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Atmospheric regime transitions are highly impactful as drivers of extreme weather events, but pose two formidable modeling challenges: predicting the next event (weather forecasting), and characterizing the statistics of events of a given severity (the risk climatology). Each event has a different duration and spatial structure, making it hard to define an objective "average event." We argue here that transition path theory (TPT), a stochastic process framework, is an appropriate tool for the task. We demonstrate TPT's capacities on a wave-mean flow model of sudden stratospheric warmings (SSWs) developed by Holton and Mass (1976), which is idealized enough for transparent TPT analysis but complex enough to demonstrate computational scalability. Whereas a recent article (Finkel et al. 2021) studied near-term SSW predictability, the present article uses TPT to link predictability to long-term SSW frequency. This requires not only forecasting forward in time from an initial condition, but also \emph{backward in time} to assess the probability of the initial conditions themselves. TPT enables one to condition the dynamics on the regime transition occurring, and thus visualize its physical drivers with a vector field called the \emph{reactive current}. The reactive current shows that before an SSW, dissipation and stochastic forcing drive a slow decay of vortex strength at lower altitudes. The response of upper-level winds is late and sudden, occurring only after the transition is almost complete from a probabilistic point of view. This case study demonstrates that TPT quantities, visualized in a space of physically meaningful variables, can help one understand the dynamics of regime transitions., Comment: 18 pages, 7 figures (main text), 19 pages, 1 figure (supplement). Accepted for publication in the Journal of the Atmospheric Sciences

Obesity and physical inactivity are considered possible U.S. national security threats because of their impact on military recruitment. The objectives of this study were to estimate the prevalence of (1) BMI eligibility for military entrance, (2) adequate physical activity participation among the BMI-eligible population, and (3) combined BMI eligibility and adequate physical activity.This cross-sectional study of nonpregnant, military-aged civilians (aged 17-42 years) used objectively measured weight and height data and self-reported aerobic physical activity data from the 2015-2020 National Health and Nutrition Examination Survey. BMI eligibility was defined as 19.0-27.5 kg/mOf military-aged participants (unweighted n=5,964), 47.3% were eligible by BMI. Among BMI-eligible participants, 72.5% reported adequate physical activity. Taken together, 34.3% were both eligible and active. The prevalence of eligible and active status was higher among males, persons who were younger and non-Hispanic White, college graduates, and those with higher family income than among their counterparts.Among the military-aged U.S. population, slightly under half were eligible to enter the military on the basis of their BMI, and only 1 in 3 met BMI eligibility and were adequately physically active. Equitable promotion of healthy weight achievement and physical activity participation may improve military preparedness.

Strain-stiffening is observed and characterized in flexible PEG hydrogel networks crosslinked via dynamic-covalent boronate ester bonds, revealing an uncommon synthetic mimic of a mechanoresponse found in natural biopolymer networks.

Protein aggregation is an obstacle for the development of new biopharmaceuticals, presenting challenges in shipping and storage of vital therapies. Though a variety of materials and methods have been explored, the need remains for a simple material that is biodegradable, nontoxic, and highly efficient at stabilizing protein therapeutics. In this work, we investigated zwitterionic polypeptides prepared using a rapid and scalable polymerization technique and conjugated to a supramolecular macrocycle host, cucurbit[7]uril, for the ability to inhibit aggregation of model protein therapeutics insulin and calcitonin. The polypeptides are based on the natural amino acid methionine, and zwitterion sulfonium modifications were compared to analogous cationic and neutral structures. Each polymer was end-modified with a single cucurbit[7]uril macrocycle to afford supramolecular recognition and binding to terminal aromatic amino acids on proteins. Only conjugates prepared from zwitterionic structures of sufficient chain lengths were efficient inhibitors of insulin aggregation and could also inhibit aggregation of calcitonin. This polypeptide exhibited no cytotoxicity in human cells even at concentrations that were five-fold of the intended therapeutic regime. We explored treatment of the zwitterionic polypeptides with a panel of natural proteases and found steady biodegradation as expected, supporting eventual clearance when used as a protein formulation additive.

Society-level discourse on single-use plastics (SUPs) increases awareness of their negative environmental impacts and reduces their usage by environmentally aware individuals, firms, and governments. This article makes a unique and timely contribution to the literature by exploring why conference venues have not been proactive in reducing their usage of SUPs. Application of a questionnaire approach to collect primary data about venues' attitudes and practices towards their level and reduction in usage of SUPs reveals that although venues claim to be motivated to reduce delegates' use of SUPs, they state that excessive costs inhibit their ability to do so, and that legal and government regulations have the strongest influence on their use of SUPs. Our findings provide a frame of reference and an order of policy priority to ensure SUPs reduction by venues.

Dynamically associating polymers have long been of interest due to their highly tunable viscoelastic behavior. Many applications leverage this tunability to create materials that have specific rheological properties, but designing such materials is an arduous, iterative process. Current models for dynamically associating polymers are phenomenological, assuming a structure for the relationship between association kinetics and network relaxation. We present the Brachiation model, a molecular-level theory of a polymer network with dynamic associations that is rooted in experimentally controllable design parameters, replacing the iterative experimental process with a predictive model for how experimental modifications to the polymer will impact rheological behavior. We synthesize hyaluronic acid chains modified with supramolecular host-guest motifs to serve as a prototypical dynamic network exhibiting tunable physical properties through control of polymer concentration and association rates. We use dynamic light scattering microrheology to measure the linear viscoelasticity of these polymers across six decades in frequency and fit our theory parameters to the measured data. The parameters are then altered by a magnitude corresponding to changes made to the experimental parameters and used to obtain new rheological predictions that match the experimental results well, demonstrating the ability for this theory to inform the design process of dynamically associating polymeric materials.

