Migrating Myeloid Cells Sense Temporal Dynamics of Chemoattractant Concentrations.

Chemoattractant-mediated recruitment of hematopoietic cells to sites of pathogen growth or tissue damage is critical to host defense and organ homeostasis. Chemotaxis is typically considered to rely on spatial sensing, with cells following concentration gradients as long as these are present. Utilizing a microfluidic approach, we found that stable gradients of intermediate chemokines (CCL19 and CXCL12) failed to promote persistent directional migration of dendritic cells or neutrophils. Instead, rising chemokine concentrations were needed, implying that temporal sensing mechanisms controlled prolonged responses to these ligands. This behavior was found to depend on G-coupled receptor kinase-mediated negative regulation of receptor signaling and contrasted with responses to an end agonist chemoattractant (C5a), for which a stable gradient led to persistent migration. These findings identify temporal sensing as a key requirement for long-range myeloid cell migration to intermediate chemokines and provide insights into the mechanisms controlling immune cell motility in complex tissue environments.

Defining "Arts Participation" for Public Health Research.

Arts participation has been linked to positive health outcomes around the globe. As more research is taking place on this topic, there is heightened need for definitions for the complex concepts involved. While significant work to define "arts participation" has taken place in the arts sector, less work has been undertaken for the purpose of researching the arts in public health. This study developed a definition for "arts participation" to guide a national arts in public health research agenda and to advance and make more inclusive previous work to define the term. A convergent mixed-methods study design with sequential elements was used to iteratively develop a definition that integrated the perspectives of field experts as well as the general public. Literature review was followed by four iterative phases of data collection, analysis, and integration, and a proposed definition was iteratively revised at each stage. The final definition includes modes, or ways, in which people engage with the arts, and includes examples of various art forms intended to frame arts participation broadly and inclusively. This definition has the potential to help advance the quality and precision of research aimed at evaluating relationships between arts participation and health, as well as outcomes of arts-based health programs and interventions in communities. With its more inclusive framing than previous definitions, it can also help guide the development of more inclusive search strategies for evidence synthesis in this rapidly growing arena and assist researchers in developing more effective survey questions and instruments.

Cyclopentane peptide nucleic acid: Gold nanoparticle conjugates for the detection of nucleic acids in a microfluidic format.

Routine patient testing for viral infections is critical to identify infected individuals for treatment and to prevent spreading of infections to others. Developing robust and reliable diagnostic tools to detect nucleic acids of viruses at the point-of-care could greatly assist the clinical management of viral infections. The remarkable stability and high binding affinity of peptide nucleic acids (PNAs) to target nucleic acids could make PNA-based biosensors an excellent starting point to develop new nucleic acid detection technologies. We report the application of cyclopentane-modified PNAs to capture target nucleic acids in a microfluidic channel, and the use of bioorthogonal PNAs conjugated to gold nanoparticles as probes to semi-quantitatively signal the presence of a target nucleic acid derived from HIV-1. The basic results presented could be used to develop more advanced devices to detect nucleic acids from viruses such as HIV, SARS-CoV-2, and a wide range of other human diseases.

Computational Modeling and Imaging of the Intracellular Oxygen Gradient.

Computational modeling can provide a mechanistic and quantitative framework for describing intracellular spatial heterogeneity of solutes such as oxygen partial pressure (pO2). This study develops and evaluates a finite-element model of oxygen-consuming mitochondrial bioenergetics using the COMSOL Multiphysics program. The model derives steady-state oxygen (O2) distributions from Fickian diffusion and Michaelis-Menten consumption kinetics in the mitochondria and cytoplasm. Intrinsic model parameters such as diffusivity and maximum consumption rate were estimated from previously published values for isolated and intact mitochondria. The model was compared with experimental data collected for the intracellular and mitochondrial pO2 levels in human cervical cancer cells (HeLa) in different respiratory states and under different levels of imposed pO2. Experimental pO2 gradients were measured using lifetime imaging of a Förster resonance energy transfer (FRET)-based O2 sensor, Myoglobin-mCherry, which offers in situ real-time and noninvasive measurements of subcellular pO2 in living cells. On the basis of these results, the model qualitatively predicted (1) the integrated experimental data from mitochondria under diverse experimental conditions, and (2) the impact of changes in one or more mitochondrial processes on overall bioenergetics.

Promoting Social and Emotional Learning in Middle School: Intervention Effects of Facing History and Ourselves.

