Programming of Distinct Chemokine-Dependent and -Independent Search Strategies for Th1 and Th2 Cells Optimizes Function at Inflamed Sites.

T-helper (Th) cell differentiation drives specialized gene programs that dictate effector T cell function at sites of infection. Here, we have shown Th cell differentiation also imposes discrete motility gene programs that shape Th1 and Th2 cell navigation of the inflamed dermis. Th1 cells scanned a smaller tissue area in a G protein-coupled receptor (GPCR) and chemokine-dependent fashion, while Th2 cells scanned a larger tissue area independent of GPCR signals. Differential chemokine reliance for interstitial migration was linked to STAT6 transcription-factor-dependent programming of integrin αVß3 expression: Th2 cell differentiation led to high αVß3 expression relative to Th1 cells. Th1 and Th2 cell modes of motility could be switched simply by manipulating the amount of αVß3 on the cell surface. Deviating motility modes from those established during differentiation impaired effector function. Thus, programmed expression of αVß3 tunes effector T cell reliance on environmental cues for optimal exploration of inflamed tissues.

Enhanced Thermal Conducting Behavior of Pressurized Graphene-Silver Flake Composites.

Modern electronics continue to shrink down the sizes while becoming more and more powerful. To improve heat dissipation of electronics, fillers used in the semiconductor packaging process need to possess both high electrical and thermal conductivity. Graphene is known to improve thermal conductivity but suffers from van der Waals interactions and thus poor processibility. In this study, we wrapped silver microflakes with graphene sheets, which can enable intercoupling of phonon- and electron-based thermal transport, to improve the thermal conductivity. Using just 1.55 wt % graphene for wrapping can achieve a 2.64-times greater thermal diffusivity (equivalent to 254.196 ± 10.123 W/m·K) over pristine silver flakes. Graphene-wrapped silver flakes minimize the increase of electrical resistivity, which is one-order higher (1.4 × 10-3 Ω·cm) than the pristine flakes (5.7 × 10-4 Ω·cm). Trace contents of wrapped graphene (<1.55 wt %) were found to be enough to bridge the void between Ag flakes, and this enhances the thermal conductivity. Graphene loading at 3.76 wt % (beyond the threshold of 1.55 wt %) results in the significant graphene aggregation that decreases thermal diffusivity to as low as 16% of the pristine Ag filler. This work recognizes that suitable amounts of graphene wrapping can enhance heat dissipation, but too much graphene results in unwanted aggregation that hinders thermal conducting performance.

Additive-free carbon nanotube dispersions, pastes, gels, and doughs in cresols.

Cresols are a group of naturally occurring and massively produced methylphenols with broad use in the chemical industry. Here, we report that m-cresol and its liquid mixtures with other isomers are surprisingly good solvents for processing carbon nanotubes. They can disperse carbon nanotubes of various types at unprecedentedly high concentrations of tens of weight percent, without the need for any dispersing agent or additive. Cresols interact with carbon nanotubes by charge transfer through the phenolic hydroxyl proton and can be removed after processing by evaporation or washing, without altering the surface of carbon nanotubes. Cresol solvents render carbon nanotubes polymer-like rheological and viscoelastic properties and processability. As the concentration of nanotubes increases, a continuous transition of four states can be observed, including dilute dispersion, thick paste, free-standing gel, and eventually a kneadable, playdough-like material. As demonstrated with a few proofs of concept, cresols make powders of agglomerated carbon nanotubes immediately usable by a broad array of material-processing techniques to create desirable structures and form factors and make their polymer composites.

Why we need mechanics to understand animal regeneration.

Mechanical forces are an important contributor to cell fate specification and cell migration during embryonic development in animals. Similarities between embryogenesis and regeneration, particularly with regards to pattern formation and large-scale tissue movements, suggest similarly important roles for physical forces during regeneration. While the influence of the mechanical environment on stem cell differentiation in vitro is being actively exploited in the fields of tissue engineering and regenerative medicine, comparatively little is known about the role of stresses and strains acting during animal regeneration. In this review, we summarize published work on the role of physical principles and mechanical forces in animal regeneration. Novel experimental techniques aimed at addressing the role of mechanics in embryogenesis have greatly enhanced our understanding at scales from the subcellular to the macroscopic - we believe the time is ripe for the field of regeneration to similarly leverage the tools of the mechanobiological research community.

Emergent perversions in the buckling of heterogeneous elastic strips.

