Septins provide microenvironment sensing and cortical actomyosin partitioning in motile amoeboid T lymphocytes.

The all-terrain motility of lymphocytes in tissues and tissue-like gels is best described as amoeboid motility. For amoeboid motility, lymphocytes do not require specific biochemical or structural modifications to the surrounding extracellular matrix. Instead, they rely on changing shape and steric interactions with the microenvironment. However, the exact mechanism of amoeboid motility remains elusive. Here, we report that septins participate in amoeboid motility of T cells, enabling the formation of F-actin and α-actinin-rich cortical rings at the sites of cell cortex-indenting collisions with the extracellular matrix. Cortical rings compartmentalize cells into chains of spherical segments that are spatially conformed to the available lumens, forming transient "hourglass"-shaped steric locks onto the surrounding collagen fibers. The steric lock facilitates pressure-driven peristaltic propulsion of cytosolic content by individually contracting cell segments. Our results suggest that septins provide microenvironment-guided partitioning of actomyosin contractility and steric pivots required for amoeboid motility of T cells in tissue-like microenvironments.

Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch.

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin's GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.

Mechanical Counterbalance of Kinesin and Dynein Motors in a Microtubular Network Regulates Cell Mechanics, 3D Architecture, and Mechanosensing.

Microtubules (MTs) and MT motor proteins form active 3D networks made of unstretchable cables with rod-like bending mechanics that provide cells with a dynamically changing structural scaffold. In this study, we report an antagonistic mechanical balance within the dynein-kinesin microtubular motor system. Dynein activity drives the microtubular network inward compaction, while isolated activity of kinesins bundles and expands MTs into giant circular bands that deform the cell cortex into discoids. Furthermore, we show that dyneins recruit MTs to sites of cell adhesion, increasing the topographic contact guidance of cells, while kinesins antagonize it via retraction of MTs from sites of cell adhesion. Actin-to-microtubule translocation of septin-9 enhances kinesin-MT interactions, outbalances the activity of kinesins over that of dyneins, and induces the discoid architecture of cells. These orthogonal mechanisms of MT network reorganization highlight the existence of an intricate mechanical balance between motor activities of kinesins and dyneins that controls cell 3D architecture, mechanics, and cell-microenvironment interactions.

Programmable DNA-augmented hydrogels for controlled activation of human lymphocytes.

Contractile forces within the planar interface between T cell and antigen-presenting surface mechanically stimulate T cell receptors (TCR) in the mature immune synapses. However, the origin of mechanical stimulation during the initial, i.e., presynaptic, microvilli-based TCR activation in the course of immune surveillance remains unknown and new tools to help address this problem are needed. In this work, we develop nucleic acid nanoassembly (NAN)-based technology for functionalization of hydrogels using isothermal toehold-mediated reassociation of RNA/DNA heteroduplexes. Resulting platform allows for regulation with NAN linkers of 3D force momentum along the TCR mechanical axis, whereas hydrogels contribute to modulation of 2D shear modulus. By utilizing different lengths of NAN linkers conjugated to polyacrylamide gels of different shear moduli, we demonstrate an efficient capture of human T lymphocytes and tunable activation of TCR, as confirmed by T-cell spreading and pY foci.

Dietary approaches to stop hypertension patterns in older Latinos with or at risk for hypertension.

BACKGROUND: Older Latinos represent a growing segment of our population, yet little is known about whether older Latinos are following the recommended Dietary Approaches to Stop Hypertension (DASH) eating plan, which promotes certain food groups to reduce blood pressure (BP) over and above established strategies. Among Latinos, greater acculturation to the American society has been associated with suboptimal dietary choices and risk for chronic diseases. Therefore, the purpose of this study was to assess differences in DASH accordance/adherence by BP status taking into account level of acculturation. METHODS: This was a descriptive, cross-sectional study involving older Latinos wherein DASH accordance and adherence were calculated on the basis of nutrient analyses of food frequency questionnaires. A DASH score of 4.5 or higher indicated accordance, and a DASH Adherence Index greater than 0 indicated adherence. Blood pressure was measured in triplicate using Omron HEM-907XL and was categorized according to BP level and/or antihypertensive medication. The Acculturation Rating Scale for Mexican Americans-II was used to rate level of acculturation. RESULTS: Participants were 169 Latinos, primarily women (73%) and older (66 ± 9.0 years); the majority were hypertensive (66%), preferred speaking in Spanish (85%), and were more Latino oriented (63%) with respect to acculturation status. Overall, participants were moderately DASH accordant (4.2 ± 1.6) and DASH adherent (-0.8 ± 0.8). Acculturation scores (odds ratio, 1.4-1.7, P < 0.02) were predictive of hypertensive status (defined as BP ≥ 140/90 mm Hg) regardless of which dietary score was modeled. CONCLUSION: Based on these findings, greater attention should be paid to identification of traditional Latino foods and food preparation that are consistent and acceptable to this older community in effort to foster greater DASH accordance and improve BP status.

The relationship between physical activity and cognition in older Latinos.

OBJECTIVES: The purpose of this study was to explore the relationship between minutes spent participating in light and moderate/vigorous-intensity physical activity (PA) and cognition in older Latinos, controlling for demographics, chronic health problems, and acculturation. METHOD: A cross-sectional study design was used. Participants were self-identified Latinos, without disability, who had a score less than 14 on a 21-point Mini-Mental State Examination. Participants were recruited from predominantly Latino communities in Chicago at health fairs, senior centers, and community centers. PA was measured with an accelerometer, worn for 7 days. Episodic memory and executive function (inference control, inattention, and word fluency) were measured with validated cognitive tests. RESULTS: Participants were 174 Latino men (n = 46) and women (n = 128) aged 50-84 years (M = 66 years). After adjusting for control variables (demographics, chronic health problems) and other cognitive measures, regression analyses revealed that minutes per day of light-intensity PA (r = -.51), moderate/vigorous PA (r = -.56), and counts per minute (r=-.62) were negatively associated with lower word fluency. DISCUSSION: Findings suggest that the cognitive benefits of both light-intensity PA and moderate/vigorous PA may be domain-specific.

What influences student experience of Graduate Entry Medicine? Qualitative findings from Swansea School of Medicine.

BACKGROUND: The Graduate Entry Programme (GEP) in Medicine delivered by Swansea University (currently in collaboration with Cardiff University) accepts students from a diverse range of academic backgrounds with no restriction in relation to the field of first degree. There is a growing body of literature, predominantly quantitative in nature, regarding the influence of academic background on student achievement but little published information on students' views. AIM: To examine students' views regarding the extent to which previous higher education and wider life experience influence their student experience on the GEP course. METHOD: Recruitment from three student cohorts and group interview data followed by descriptive thematic analysis of anonymized data. RESULTS: Data themes were: (1) previous study experience and its impact on present student experience; (2) the impact of life experience; (3) the impact of the present study on life experience; (4) skills, status and difference; (5) characteristics and expectations of the course; (6) finances and (7) next steps. Previous study experience had little impact on present student experience. However, previous life experience, with time between first degree and GEP, clearly enhances the learning experience. Added maturity and early clinical contact enables students to manage the challenges of the course and the NHS environment despite financial strain and heavy coursework. CONCLUSIONS: Analysing students' views is informative and provides richer insight into experience and expectations than that accessible from quantitative data alone.