There are fewer evidence-based social and emotional learning programs for middle school students compared to younger grades. This randomized controlled trial tests the effectiveness of Facing History and Ourselves (hereafter, Facing History) with a sample of 694 (Facing History n = 437; Comparison n = 257) students from a low-resourced school district. Youth self-identified as female (59%), Black/African American (61%), Hispanic/Latinx (18%), White (2%), and multi-racial or some other race/ethnicity (19%). Intervention students perceived their classrooms as more caring and democratic than students in the comparison group. They reported higher levels of empathy, prosocial behavior, and stronger participatory citizenship beliefs. This study expands the evidence-based of effective SEL programs available to schools.

The interaction of exposure to adverse childhood and combat experiences on the current mental health of new post-9/11 veterans.

Military veterans have greater exposure to adverse childhood experiences (ACEs) than civilians and many also encounter warfare exposures, which can increase the likelihood of mental health problems. The purpose of this study was to test an interaction between childhood traumas and warfare exposures on the mental health of a sample of nearly 10,000 new post-9/11 veterans. Results revealed that male veterans exposed to one or two ACEs, but no warfare, were more likely to experience anxiety, depression, suicidal thinking, and angry outbursts than the reference group (i.e., no ACEs and no warfare exposure). Female veterans exposed to one or two ACEs, but no warfare, were only more likely to experience suicidal thinking. Male and female veterans exposed to three or more ACEs and no warfare were more likely to experience probable posttraumatic stress disorder (PTSD), anxiety, depression, suicidality, and angry outbursts. Among those veterans who experienced corollaries of combat only (e.g., seeing someone killed or seriously wounded), male, but not female veterans were more likely to have probable PTSD, anxiety, and depression. Veterans exposed to warfare (i.e., combat and the corollaries of combat), irrespective of ACEs exposure, were the most likely to report mental health symptoms. Implications for community-based mental health services are discussed.

The Moral Injury Symptoms Scale-Military Version-Short Form: Further Scale Validation in a U.S. Veteran Sample.

This study assessed the Moral Injury Symptoms Scale - Military Version - Short Form's (MISS-M-SF) factor structure and construct validity. Participants included 3650 combat-deployed U.S. veterans who answered all 10 MISS-M-SF items from the sixth wave of The Veterans Metric Initiative (TVMI). EFA results suggested a two-factor solution, based on item wording, fit best. CFA results indicated a bifactor model (one general factor and two method factors, based on item wording) fit best. Further investigation revealed that a one-factor model could be used despite the data's multidimensionality. Item-level analyses revealed four items represented the general factor exceptionally well, potentially simplifying assessment in research and clinical applications. Construct validity was also demonstrated through moderate to high correlations with conceptually related measures.

Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus.

OBJECTIVES: Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE. METHODS: Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively. RESULTS: Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM. CONCLUSIONS: Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.

Microfluidic Chip Device for In Situ Mixing and Fabrication of Hydrogel Microspheres via Michael-Type Addition.

Hydrogel microspheres are sought for a variety of biomedical applications, including therapeutic and cellular delivery, sensors, and lubricants. Robust fabrication of hydrogel microspheres with uniform sizes and properties can be achieved using microfluidic systems that rely on droplet formation and subsequent gelation to form microspheres. Such systems work well when gelation is initiated after droplet formation but are not practical for timed gelation systems where gelation is initiated prior to droplet formation; premature gelation can lead to device blockage, variable microsphere diameter due to viscosity changes in the precursor solution, and limited numbers of microspheres produced in a single run. To enable microfluidic fabrication of microspheres from timed gelation hydrogel systems, an in situ mixing region is needed so that various hydrogel precursor components can be added separately. Here, we designed and evaluated three mixing devices for their effectiveness at mixing hydrogel precursor solutions prior to droplet formation and subsequent gelation. The serpentine geometry was found to be the most effective and was further improved with the inclusion of a pillar array to increase agitation. The optimized device was shown to fully mix precursor solutions and enable the fabrication of monodisperse polyethylene glycol microspheres, offering great potential for use with timed gelation hydrogel systems.

Moral Injury and Social Well-Being: A Growth Curve Analysis.