A perversion in an otherwise uniform helical structure, such as a climbing plant tendril, refers to a kink that connects two helices with opposite chiralities. Such singularity structures are widely seen in natural and artificial mechanical systems, and they provide the fundamental mechanism of helical symmetry breaking. However, it is still not clear how perversions arise in various helical structures and which universal principles govern them. As such, a heterogeneous elastic bistrip system provides an excellent model to address these questions. Here, we investigate intrinsic perversion properties which are independent of strip shapes. This study reveals the rich physics of perversions in the 3D elastic system, including the condensation of strain energy over perversions during their formation, the repulsive nature of the perversion-perversion interaction, and the coalescence of perversions that finally leads to a linear defect structure. This study may have implications for understanding relevant biological motifs and for use of perversions as energy storers in the design of micromuscles and soft robotics.

Mechanical signaling coordinates the embryonic heartbeat.

In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, ß-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats.

Minimal model for collective kinetochore-microtubule dynamics.

Chromosome segregation during cell division depends on interactions of kinetochores with dynamic microtubules (MTs). In many eukaryotes, each kinetochore binds multiple MTs, but the collective behavior of these coupled MTs is not well understood. We present a minimal model for collective kinetochore-MT dynamics, based on in vitro measurements of individual MTs and their dependence on force and kinetochore phosphorylation by Aurora B kinase. For a system of multiple MTs connected to the same kinetochore, the force-velocity relation has a bistable regime with two possible steady-state velocities: rapid shortening or slow growth. Bistability, combined with the difference between the growing and shrinking speeds, leads to center-of-mass and breathing oscillations in bioriented sister kinetochore pairs. Kinetochore phosphorylation shifts the bistable region to higher tensions, so that only the rapidly shortening state is stable at low tension. Thus, phosphorylation leads to error correction for kinetochores that are not under tension. We challenged the model with new experiments, using chemically induced dimerization to enhance Aurora B activity at metaphase kinetochores. The model suggests that the experimentally observed disordering of the metaphase plate occurs because phosphorylation increases kinetochore speeds by biasing MTs to shrink. Our minimal model qualitatively captures certain characteristic features of kinetochore dynamics, illustrates how biochemical signals such as phosphorylation may regulate the dynamics, and provides a theoretical framework for understanding other factors that control the dynamics in vivo.

Mechanical stress inference for two dimensional cell arrays.

Many morphogenetic processes involve mechanical rearrangements of epithelial tissues that are driven by precisely regulated cytoskeletal forces and cell adhesion. The mechanical state of the cell and intercellular adhesion are not only the targets of regulation, but are themselves the likely signals that coordinate developmental process. Yet, because it is difficult to directly measure mechanical stress in vivo on sub-cellular scale, little is understood about the role of mechanics in development. Here we present an alternative approach which takes advantage of the recent progress in live imaging of morphogenetic processes and uses computational analysis of high resolution images of epithelial tissues to infer relative magnitude of forces acting within and between cells. We model intracellular stress in terms of bulk pressure and interfacial tension, allowing these parameters to vary from cell to cell and from interface to interface. Assuming that epithelial cell layers are close to mechanical equilibrium, we use the observed geometry of the two dimensional cell array to infer interfacial tensions and intracellular pressures. Here we present the mathematical formulation of the proposed Mechanical Inverse method and apply it to the analysis of epithelial cell layers observed at the onset of ventral furrow formation in the Drosophila embryo and in the process of hair-cell determination in the avian cochlea. The analysis reveals mechanical anisotropy in the former process and mechanical heterogeneity, correlated with cell differentiation, in the latter process. The proposed method opens a way for quantitative and detailed experimental tests of models of cell and tissue mechanics.

Transferrable Electrospinning Nanofiber Meshes as Strongly Adhered Scaffolds for Slippery Liquid-Infused Porous Surfaces.

Slippery liquid-infused porous surfaces (SLIPS) are self-healing protective coatings that can be made by infiltration of a porous scaffold with a chemically resistant oil. A popular method to apply a SLIPS coating is using electrospinning to deposit a nanofiber mesh onto the intended substrate. However, electrospinning only lightly deposits the nanofibers onto the intended substrate, so the coating detaches easily even when unintended. We report a simple, yet effective, solution to the adhesion problem. Electrospun nanofiber meshes are typically well entangled and cohesive, so they can be detached from the electrospinning target and transferred onto the final target. Using a thin layer of adhesive on the intended surface, the electrospinning mesh can be securely attached and infiltrated with protective oil to yield a more stable SLIPS coating. An adhered coating can be submerged under corrosive solution and repeatedly self-heal from damage to the same spot. With the electrospun nanofiber meshes' flexibility and stretchability, the meshes can be fitted around a wide range of targets including ones that are otherwise difficult to apply a nanofiber mesh on. The use of an adhesive interlayer between the nanofiber mesh and substrate is a simple solution to improve coating stability, and the solution facilitates application of SLIPS onto a broader range of substrates.

