The ability to study biomolecules in their native environments using chemical tools drives much of the development and innovation in chemical biology. The bioorthogonal chemical reporter strategy has proven useful for labeling biomolecules to study natural processes with minimal perturbation. However, this approach suffers from drawbacks, including difficulty achieving fast reactivity in dilute cellular media. One potential strategy to overcome this limitation is to employ non-covalent bonding: namely, supramolecular host–guest chemistry. We aim to develop new host–guest systems that rely on rare-in-biology non-covalent interactions to employ in the chemical reporter strategy; to do so, we need to develop and systematically study synthetic systems, with the ability to synthetically tune many key aspects.The present work establishes important design principles for bioorthogonal host–guest systems. Two polycyclic aromatic hydrocarbon (PAH) scaffolds are featured: phenanthrene and olympicene. These motifs recognize perfluoroarenes, options for bioorthogonal, non-covalent chemical reporters. Earlier work in the lab established a phenanthrene-based host to recognize perfluoroaromatic guests, but the individual contributions of different non-covalent forces in different solvents were not dissected. Here, it is shown that the phenanthrene system displays strong binding with electron-deficient guests in organic solvent through a combination of preorganization and hydrogen bonding. These results are informing design choices for a cell-labeling platform. In exploring alternative aromatic systems to phenanthrene, it was found that chemistry off the olympicene PAH was poorly characterized, igniting a synthetic endeavor to probe both its potential uses and limitations. The work presented here begins to fill in the large methodology gap for achieving diverse functionality from this intriguing and understudied PAH. Both stories highlight new directions for chemical biology tool development and the use of different PAHs in organic synthesis for designing new materials.Chapter One is a perspective on the field of bioorthogonal chemistry. It begins with exploration of the fundamental organic reactions that represent the first bioorthogonal reactions, then evaluates advances and new additions to these chemistries. Alternatives to covalent bond formation are also discussed, including applications of host–guest chemistry in biological labeling. Examples of using bioorthogonal chemistry to study biology and make new discoveries are then explored, followed by applications in medicine and implications for the future of disease treatments based on bioorthogonal chemistry.Chapter Two is a perspective on the applications of perfluoroaromatics in chemical biology. The first section explores modifications to biomolecules and the reactivity of the perfluoroarene motif. The second half explores the non-covalent interactions of perfluroroarenes and applications therein. The chapter contains proposals of how both the reactivity and non-covalent interaction tendencies of perfluoroaromatics may be combined and used in future biological studies.Chapter Three summarizes the characterization of a phenanthrene-based host platform and the principles that guide its binding with various phenolic guests in organic media. Through studies with both fluorinated and non-fluorinated guests, the roles of both cavity preorganization and hydrogen bonding in guest recognition are thoroughly examined. This work importantly establishes a foundation for future developments using this fully synthetic and tunable host–guest platform.Chapter Four is a summary of the first attempts to create a nucleophile-functionalized version of the host described in Chapter Three. Here, binding of perfluoroaromatic guests, the interaction discussed in Chapter Three, is expected to promote reactivity with a nucleophile strategically placed in the host cavity. The synthesis of alternative linkers, including the various considerations for compatible chemistries, is discussed, ending with successful synthesis of a new host and preliminary screens for final nucleophile installation. This work highlights challenges and necessary future directions for establishing such a functionalized host. Chapter Five summarizes the attempts to build a host platform based on the olympicene PAH as an alternative to phenanthrene, with a larger surface area expected to enhance non-covalent interactions with perfluoroarenes. The first half is a synthetic endeavor to access unprecedented substitution patterns on the symmetric olympicene ketone. The second half details the challenges faced attempting to synthesize a simplified, more flexible host based on olympicene. Some of the synthetic and stability challenges here are addressed in more detail in Chapter Six. Chapter Six classifies the distinct reactivities of three related olympicene starting materials. The most used olympicene synthon, a symmetric polycyclic aromatic ketone, is found to give many unstable products. The reduced form, base olympicene, had only been used synthetically once before; the chemistry here shows that this starting material is likely a more viable starting point for many functional olympicene syntheses. Finally, a separate ketone isomer with previously undocumented chemistry is explored. Preliminary work included at the end highlights a new class of olympicene compounds with potential for chiral material synthesis and new PAH-based fluorescent probes.

The buildup of low energy electrons in an accelerator, known as electron cloud, can be severely detrimental to machine performance. Under certain beam conditions, the beam can become resonant with the cloud dynamics, accelerating the buildup of electrons. This paper will examine two such effects: multipacting resonances, in which the cloud development time is resonant with the bunch spacing, and cyclotron resonances, in which the cyclotron period of electrons in a magnetic field is a multiple of bunch spacing. Both resonances have been studied directly in dipole fields using retarding field analyzers installed in the Cornell Electron Storage Ring. These measurements are supported by both analytical models and computer simulations.

Traditional teaching methods in radiology education have not kept pace with advances in technology that foster successful transition into independent practice. This deficit has been exacerbated by the COVID-19 pandemic, as the need for social distancing and the introduction of hybrid staffing models have decreased the critical educational interactions at the reading room workstations between staff and trainees. By leveraging interactive, case-based learning, educators have the opportunity to bridge the substantial gap between basic pattern recognition and successfully making a diagnosis in independent practice. For the educator, this signals a shift away from perfect case selection and presenter authority, and toward the role of a guide facilitating an active case-based learning experience. This form of learning is best accompanied by guided interpretation and iterative feedback with the goal of developing similar levels of mastery and autonomy among graduating trainees. In this article, we present the tools and methods for incorporating interactive cases into existing and novel teaching materials to meet the unique challenges educators are facing today.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.