Moral injury (MI) may occur in the context of committing transgressions (i.e., self-directed MI reactions), witnessing transgressions, or being the victims of others' transgressions (i.e., other-directed MI reactions) that violate an individual's moral principles. Veterans with MI may experience impaired social well-being (SWB). Studies on MI and veterans' SWB have focused almost exclusively on social support and used cross-sectional data. The present study used growth curve analyses to examine the associations between self- and other-directed MI reactions and veterans' levels of social support, social functioning, social activities, and social satisfaction over the first 18 to 21 months of their transition to civilian life (N = 9,566). The results demonstrated declines in all SWB outcomes, with self- and other-directed MI reactions having differential effects. Higher versus lower levels of other-directed MI reactions were related to lower baseline scores on all SWB outcomes, ßs = -.06 to -.20, and steeper declines over time in social functioning, ß = -.09, and social satisfaction, ß = -.10. Higher versus lower levels of self-directed MI reactions were related to lower baseline levels of social functioning, ß = -.07, but higher baseline levels of social activity, ß = .04. Higher versus lower levels of self-directed MI reactions were related to a steeper decline in social activity over time, ß = -.10. These findings present a more nuanced picture than that depicted by current MI theoretical frameworks and support further research to uncover moderators of the associations between self- and other-directed MI reactions and SWB outcomes.

Reducing barriers to post-9/11 veterans' use of programs and services as they transition to civilian life.

BACKGROUND: Numerous programs exist to support veterans in their transitions to civilian life. Programs are offered by a host of governmental and non-governmental stakeholders. Veterans report encountering many barriers to program participation. This study identified barrier reduction strategies offered by programs that new post-9/11 veterans reported using, determined which strategies veterans use and value, and examined veteran characteristics that impact their odds of using programs that offer barrier reduction strategies. METHOD: This study reflects findings from the first wave of data collection of The Veterans Metrics Initiative (TVMI), a longitudinal study examining the military-to-civilian reintegration of new post-9/11 veterans. The websites of programs used by respondents were coded for barrier reduction components. Veterans also indicated which barrier reduction components they found most helpful in meeting their reintegration goals. RESULTS: Of 9566 veterans who participated in Wave 1 data collection, 84% reported using a program that offered at least one barrier reduction component. Barrier reduction components included tangible supports (e.g., scholarships, cash), increased access to programs, decreased stigma, and encouraged motivation to change. Although only 4% of programs that were used by veterans focused on helping them obtain Veterans Administration benefits, nearly 60% of veterans reported that this component was helpful in reaching their goals. Access assistance to other resources and supports was also reported as a helpful barrier reduction component. For instance, approximately 20% of veterans nominated programs that offered transportation. The study also found evidence of a misalignment between the kinds of barrier reduction components veterans valued and those which programs offered. Veterans from the most junior enlisted ranks, who are at most risk, were less likely than those from other ranks to use barrier reduction components. Study limitations and ideas for future research are discussed. CONCLUSIONS: Despite the evidence that barrier reduction components enhance access to programs and contribute to program sustainability, many programs used by post-9/11 veterans do not offer them. There was also a misalignment between the barrier reduction strategies that veterans value and the strategies offered by programs. Veteran serving organizations should increasingly implement barrier reduction strategies valued by veterans.

Response to Blast-like Shear Stresses Associated with Mild Blast-Induced Brain Injury.

Toward the goal of understanding the pathophysiology of mild blast-induced traumatic brain injury and identifying the physical forces associated with the primary injury phase, we developed a system that couples a pneumatic blast to a microfluidic channel to precisely and reproducibly deliver shear transients to dissociated human central nervous system (CNS) cells, on a timescale comparable to an explosive blast but with minimal pressure transients. Using fluorescent beads, we have characterized the shear transients experienced by the cells and demonstrate that the system is capable of accurately and reproducibly delivering uniform shear transients with minimal pressure across the cell culture volume. This system is compatible with high-resolution, time-lapse optical microscopy. Using this system, we demonstrate that blast-like shear transients produced with minimal pressure transients and submillisecond rise times activate calcium responses in dissociated human CNS cultures. Cells respond with increased cytosolic free calcium to a threshold shear stress between 8 and 21 Pa; the propagation of this calcium response is a result of purinergic signaling. We propose that this system models, in vitro, the fundamental injury wave produced by shear forces consequent to blast shock waves passing through density inhomogeneity in human CNS cells.

Spatial control of oxygen delivery to three-dimensional cultures alters cancer cell growth and gene expression.

Commonly used monolayer cancer cell cultures fail to provide a physiologically relevant environment in terms of oxygen delivery. Here, we describe a three-dimensional (3D) bioreactor system where cancer cells are grown in Matrigel in modified six-well plates. Oxygen is delivered to the cultures through a polydimethylsiloxane (PDMS) membrane at the bottom of the wells, with microfabricated PDMS pillars to control oxygen delivery. The plates receive 3% oxygen from below and 0% oxygen at the top surface of the media, providing a gradient of 3-0% oxygen. We compared growth and transcriptional profiles for cancer cells grown in Matrigel in the bioreactor, 3D cultures grown in 21% oxygen, and cells grown in a standard hypoxia chamber at 3% oxygen. Additionally, we compared gene expression of conventional two-dimensional monolayer culture and 3D Matrigel culture in 21% oxygen. We conclude that controlled oxygen delivery may provide a more physiologically relevant 3D system.