A time-course prediction model of global COVID-19 mortality.

Introduction: The COVID-19 pandemic has caused over 6 million deaths worldwide and is a significant cause of mortality. Mortality dynamics vary significantly by country due to pathogen, host, social and environmental factors, in addition to vaccination and treatments. However, there is limited data on the relative contribution of different explanatory variables, which may explain changes in mortality over time. We, therefore, created a predictive model using orthogonal machine learning techniques to attempt to quantify the contribution of static and dynamic variables over time. Methods: A model was created using Partial Least Squares Regression trained on data from 2020 to rank order the significance and effect size of static variables on mortality per country. This model enables the prediction of mortality levels for countries based on demographics alone. Partial Least Squares Regression was then used to quantify how dynamic variables, including weather and non-pharmaceutical interventions, contributed to the overall mortality in 2020. Finally, mortality levels for the first 60 days of 2021 were predicted using rolling-window Elastic Net regression. Results: This model allowed prediction of deaths per day and quantification of the degree of influence of included variables, accounting for timing of occurrence or implementation. We found that the most parsimonious model could be reduced to six variables; three policy-related variables - COVID-19 testing policy, canceled public events policy, workplace closing policy; in addition to three environmental variables - maximum temperature per day, minimum temperature per day, and the dewpoint temperature per day. Conclusion: Country and population-level static and dynamic variables can be used to predict COVID-19 mortality, providing an example of how broad temporal data can inform a preparation and mitigation strategy for both COVID-19 and future pandemics and assist decision-makers by identifying population-level contributors, including interventions, that have the greatest influence in mitigating mortality, and optimizing the health and safety of populations.

Comparative intravital imaging of human and rodent malaria sporozoites reveals the skin is not a species-specific barrier.

Malaria infection starts with the injection of Plasmodium sporozoites into the host's skin. Sporozoites are motile and move in the skin to find and enter blood vessels to be carried to the liver. Here, we present the first characterization of P. falciparum sporozoites in vivo, analyzing their motility in mouse skin and human skin xenografts and comparing their motility to two rodent malaria species. These data suggest that in contrast to the liver and blood stages, the skin is not a species-specific barrier for Plasmodium. Indeed, P. falciparum sporozoites enter blood vessels in mouse skin at similar rates to the rodent malaria parasites. Furthermore, we demonstrate that antibodies targeting sporozoites significantly impact the motility of P. falciparum sporozoites in mouse skin. Though the sporozoite stage is a validated vaccine target, vaccine trials have been hampered by the lack of good animal models for human malaria parasites. Pre-clinical screening of next-generation vaccines would be significantly aided by the in vivo platform we describe here, expediting down-selection of candidates prior to human vaccine trials.

Neurovascular findings in children and young adults with Loeys-Dietz syndromes: Informing recommendations for screening.

INTRODUCTION: Loeys-Dietz Syndromes (LDS) are a group of connective tissue disorders associated with vascular abnormalities, including arterial tortuosity, aneurysms, and dissections. While neurovascular involvement is common, no pediatric or young adult recommendations for screening exist. We aimed to review our institution's experience with special focus on neurovascular imaging to better understand the pathology and guide screening. METHODS: A retrospective cohort study of patients with LDS was performed. Demographics, genetic subtype, clinical and radiographical data were analyzed. Primary outcome measures included pathology on neurovascular imaging, time to progression, and arterial tortuosity indexes for bilateral cervical internal carotid arteries (ICA) and vertebral arteries (VA). RESULTS: Of 47 patients with LDS identified, 39 (83.0%) were found to have neuroimaging. Intracranial and cervical vascular tortuosity were seen in 79.5% and 64.1%, respectively. Twenty-one patients (44.7%) received follow-up screening, of which 3 were found to have progression. Time to progression was an average of 2.1 years. Average follow-up was 607 days (range 123-3070 days). Mean Arterial Tortuosity Index for the right ICA, left ICA, right VA, and left VA were 18, 20, 49, and 47, respectively. Comparison of interval percent change in Arterial Tortuosity Index over the course of follow-up demonstrated small changes in the right ICA (mean 5%), left ICA (mean 1%), right VA (mean 1%), and left VA (mean 2%). CONCLUSIONS: Arterial tortuosity was most prevalent, though it did not progress significantly over time. We suggest an algorithm for management and serial screening to guide management of pediatric and young adults with LDS.

Bending-Tolerant Anodes for Lithium-Metal Batteries.

