Photochemical Upconversion.

Photochemical upconversion is a process whereby two lower-energy photons are converted into a higher-energy photon by sensitized triplet-triplet annihilation. While recent interest in this process has been motivated by improving the efficiencies of solar cells, many applications are being explored. In this review, we address the underlying physicochemical phenomena that are responsible for photochemical upconversion. We review their kinetics, and the requirements for annihilators and sensitizers to design efficient upconversion systems. We discuss the spin physics of the bi-excitonic interactions and how the spin character of the triplet pairs can fundamentally limit the upconversion efficiency and give rise to the magnetic field effect on delayed photoluminescence. Finally, we address light-matter coupling phenomena that could be employed to enhance photochemical upconversion.

Update on the current and future use of CAR-T to treat multiple myeloma.

Chimeric antigen receptor T-cell (CAR-T) therapy has become an important intervention in the management of relapsed and relapsed/refractory multiple myeloma (MM). Currently, B-cell maturation antigen (BCMA) is the most targeted surface protein due to its ubiquitous expression on plasma cells, with increasing expression of this essential transmembrane protein on malignant plasma cells as patients develop more advanced disease. This review will explore the earliest CAR-T trials in myeloma, discuss important issues involved in CAR-T manufacturing and processing, as well as review current clinical trials that led to the approval of the two commercially available CAR-T products, Idecabtagene vicleucel and ciltacabtagene autoleucel. The most recent data from trials investigating the use of CAR-T as an earlier line of therapy will be presented. Finally, the problem of relapses after CAR-T will be presented, including several theories as to why CAR-T therapies fail and possible clinical caveats. The next generation of MM-specific CAR-T will likely include new targets such as G-protein-coupled receptor class C, Group 5, member D (GPRC5D) and signaling lymphocyte activation molecular Family 7 (SLAMF7). The role of CAR-T in the treatment of MM will undoubtedly increase exponentially in the next decade.

Photodissociation of dicarbon: How nature breaks an unusual multiple bond.

The dicarbon molecule (C2) is found in flames, comets, stars, and the diffuse interstellar medium. In comets, it is responsible for the green color of the coma, but it is not found in the tail. It has long been held to photodissociate in sunlight with a lifetime precluding observation in the tail, but the mechanism was not known. Here we directly observe photodissociation of C2 From the speed of the recoiling carbon atoms, a bond dissociation energy of 602.804(29) kJ·mol[Formula: see text] is determined, with an uncertainty comparable to its more experimentally accessible N2 and O2 counterparts. The value is within 0.03 kJ·mol-1 of high-level quantum theory. This work shows that, to break the quadruple bond of C2 using sunlight, the molecule must absorb two photons and undergo two "forbidden" transitions.

The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement.

Mice deficient in sphingosine 1-phosphate receptor type 2 (S1P(2)) develop diffuse large B cell lymphoma. However, the role of S1P(2) in normal germinal center (GC) physiology is unknown. Here we show that S1P(2)-deficient GC B cells outgrew their wild-type counterparts in chronically established GCs. We found that antagonism of the kinase Akt mediated by S1P(2) and its downstream mediators Gα(12), Gα(13) and p115RhoGEF regulated cell viability and was required for growth control in chronically proliferating GCs. Moreover, S1P(2) inhibited GC B cell responses to follicular chemoattractants and helped confine cells to the GC. In addition, S1P(2) overexpression promoted the centering of activated B cells in the follicle. We suggest that by inhibiting Akt activation and migration, S1P(2) helps restrict GC B cell survival and localization to an S1P-low niche at the follicle center.

Intramolecular hole-transfer in protonated anthracene.

Excitation spectra of protonated and deuteronated anthracene are obtained by triple-resonance dissociation spectroscopy. Very cold cations, protonated/deuteronated exclusively at the 9-position, are generated from two-colour two-photon threshold ionisation of 9-dihydroanthracenyl radicals (C14H11). The excitation spectra reveal rich structure, not resolved in previous studies, that is assigned based on anharmonic and Herzberg-Teller coupling calculations. This work reveals that the excitation of protonated anthracene induces a symmetry-breaking intramolecular charge-transfer process along a Marcus-Hush coordinate, where the positively charged hole hops from the central bridging sp2 carbon, onto one of the aromatic rings. Signatures of this charge-transfer event are observed in the excitation spectrum, through active Herzberg-Teller progressions.

Photochemical Upconversion in Solution: The Role of Oxygen and Magnetic Field Response.