Pseudomonas aeruginosa increases MUC1 expression in macrophages through the TLR4-p38 pathway.

Alveolar macrophages (AMs) play a critical role in the clearance of Pseudomonas aeruginosa (Pa) from the airways. However, hyper-activation of macrophages can impair bacterial clearance and contribute to morbidity and mortality. MUC1 mucin is a membrane-tethered, high molecular mass glycoprotein expressed on the apical surface of mucosal epithelial cells and some hematopoietic cells, including macrophages, where it counter-regulates inflammation. We recently reported that Pa up-regulates the expression of MUC1 in primary human AMs and THP-1 macrophages, and that increased MUC1 expression in these cells prevents hyper-activation of macrophages that appears to be important for host defense against severe pathology of Pa lung infection. The aims of this study were to elucidate the mechanism by which Pa increases MUC1 expression in macrophages. The results showed that: (a) Pa stimulation of THP-1 macrophages increased MUC1 expression both at transcriptional and protein levels in a dose-dependent manner; (b) Both Pa- and LPS-induced MUC1 expression in THP-1 cells were significantly diminished by an inhibitory peptide of TLR4; and (c) LPS-stimulated MUC1 expression was diminished at both the mRNA and protein levels by an inhibitor of the p38 mitogen-activated protein kinase, but not by inhibitors of ERK1/2, JNK, or IKK. We conclude that Pa-stimulated MUC1 expression in THP-1 macrophages is regulated mainly through the TLR4-p38 signaling pathway.

Motionless phase stepping in X-ray phase contrast imaging with a compact source.

X-ray phase contrast imaging offers a way to visualize the internal structures of an object without the need to deposit significant radiation, and thereby alleviate the main concern in X-ray diagnostic imaging procedures today. Grating-based differential phase contrast imaging techniques are compatible with compact X-ray sources, which is a key requirement for the majority of clinical X-ray modalities. However, these methods are substantially limited by the need for mechanical phase stepping. We describe an electromagnetic phase-stepping method that eliminates mechanical motion, thus removing the constraints in speed, accuracy, and flexibility. The method is broadly applicable to both projection and tomography imaging modes. The transition from mechanical to electromagnetic scanning should greatly facilitate the translation of X-ray phase contrast techniques into mainstream applications.

The differential impact of COVID-19 on the psychological stress of post-9/11 veterans: Gender, race, and ethnicity.

The COVID-19 pandemic has led to economic turndowns, social restrictions, and family life alterations. The stress induced by the public health crisis and its consequences are beginning to be explored. This study examined stress experiences since the pandemic'sonset in work, financial, social, and health domainsamong a large sample of post-9/11, United States military veterans. The sample, who separated from active-duty service or deactivated from active status in a reserve component in 2016, completed an online survey (n = 3180) in 2020. Participants were 70% White non-Hispanic, 81% male, and had an average age of 38 years. Frequencies and descriptive statistics were calculated. Female veterans and veterans of colour reported significantly higher levels of stress across most life domains. The results suggest White, male, post-9/11 veterans may be somewhat protected from COVID-19 stress, but that the pandemic is exacerbatinghealth and social disparities experienced by post-9/11 veterans of colour and female veterans. Supports and comprehensive care, particularly targeted towardsat-risk populations, are likely needed to provide sufficient resources for resiliency during and after the pandemic.

The Impact of Adversity on Body Mass Index as Veterans Transition to Civilian Life.

