinical data, and administrative claims to evaluate the feasibility, acceptability, and safety of TeamBirth. RESULTS: A total of 2,669 patients (approximately 28% of eligible delivery volume) and 375 clinicians (78% response rate) responded to surveys on their experiences with TeamBirth. Among patients surveyed, 89% reported experiencing at least one structured full care team conversation ("huddle") during labor and 77% reported experiencing multiple huddles. There was a significant relationship between the number of reported huddles and patient acceptability (P < 0.001), suggestive of a dose response. Among clinicians surveyed, 90% would recommend TeamBirth for use in other labor and delivery units. There were no significant changes in maternal and newborn safety measures. CONCLUSIONS: Implementing a care process that aims to improve communication and teamwork during labor with high fidelity is feasible. The process is acceptable to patients and clinicians and shows no negative effects on patient safety. Future work should evaluate the effectiveness of TeamBirth in improving care experience and health outcomes.

Race/Ethnicity and Community Participation Among Veterans and Service Members With Traumatic Brain Injury: A VA Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To examine racial/ethnic disparities in community participation among veterans and active duty service members with traumatic brain injury (TBI). SETTING: Five Department of Veterans Affairs (VA) TBI Model Systems (TBIMS) Polytrauma Rehabilitation Centers (PRCs). Participants: Three hundred forty-two community-dwelling adults (251 White, 34 Black, and 57 Hispanic) with TBI enrolled in the VA TBIMS National Database who completed a 1-year follow-up interview. Mean age was 38.6 years (range, 19-84 years). DESIGN: Cross-sectional analysis of a prospective observational cohort study. Main Measures: Community participation at 1 year postinjury assessed by 3 domains of the Participation Assessment with Recombined Tools-Objective (PART-O): Out & About, Productivity, and Social Relations. RESULTS: Significant differences were observed among race/ethnicity groups in PART-O Productivity and Out & About domains without controlling for relevant participant characteristics; Productivity scores were significantly higher for non-Hispanic Black than for non-Hispanic White participants (t = 2.40, P = .0169). Out & About scores were significantly higher for Hispanic than for non-Hispanic White participants (t = 2.79, P = .0056). However, after controlling for demographic, injury severity, and 1-year follow-up characteristics, only differences in the Out & About domain remained statistically significant (t = 2.62, P = .0094), with scores being significantly higher for Hispanics than for non-Hispanic Whites. CONCLUSIONS: The results, which differ from findings from studies conducted in non-VA healthcare settings where there are greater racial/ethnic disparities in participation outcomes, could reflect differences between military and civilian samples that may reduce disparities.

Efficient cell delivery mediated by lipid-specific endosomal escape of supercharged branched peptides.

Various densely charged polycationic species, whether of biological or synthetic origin, can penetrate human cells, albeit with variable efficiencies. The molecular underpinnings involved in such transport remain unclear. Herein, we assemble 1, 2 or 3 copies of the HIV peptide TAT on a synthetic scaffold to generate branched cell-permeable prototypes with increasing charge density. We establish that increasing TAT copies dramatically increases the cell penetration efficiency of the peptides while simultaneously enabling the efficient cytosolic delivery of macromolecular cargos. Cellular entry involves the leaky fusion of late endosomal membranes enriched with the anionic lipid BMP. Derivatives with multiple TAT branches induce the leakage of BMP-containing lipid bilayers, liposomal flocculation, fusion and an increase in lamellarity. In contrast, while the monomeric counterpart 1TAT binds to the same extent and causes liposomal flocculation, 1TAT does not cause leakage, induce fusion or a significant increase in lamellarity. Overall, these results indicate that an increase in charge density of these branched structures leads to the emergence of lipid specific membrane-disrupting and cell-penetrating activities.

Evaluation of a Brief, Skill-Building, Supportive, and Educational Intervention for Couples After Brain Injury.

OBJECTIVE: To examine the effectiveness of an intervention (Therapeutic Couples Intervention, TCI) designed to improve relationship quality for couples after acquired brain injury. SETTING: Outpatient brain injury rehabilitation center. PARTICIPANTS: Persons with brain injury (n = 75) and their intimate partners (n = 75). DESIGN: Two-arm parallel, randomized, controlled trial with wait-listed control. METHODS: Composed of 5 to 6 2-hour sessions, the TCI is a manualized, treatment program designed to enhance relationship quality by addressing issues and concerns most often identified by persons with brain injury and their partners. MAIN MEASURE: Revised Dyadic Adjustment Scale completed by the persons with brain injury and their partners. RESULTS: Persons with brain injury and their partners in the treatment group showed an improvement in relationship quality, both compared with their own baseline values and the control group. CONCLUSIONS: Investigation provided evidence that a curriculum-based education, skill-building, and supportive intervention can benefit couples for up to 3 months after treatment. Additional research is needed to ascertain the long-term benefits of intervention and the efficacy of alternative delivery methods (eg, Internet, telephone, and group).