Upconversion processes effectively convert two or more low energy photons into one higher energy photon, and they have diverse prospective applications in photovoltaics and biomedicine. We focus on two specific mechanisms for photochemical upconversion in solution: triplet-triplet annihilation (TTA) and singlet oxygen mediated energy transfer (SOMET). TTA is spin-selective, whereas SOMET is not, so the interplay between these two upconversion mechanisms can be examined via their different magnetic field responses. A kinetic model is developed and applied to explain the different photoluminescence profiles of oxygenated versus deoxygenated systems. From the magnetic field response, the triplet-triplet annihilation rate constant is estimated. The conditions required to maximize upconversion photoluminescence intensity in oxygenated solution are determined, providing a set of design principles to guide molecule choices for robust and air-stable upconversion systems in the future.

The Spectroscopy of C2: A Cosmic Beacon.

ConspectusDicarbon, the molecule formed from two carbon atoms, is among the most abundant molecules in the universe. Said by some to exhibit a quadruple bond, it is bound by more than 6 eV and supports a large number of valence electronic states. It thus has a rich spectroscopy, with 19 one-photon band systems, four of which were discovered by the author and co-workers. Its spectrum was among the first to be described: Wollaston reported the emission spectra from blue flames in 1802.C2 is observed in a variety of astronomical objects, including stars, circumstellar shells, nebulae, comets and the interstellar medium. It is responsible for the green color of cometary comae but is not observed in the comet tail. It can be observed in absorption and emission by optical spectroscopy in the infrared, visible, and ultraviolet regions of the spectrum, and because it has no electric-dipole-allowed vibrational or rotational transitions, its spectral signature is a sensitive probe of the local environment.Before the work described in this Account, models of C2 photophysics included the thitherto-unobserved c3Σu+ state and parametrized the strength of spin-forbidden intercombination transitions. Furthermore, they did not account for photodissociation of C2, even though it was identified in the 1930s as a key process. Inspired by the observation of C2 in the Red Rectangle nebula, the author was motivated to instill rigor into C2 models and embarked on a spectroscopic and computational journey that has lasted 15 years.We were the first to identify the c3Σu+ state through the d3Πg-c3Σu+ transitions, which were to become known as the "Duck" system. This minor partner to the well-known Swan bands is a key part of astrophysical C2 models and can now be included with rigor. We identified the e3Πg-c3Σu+ system, and the c3Σu+ state is now well-studied. Meanwhile others described the singlet-triplet and triplet-quintet interactions in exquisite detail, allowing rigorous modeling of the a-X and c-X intercombination transitions.The final piece of the C2 puzzle would be understanding how long it survives before being broken into carbon atom fragments. Though predicted by Herzberg, predissociation in the e3Πg state had never been observed. To find it would require the complicated ultraviolet spectroscopy of C2 to be disentangled. In so doing, we identified the 43Πg and 33Πg states of C2, thus uncovering two new band systems. The 43Πg state allowed the first accurate determination of the ionization energy of C2. With these new band systems secure, we extracted new levels of the D1Σu+ state (Mulliken bands) and the e3Πg state (Fox-Herzberg bands) from our spectra. Upon climbing the energy ladder in the e3Πg state to v = 12, we finally identified the route to predissociation of C2 via non-adiabatic coupling to the d3Πg state. This observation provided the first laboratory evidence for why C2 is observed in the coma of a comet but not the tail.

Impact of autologous hematopoietic cell transplantation on disease burden quantified by next-generation sequencing in multiple myeloma treated with quadruplet therapy.

The incremental impact of autologous hematopoietic cell transplantation (AHCT) on disease burden with quadruplet induction in newly diagnosed multiple myeloma (NDDM) can be reappraised with the serial assessment of minimal residual disease (MRD). We describe the impact of AHCT on MM burden assessed by next-generation sequencing (NGS) for patients enrolled in a clinical trial utilizing quadruplet induction, AHCT, followed by MRD-adapted consolidation. We describe quantitative changes in MRD burden with AHCT and explore patient and disease features influencing the magnitude of MRD reduction with AHCT. Among 123 included patients, 109 underwent AHCT and had MRD assessment pre and post AHCT. Forty percent achieved MRD < 10-5 post-induction, increasing to 70% after AHCT. Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT. The median reduction in MRD with AHCT was 1.10 log10 (range, -1.26 to 3.41). Patients with high-risk cytogenetic abnormalities (HRCA) had greater reduction in MRD burden (p = .02) after AHCT. Median relative reduction was 0.91 log10 (range, -0.75 to 2.14), 1.26 log10 (range, -0.21 to 3.26) and 1.34 log10 (range, -1.28 to 3.41) for patients with 0, 1 and 2+ HRCA, respectively. The presence of HRCA was the only factor associated with greater than 1 log10 reduction in MRD burden with AHCT. Serial NGS MRD demonstrates the incremental effect of AHCT in MM marrow burden in the context of quadruplet induction, particularly in high-risk MM.