Bendable energy-storage systems with high energy density are demanded for conformal electronics. Lithium-metal batteries including lithium-sulfur and lithium-oxygen cells have much higher theoretical energy density than lithium-ion batteries. Reckoned as the ideal anode, however, Li has many challenges when directly used, especially its tendency to form dendrite. Under bending conditions, the Li-dendrite growth can be further aggravated due to bending-induced local plastic deformation and Li-filaments pulverization. Here, the Li-metal anodes are made bending tolerant by integrating Li into bendable scaffolds such as reduced graphene oxide (r-GO) films. In the composites, the bending stress is largely dissipated by the scaffolds. The scaffolds have increased available surface for homogeneous Li plating and minimize volume fluctuation of Li electrodes during cycling. Significantly improved cycling performance under bending conditions is achieved. With the bending-tolerant r-GO/Li-metal anode, bendable lithium-sulfur and lithium-oxygen batteries with long cycling stability are realized. A bendable integrated solar cell-battery system charged by light with stable output and a series connected bendable battery pack with higher voltage is also demonstrated. It is anticipated that this bending-tolerant anode can be combined with further electrolytes and cathodes to develop new bendable energy systems.

Crumpled graphene ball-based broadband solar absorbers.

Sheet-like graphene tends to stack with each other in thin films, resulting in relatively smooth microstructures with increased reflection as the thickness increases. In contrast, when the sheets are crumpled into a shape like paper balls, reflection is greatly reduced. In this work, crumpled graphene balls are found to be strong light absorbers in the visible and near-infrared regions. Average absorption of thin films made of crumpled graphene balls can reach up to 97.4% in the wavelength region of 350-2500 nm. When crumpled graphene balls are used as the solar absorber for the interfacial evaporation system, an evaporation efficiency of 84.6% was obtained under one sun at ambient pressure. Enhanced solar absorption of crumpled graphene balls, coupled with their aggregation-resistance and universal solution processability, makes them promising candidates for solar heating/distillation applications.

Prevalence and Severity of Anemia in Children Hospitalized with Acute Heart Failure.

OBJECTIVE: Anemia is common among adult heart failure patients and is associated with adverse outcomes, but data are lacking in children with heart failure. The purpose of this study was to determine the prevalence of anemia in children hospitalized with acute heart failure and to evaluate the association between anemia and adverse outcomes. DESIGN: Review of the medical records of 172 hospitalizations for acute heart failure. SETTING: Single, tertiary children's hospital. PATIENTS: All acute heart failure admissions to our institution from 2007 to 2012. INTERVENTIONS: None. OUTCOME MEASURES: Composite endpoint of death, mechanical circulatory support deployment, or cardiac transplantation. RESULTS: Patients ages ranged in age from 4 months to 23 years, with a median of 7.5 years, IQR 1.2, 15.9. Etiologies of heart failure included: dilated cardiomyopathy (n = 125), restrictive cardiomyopathy (n = 16), transplant coronary artery disease (n = 18), ischemic cardiomyopathy (n = 7), and heart failure after history of congenital heart disease (n = 6). Mean hemoglobin concentration at admission was 11.8 g/dL (±2.0 mg/dL). Mean lowest hemoglobin prior to outcome was 10.8 g/dL (±2.2 g/dL). Anemia (hemoglobin <10 g/dL) was present in 18% of hospitalizations at admission and in 38% before outcome. Anemia was associated with increased risk of death, transplant, or mechanical circulatory support deployment (adjusted odds ratio 1.79, 95% confidence interval = 1.12-2.88, P = .011). For every 1 g/dL increase in the patients' lowest hemoglobin during admission, the odds of death, transplant, or mechanical circulatory support deployment decreased by 18% (adjusted odds ratio = 0.82, 95% confidence interval = 0.74-0.93, P = 0.002). CONCLUSIONS: Anemia occurs commonly in children hospitalized for acute heart failure and is associated with increased risk of transplant, mechanical circulatory support, and inhospital mortality.

Longitudinal analysis of Plasmodium sporozoite motility in the dermis reveals component of blood vessel recognition.

Malaria infection starts with injection of Plasmodium sporozoites by an Anopheles mosquito into the skin of the mammalian host. How sporozoites locate and enter a blood vessel is a critical, but poorly understood process. In this study, we examine sporozoite motility and their interaction with dermal blood vessels, using intravital microscopy in mice. Our data suggest that sporozoites exhibit two types of motility: in regions far from blood vessels, they exhibit 'avascular motility', defined by high speed and less confinement, while in the vicinity of blood vessels their motility is more constrained. We find that curvature of sporozoite tracks engaging with vasculature optimizes contact with dermal capillaries. Imaging of sporozoites with mutations in key adhesive proteins highlight the importance of the sporozoite's gliding speed and its ability to modulate adhesive properties for successful exit from the inoculation site.