INTRODUCTION: The impact of adverse childhood experiences (ACEs), warfare exposure, and mental health symptoms upon changes in body mass index (BMI) were examined in a large U.S. post-9/11 veteran sample to assess gender-specific changes in BMI within the first 2½ years after military service. MATERIALS AND METHODS: Data were collected with institutional approval in 6 waves between 2016 and 2019 from veterans who (1) separated from active duty component service branches (i.e., Army, Navy, Air Force, and Marine Corps) or National Guard or Reserve or (2) deactivated from active duty status after serving in a National Guard or Reserve component. Veterans self-reported height and weight at separation/deactivation at wave 2, and weight was asked at each subsequent wave. Multilevel growth model analyses estimated the relationship between ACEs, warfare exposure, and mental health symptoms and BMI for males and females. Weighted wave 5 analyses were conducted to ensure the sample was calibrated for nonresponse based on wave 1 and the full sample (n = 48,965) for each cross-classification of the weighting variables of gender, rank, and branch. RESULTS: Approximately one-third of the veterans reported a normal BMI at separation/deactivation in comparison to being overweight (51%) or obese (20%). Twenty-six percent of male veterans had a normal BMI in contrast to almost half of the female veterans. Male veterans who experienced 3-7 ACEs had a higher BMI (0.74) compared to male veterans without any ACEs, where a BMI increase of 0.08 per year was reported. Female veterans who experienced 1-2 ACEs had a higher BMI (0.89) compared to female veterans without ACEs. Male veterans who engaged in warfare (e.g., combat patrols and firing a weapon at enemy combatants) and experienced corollaries (i.e., consequences of combat) or who experienced corollaries alone (e.g., saw refugees who lost their homes/belongings) had higher BMIs (1.14 and 0.82, respectively) compared to male veterans without warfare exposure. Female veterans who experienced corollaries had a higher BMI (0.94) compared to female veterans with no warfare exposure. Female veterans who experienced warfare (i.e., corollaries and combat) had a higher BMI (0.71) compared to female veterans with no warfare exposure. Male veterans who screened positive for likely post-traumatic stress disorder (PTSD) or depressive symptoms had a higher BMI (1.01 and 0.52, respectively) compared to male veterans who did not screen positive. Male veterans who screened positive for likely PTSD increased their BMI by 0.10 per year. Male veterans who screened positive for both likely PTSD and depressive symptoms had a higher BMI (1.32) compared to male veterans who did not screen positive, and they increased their BMI by 0.21 per year. Female veterans who screened positive for likely PTSD and depressive symptoms had a higher BMI (0.78) and increased their BMI by 0.25 per year compared to female veterans who did not screen positive. CONCLUSIONS: Boosting veterans' and service members' mental and emotional healing from childhood and warfare adversities through sound health promotion policies and increased access to evidence-informed interventions is imperative for optimal body weight and physical health.

Lineage-specific CDK activity dynamics characterize early mammalian development.

Cyclin-dependent kinases (CDK) are key regulatory enzymes that regulate proliferation dynamics and cell fate in response to extracellular inputs. It remains largely unknown how CDK activity fluctuates and influences cell commitment in vivo during early mammalian development. Here, we generated a transgenic mouse model expressing a CDK kinase translocation reporter (KTR) that enabled quantification of CDK activity in live single cells. By examining pre- and post-implantation mouse embryos at different stages, we observed a progressive decrease in CDK activity in cells from the trophectoderm (TE) prior to implantation. This drop correlated with the establishment of an FGF4-dependent signaling gradient through the embryonic-abembryonic axis. Furthermore, we showed that CDK activity levels do not determine cell fate decisions during pre-implantation development. Finally, we uncovered the existence of conserved regulatory mechanisms in mammals by revealing lineage-specific regulation of CDK activity in TE-like human cells.

Associations among combat exposure, adverse childhood experiences, moral injury, and posttraumatic growth in a large cohort of post-9/11 veterans.

OBJECTIVE: Post-9/11 veterans experienced more deployments, combat exposure, and disability than earlier military cohorts. Those in the military are also more likely to have experienced adverse childhood experiences. Despite these traumatic exposures, a substantial number of veterans report experiencing personal growth, development, and maturity from their military service. METHOD: This longitudinal survey study (n = 5,245) examined the degree to which posttraumatic growth (PTG) was present among post-9/11 veterans. Several components of PTG were examined, including relating to others, seeing new possibilities, personal strength, spiritual growth, and appreciation for life. RESULTS: Respondents rated their degree of personal growth and new appreciation of life most highly, while spiritual growth and appreciation of others were the least highly rated. Female veterans reported greater PTG. Veterans who experienced traumatic events (i.e., combat exposure, adverse childhood experiences), screened positive for posttraumatic stress disorder, and moral injury reported greater PTG than those who had not experienced those events or screened positive for posttraumatic stress disorder. Veterans reporting higher levels of social support and personal resilience were less likely to experience PTG. Veterans with other protective factors were more likely to experience PTG. CONCLUSIONS: Post-9/11 veterans report PTG in the face of various traumatic exposures. (PsycInfo Database Record (c) 2024 APA, all rights reserved).