Biomaterials offer elegant frameworks to uncover mysteries of biology and vital tools to treat diseased or damaged tissues. Complex natural materials in the living world inspire the design of many engineered biomaterial constructs. Yet, complexity in materials design introduces practical, functional, and economic constraints. These challenges point to some virtues for a simplified approach in the design of biomaterials, especially when intended for clinical impact. But what is simplicity, and how can simple synthetic systems interface and intervene with application-specific complexities in the living world? Herein, both the philosophy and inherent benefits of simplicity in biomaterials design are discussed.

Dynamic-covalent motifs are increasingly used for hydrogel crosslinking, leveraging equilibrium-governed reversible bonds to prepare viscoelastic materials with dynamic properties and self-healing character. The bonding between aryl boronates and diols is one dynamic-covalent chemistry of interest. The extent of network crosslinking using this motif may be subject to competition from ambient diols such as glucose; this approach has long been explored for glucose-directed release of insulin to control diabetes. However, the majority of such work has used phenylboronic acids (PBAs) that suffer from low-affinity glucose binding, limiting material responsiveness. Moreover, many PBA chemistries also bind with higher affinity to certain non-glucose analytes like fructose and lactate than they do to glucose, limiting their specificity of sensing and therapeutic deployment. Here, dynamic-covalent hydrogels are prepared that, for the first time, use a new diboronate motif with enhanced glucose binding-and importantly improved glucose specificity-leveraging the ability of rigid diboronates to simultaneously bind two sites on a single glucose molecule. Compared to long-used PBA-based approaches, diboronate hydrogels offer more glucose-responsive insulin release that is minimally impacted by non-glucose analytes. Improved responsiveness translates to more rapid blood glucose correction in a rodent diabetes model. Accordingly, this new dynamic-covalent crosslinking chemistry is useful in realizing more sensitive and specific glucose-responsive materials.

Peptide–drug conjugates that self-assemble into supramolecular nanomaterials have promise for uses in drug delivery. These discrete molecular species offer high and precise drug loading, affording efficient carriers for various therapeutic agents. Their peptide modules, meanwhile, enable biological targeting and stimuli-responsive function while also ordering the assembled nanostructure. The often hydrophobic drug payload likewise acts as a directive for self-assembly in aqueous media. Though accessible synthetic methods have allowed for extensive exploration of the peptide design space, the specific contributions of the drug molecule and its linker to the resulting assembly have been less explored. Hydrophobic drugs frequently have planar domains, conjugated π-systems, and isolated polar groups, which in turn can lead to specific and directional self-interactions. These energies of interaction affect the free energy landscape of self-assembly, and may impact the form and assembly process of the desired nanomaterial. Here, two model supramolecular peptide–drug conjugates (sPDCs) are explored, composed of the corticosteroid dexamethasone conjugated to a conserved peptide sequence via two different linker chemistries. The choice of linker, which alters the orientation, rotational freedom, and number of stereoisomers of the prodrug in the final sPDC, impacts the mechanism and energetic barrier of assembly as well as the nano/macro scale properties of the resultant supramolecular materials. Accordingly, this work demonstrates the non-zero energetic contributions of the drug and its linker to sPDC self-assembly, provides a quantitative exploration of the sPDC free energy landscape, and suggests design principles for the enhanced control of sPDC nanomaterials to inform future applications as therapeutic drug carriers.

Hydrogels prepared from supramolecular cross-linking motifs are appealing for use as biomaterials and drug delivery technologies. The inclusion of macromolecules (e.g., protein therapeutics) in these materials is relevant to many of their intended uses. However, the impact of dynamic network cross-linking on macromolecule diffusion must be better understood. Here, hydrogel networks with identical topology but disparate cross-link dynamics are explored. These materials are prepared from cross-linking with host-guest complexes of the cucurbit[7]uril (CB[7]) macrocycle and two guests of different affinity. Rheology confirms differences in bulk material dynamics arising from differences in cross-link thermodynamics. Fluorescence recovery after photobleaching (FRAP) provides insight into macromolecule diffusion as a function of probe molecular weight and hydrogel network dynamics. Together, both rheology and FRAP enable the estimation of the mean network mesh size, which is then related to the solute hydrodynamic diameters to further understand macromolecule diffusion. Interestingly, the thermodynamics of host-guest cross-linking are correlated with a marked deviation from classical diffusion behavior for higher molecular weight probes, yielding solute aggregation in high-affinity networks. These studies offer insights into fundamental macromolecular transport phenomena as they relate to the association dynamics of supramolecular networks. Translation of these materials from in vitro to in vivo is also assessed by bulk release of an encapsulated macromolecule. Contradictory in vitro to in vivo results with inverse relationships in release between the two hydrogels underscores the caution demanded when translating supramolecular biomaterials into application.