Acute Funisitis Correlates With the Risk of Early-Onset Sepsis in Term Newborns Assessed Using the Kaiser Sepsis Calculator.

BACKGROUND: The risk of neonatal early-onset sepsis (EOS) is traditionally assessed on maternal signs of clinical chorioamnionitis. Recently, an online EOS risk calculator was developed by Kaiser Permanente using maternal and neonatal clinical parameters. We were interested in whether an increased Kaiser sepsis risk score correlates with histologic acute chorioamnionitis or acute funisitis. DESIGN: Included in this retrospective review are 119 chorioamnionitis-exposed term neonates from January 1, 2015 and December 31, 2016. Clinical charts from mother-baby pairs were reviewed. An EOS risk score was obtained using the online Kaiser Sepsis Calculator. The presence and severity of acute chorioamnionitis and acute funisitis were recorded. A SPSS software was used for statistical analysis (IBM, New Jersey, USA). RESULTS: The Kaiser Sepsis Calculator could identify 97 of 119 (81.5%) neonates without increased risk for sepsis. Histologic acute chorioamnionitis was present in 100 of 119 cases (84%), in which 44 cases (44%) show severe acute chorioamnionitis. Acute funisitis was recognized in 87 of 119 (73.1%) cases, all of which had concurrent acute chorioamnionitis. Severe funisitis was seen in 38 of the 87 cases (43.7%). The Kaiser Sepsis risk score correlates with the presence and severity of acute funisitis (P = .037 and P = .044, respectively) but not with the presence or the severity of acute chorioamnionitis (P = .105 and P = .672, respectively). CONCLUSION: Our study provides histological evidence to support that the Kaiser Sepsis Calculator may help to effectively reduce unwarranted blood culture, antibiotics exposure, and neonatal intensive care unit admission in term neonates.

Depression as a Predictor of Long-term Employment Outcomes Among Individuals With Moderate-to-Severe Traumatic Brain Injury.

OBJECTIVE: To examine the predictive ability of depression when considering long-term employment outcomes for individuals with moderate-to-severe traumatic brain injury (TBI) after controlling for key preinjury and injury-related variables. DESIGN: Secondary data analysis. SETTING: Community follow-up after discharge from an inpatient rehabilitation center. PARTICIPANTS: Individuals between 18 and 60 years old with moderate-to-severe TBI enrolled in the Traumatic Brain Injury Model Systems database. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Employment status. RESULTS: The prevalence of employment at 2 and 5 years post injury was 40.3% and 44.5%, respectively. Individuals identified as depressed at 1 year were more likely to be unemployed at 2 years post injury (odds ratio [OR], 1.77; 95% CI, 1.38-2.27; P<.0001). Similar relations between current depression and future employment were observed from 1- and 2-year depression status predicting 5-year employment (1-year: OR, 1.88; 95% CI, 1.48-2.40; P<.0001: 2-year: OR, 1.72; 95% CI, 1.36-2.17; P<.0001). CONCLUSIONS: After controlling for baseline predictors variables, the experience of postinjury depression-a modifiable condition-contributes predictive ability to future employment outcomes. Incorporating assessments and/or interventions for depression into postacute rehabilitation programs could promote favorable employment outcomes after TBI.

Employment Stability in the First 5 Years After Moderate-to-Severe Traumatic Brain Injury.

OBJECTIVE: To characterize employment stability and identify predictive factors of employment stability in working-age individuals after moderate-to-severe traumatic brain injury (TBI) that may be clinically addressed. DESIGN: Longitudinal observational study of an inception cohort from the Traumatic Brain Injury Model Systems National Database (TBIMS-NDB) using data at years 1, 2, and 5 post-TBI. SETTING: Inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals enrolled in the TBIMS-NDB since 2001, aged 18-59, with employment data at 2 or more follow-up interviews at years 1, 2, and 5 (N=5683). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Employment stability, categorized using post-TBI employment data as no paid employment (53.25%), stably (27.20%), delayed (10.24%), or unstably (9.31%) employed. RESULTS: Multinomial regression analyses identified predictive factors of employment stability, including younger age, white race, less severe injuries, preinjury employment, higher annual earnings, male sex, higher education, transportation independence postinjury, and no anxiety or depression at 1 year post-TBI. CONCLUSIONS: Employment stability serves as an important measure of productivity post-TBI. Psychosocial, clinical, environmental, and demographic factors predict employment stability post-TBI. Notable predictors include transportation independence as well as the presence of anxiety and depression at year 1 post-TBI as potentially modifiable intervention targets.

Using Decision Tree Methodology to Predict Employment After Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To build decision tree prediction models for long-term employment outcomes of individuals after moderate to severe closed traumatic brain injury (TBI) and assess model accuracy in an independent sample. SETTING: TBI Model Systems Centers. PARTICIPANTS: TBI Model Systems National Database participants injured between January 1997 and January 2017 with moderate to severe closed TBI. Sample sizes were 7867 (year 1 postinjury), 6783 (year 2 postinjury), and 4927 (year 5 postinjury). DESIGN: Cross-sectional analyses using flexible classification tree methodology and validation using an independent subset of TBI Model Systems National Database participants. MAIN MEASURES: Competitive employment at 1, 2, and 5 years postinjury. RESULTS: In the final employment prediction models, posttraumatic amnesia duration was the most important predictor of employment in each outcome year. Additional variables consistently contributing were age, preinjury education, productivity, and occupational category. Generally, individuals spending fewer days in posttraumatic amnesia, who were competitively employed preinjury, and more highly educated had better outcomes. Predictability in test data sets ranged from a C-statistic of 0.72 (year 5; confidence interval: 0.68-0.76) to 0.77 (year 1; confidence interval: 0.74-0.80). CONCLUSION: An easy-to-use decision tree tool was created to provide prognostic information on long-term competitive employment outcomes in individuals with moderate to severe closed TBI. Length of posttraumatic amnesia, a clinical marker of injury severity, and preinjury education and employment status were the most important predictors.

The Associations Between Physical and Psychological Symptoms and Traumatic Military Deployment Exposures.

Current paradigms regarding the effects of traumatic exposures on military personnel do not consider physical symptoms unrelated to injury or illness as independent outcomes of trauma exposure, characteristically dealing with these symptoms as comorbidities of psychological disorders. Our objective was to ascertain the proportions of deployed military personnel who experienced predominantly physical symptoms, predominantly psychological symptoms, and comorbidity of the two and to examine the association between traumatic deployment exposures (TDEs) and these symptomatic profiles. Data were taken from a cross-sectional study of Australian Defence Force personnel who were deployed to the Middle East during 2001-2009 (N = 14,032). Four groups were created based on distributional splits of physical and psychological symptom scales: low-symptom, psychological, physical, and comorbid. Multinomial logistic regression models assessed the probability of symptom group membership, compared with low-symptom, as predicted by self-reported TDEs. Group proportions were: low-symptom, 78.3%; physical, 5.0%; psychological, 9.3%; and comorbid, 7.5%. TDEs were significant predictors of all symptom profiles. For subjective, objective, and human death and degradation exposures, respectively, the largest relative risk ratios (RRRs) were for the comorbid profile, RRRs = 1.47, 1.19, 1.48; followed by the physical profile, RRRs = 1.27, 1.15, 1.40; and the psychological profile, RRRs = 1.22, 1.07, 1.22. Almost half of participants with physical symptoms did not have comorbid psychological symptoms, suggesting that physical symptoms can occur as a discrete outcome trauma exposure. The similar dose-response association between TDEs and the physical and psychological profiles suggests trauma is similarly associated with both outcomes.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) La relación de exposición de despliegue militar traumática con síntomas físicos y psicológicos. SÍNTOMAS FÍSICOS Y PSICOLÓGICOS DE TRAUMA Los paradigmas actuales relacionados con los efectos de la exposición al trauma en personal militar no consideran los síntomas físicos no relacionados a lesiones o enfermedades como resultados independientes de la exposición al trauma, manejando característicamente estos síntomas como comorbilidades de trastornos psicológicos. Nuestro objetivo fue determinar la proporción de personal militar desplegado que había experimentado predominantemente síntomas físicos, síntomas psicológicos y comorbilidad entre ellos y examinar la asociación entre las exposiciones de despliegue traumático (TDEs en su sigla en inglés) y estos perfiles sintomáticos. Los datos fueron recolectados de un estudio de tipo transversal del Personal de Fuerza de Defensa Australiana que fueron desplegados en el medio oriente durante 2001- 2009 (N = 14,032). Se crearon cuatro grupos basados en distribución separadas de escalas de síntomas físicos y psicológicos: síntomas bajos, psicológicos, físicos y comórbidos. Una regresión logística multimodal evaluó la probabilidad de los síntomas de los miembros del grupo, comparado con bajos síntomas, como predictor del auto reporte de TDEs. La proporción de los grupos fue: síntomas bajos, 78.3%; físicos, 5%; psicológicos, 9.3%; y comórbido, 7.5%. TDEs fueron predictores significativos de todos los perfiles de síntomas. Para las exposiciones subjetivas, objetivas y de muerte y degradación humana, respectivamente, los mayores índices de riesgo relativo (RRRs en su sigla en inglés) fueron para el perfil comórbido, RRRs = 1.47, 1.19, 1.48; seguido por el perfil físico, RRRs = 1.27, 1.15, 1.40; y el perfil psicológico, RRRs = 1.22, 1.07, 1.22. Casi la mitad de los participantes con síntomas físicos no tenían síntomas psicológicos comórbidos, lo que sugiere que los síntomas físicos pueden ocurrir como un resultado discreto de la exposición al trauma. La asociación similar dosis- respuesta entre TDEs y los perfiles físicos y psicológicos sugieren que el trauma se asocia similarmente con ambos resultados.

Effects of Depression and Antidepressant Use on Cognitive Deficits and Functional Cognition Following Severe Traumatic Brain Injury.

OBJECTIVE: To use a Rehabilomics framework to evaluate relations hips between post-traumatic brain injury (TBI) depression (PTD) and potential associated factors, including antidepressant use, on cognitive recovery following severe TBI. PARTICIPANTS: Severe TBI survivors (n = 154), recruited from a level 1 trauma center. DESIGN: Prospective cohort study with assessments at 6 and 12 months postinjury. MAIN MEASURES: Patient Health Questionnaire-9 (PTD symptoms); cognitive composite score from a neuropsychological assessment battery (cognitive impairment); and Functional Independence Measure-Cognition (FIM-Cog, self-reported functional cognition). RESULTS: Individuals with and without PTD did not differ with respect to cognitive impairment. However, antidepressant use, regardless of PTD status, was associated with cognitive impairment. Individuals with PTD reported lower FIM-Cog scores at both time points compared with those without PTD. In a post hoc longitudinal analysis, individuals with late-onset PTD had worse cognitive impairment. CONCLUSION: These results suggest that antidepressant use impairs cognition among individuals without PTD. Also, PTD did not directly affect cognitive impairment but may affect functional cognitive limitations through self-evaluation and apathy/motivation factors.

Pilot feasibility of an mHealth system for conducting ecological momentary assessment of mood-related symptoms following traumatic brain injury.

OBJECTIVE: This study assessed pilot feasibility and validity of a mobile health (mHealth) system for tracking mood-related symptoms after traumatic brain injury (TBI). DESIGN: A prospective, repeated measures design was used to assess compliance with daily ecological momentary assessments (EMA) conducted via a smartphone application over an 8-week period. METHODS: An mHealth system was developed specifically for individuals with TBI and utilized previously validated tools for depressive and anxiety symptoms (Patient Health Questionnaire-9, Generalized Anxiety Disorder-7). Feasibility was assessed in 20 community-dwelling adults with TBI via an assessment of compliance, satisfaction and usability of the smartphone applications. The authors also developed and implemented a clinical patient safety management mechanism for those endorsing suicidality. RESULTS: Participants correctly completed 73.4% of all scheduled assessments, demonstrating good compliance. Daily assessments took <2 minutes to complete. Participants reported high satisfaction with smartphone applications (6.3 of 7) and found them easy to use (6.2 of 7). Comparison of assessments obtained via telephone-based interview and EMA demonstrated high correlations (r = 0.81-0.97), supporting the validity of conducting these assessments via smartphone application in this population. CONCLUSIONS: EMA conducted via smartphone demonstrates initial feasibility among adults with TBI and presents numerous opportunities for long-term monitoring of mood-related symptoms in real-world settings.

Kinetic trapping organizes actin filaments within liquid-like protein droplets.

Several actin-binding proteins (ABPs) phase separate to form condensates capable of curating the actin network shapes. Here, we use computational modeling to understand the principles of actin network organization within VASP condensate droplets. Our simulations reveal that the different actin shapes, namely shells, rings, and mixture states are highly dependent on the kinetics of VASP-actin interactions, suggesting that they arise from kinetic trapping. Specifically, we show that reducing the residence time of VASP on actin filaments reduces degree of bundling, thereby promoting assembly of shells rather than rings. We validate the model predictions experimentally using a VASP-mutant with decreased bundling capability. Finally, we investigate the ring opening within deformed droplets and found that the sphere-to-ellipsoid transition is favored under a wide range of filament lengths while the ellipsoid-to-rod transition is only permitted when filaments have a specific range of lengths. Our findings highlight key mechanisms of actin organization within phase-separated ABPs.

PTSD biomarkers: Neuroendocrine signaling to epigenetic variants.

Posttraumatic stress disorder (PTSD) is characterized by exposure to traumatic events and involves symptom domains such as intrusive thoughts, avoidant behaviors, negative mood, and cognitive dysfunction. The disorder can be chronic and debilitating, and the heterogenous nature and varied presentation of PTSD has afforded difficulty in determining efficacious treatment. The ability to identify biomarkers for PTSD risk, prognosis, or for the purposes of treatment, would be highly valuable. There is evidence for peripheral biomarkers related to the hypothalamic-pituitary-adrenal axis, the immune system, neurotransmitters and neurohormones, while genome and epigenome wide association studies have identified genes of interest relating to neurocircuitry, monoaminergic function, and the immune system. Importantly, however, reproducibility is a persistent issue. Considerations for future research include the need for well-powered and well-designed studies to determine directionality, in addition to considering biomarkers as they relate to symptom domains and the spectrum of symptom severity rather than dichotomous diagnostic outcomes. We conclude by recommending the staging of biological processes and PTSD symptoms, from subsyndromal to chronic, which could eventually facilitate selection of personalized treatment interventions for individuals with PTSD, in addition to serving as a future framework for biomarker data.

Measuring 24-h use of time in people with a diabetes-related foot ulcer: A feasibility study.

BACKGROUND: Physical activity (PA), sleep and sedentary time are now recognised as mutually exclusive and exhaustive parts of the 24-h day-if PA decreases, time spent sleeping, being sedentary or both must increase so that all components equate to 24 h. Recent advances in time-use epidemiology suggest that we should not consider time-use domains (PA, sleep and sedentary time) in isolation from each other, but in terms of a composition-the mix of time-use domains across the 24-h day. While interrelated daily activities are known to be important in the management of diabetes mellitus, few studies have investigated the interrelated daily activities in people with an active diabetes-related foot ulcer (DFU) and their impact on important outcomes such as wound severity, blood glucose control and health-related quality of life (HRQoL). This feasibility study aims to determine the acceptability and practicality of measuring 24-h use of time data in people with a DFU and its associations on important outcome measures for this population. METHODS: Participants wore a wrist-worn accelerometer for two weeks and completed demographic and HRQoL questionnaires. Outcomes were participant engagement, reported levels of study burden and value and compositional data analysis as a methodological approach for evaluating 24-h use of time data. RESULTS: Twenty-six participants reported low levels of study burden and rated the study value highly. The protocol appears feasible in terms of recruitment (81%) and retention rate (86%). On average, participants were relatively sedentary spending 747, 172 and 18 min in sedentary time, light physical activity and moderate-to-vigorous activity, respectively. Sleep appeared adequate with participants obtaining an average of 485 min, but quality of sleep was notably poor with average sleep efficiency of 75%. Compositional data analysis was able to quantify the integrated associations of 24-h use of time with HRQoL. CONCLUSION: The protocol provides an acceptable method to collect 24-h use of time data in people with a DFU. Efforts to consider and analyse PA as part of a 24-h activity composition may provide holistic and realistic understandings of PA in this clinical population.

Liquid-like condensates that bind actin drive filament polymerization and bundling.

Liquid-like protein condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that polymerize and bundle actin. To minimize their curvature, filaments accumulated at the inner condensate surface, ultimately deforming the condensate into a rod-like shape, filled with a bundle of parallel filaments. Here we show that this behavior does not require proteins with specific polymerase activity. Specifically, we found that condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of polymerizing and bundling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds actin could bundle filaments through multivalent crosslinking. To test this idea, we added an actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that drove efficient actin polymerization and bundling. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any actin-binding protein that participates in protein condensation.