The Hitchhiker's Guide to the Wave Function∥.

The electronic wave function of molecules is 3N-dimensional and inseparable in the coordinates of the N electrons. Whereas molecular orbitals are often invoked to visualize the electronic structure, they are nonunique, with the same 3N-dimensional wave function being represented by an infinite number of 3-D, one-electron functions (orbitals). Furthermore, multireference wave functions cannot be described by an antisymmetrized product of a single set of occupied orbitals. What is required is a way to visualize the full dimensionality of the wave function, including the effects of correlation, as a 3N-dimensional being would be able to do. In the past 5 years, we have been developing a way to analyze and visualize highly dimensional wave functions by focusing on the structure of the repeating unit demanded by fermionic behavior. This 3N-dimensional repeating unit, the wave function "tile", can be projected onto the three dimensions of each electron, in turn, to reveal the complete electronic structure. It is found that the tile reproduces canonical chemical motifs such as core-electrons, single bonds and lone pairs. Multiple bonds emerge as the "banana" bonds favored by Pauling. As a function of the reaction coordinate, electron motions are visualized that correspond to the curly arrow notation of organic chemists. Excited states can also be inspected. Analyzing a wave function in terms of fermionic tiling allows for insight not facilitated by the inspection of orbitals or configuration interaction vectors: The wave function tiles of resonance structures reveal that electron correlation in benzene pushes opposing spin electrons to occupy alternate Kekulé structures, and in C2, the emerging structure supports the notion of a triply bonded structure with a weak, fourth bonding contribution.

Diabatic Valence-Hole States in the C2 Molecule: "Putting Humpty Dumpty Together Again".

Despite the long history of spectroscopic studies of the C2 molecule, fundamental questions about its chemical bonding are still being hotly debated. The complex electronic structure of C2 is a consequence of its dense manifold of near-degenerate, low-lying electronic states. A global multi-state diabatic model is proposed here to disentangle the numerous configuration interactions that occur within four symmetry manifolds of excited states of C2 (1Πg, 3Πg, 1Σu+ , and 3Σu+ ). The key concept of our model is the existence of two "valence-hole" configurations, 2σg22σu11πu33σg2 for 1,3Πg states and 2σg22σu11πu43σg1 for 1,3Σu+ states, that are derived from 3σg ← 2σu electron promotion. The lowest-energy state from each of the four C2 symmetry species is dominated by this type of valence-hole configuration at its equilibrium internuclear separation. As a result of their large binding energy (nominal bond order of 3) and correlation with the 2s22p2 + 2s2p3 separated-atom configurations, the presence of these valence-hole configurations has a profound impact on the global electronic structure and unimolecular dynamics of C2.

PAH Growth in Flames and Space: Formation of the Phenalenyl Radical.

Polycyclic aromatic hydrocarbons (PAHs) are intermediates in the formation of soot particles and interstellar grains. However, their formation mechanisms in combustion and interstellar environments are not fully understood. The production of tricyclic PAHs and, in particular, the conversion of a PAH containing a five-membered ring to one with a six-membered ring are of interest to explain PAH abundances in combustion processes. In the present work, resonant ionization mass spectrometry in conjunction with isotopic labeling is used to investigate the formation of the phenalenyl radical from acenaphthylene and methane in an electrical discharge. We show that in this environment the CH cycloaddition mechanism converts a five-membered ring to a six-membered ring. This mechanism can occur in tandem with other PAH formation mechanisms such as hydrogen abstraction/acetylene addition (HACA) to produce larger PAHs in flames and the interstellar medium.

Velocity map imaging spectroscopy of C2H- and C2D-: A benchmark study of vibronic coupling interactions.

High-resolution velocity-map imaged photoelectron spectra of the ethynyl anions C2H- and C2D- are measured at photon wavelengths between 355 and 266 nm to investigate the complex interactions between the closely lying X̃2Σ+ and Ã2Π electronic states. An indicative kinetic energy resolution of 0.4%, together with the full angular dependence of the fast electrons, provides a detailed description of the vibronically coupled structure. It is demonstrated that a modest quadratic vibronic coupling model, parameterized by the quasidiabatic ansatz, is sufficient to accurately recreate all the observed vibronic interactions. Simulated spectra are shown to be in excellent agreement with the experimental data, verifying the proposed model and providing a framework that may be used to accurately simulate spectra of larger C2nH monohydride carbon chains. New spectral assignments are supported by experimental electron anisotropy measurements and Dyson orbital calculations.

Velocity Map Imaging Spectroscopy of the Dipole-Bound State of CH2CN-: Implications for the Diffuse Interstellar Bands.

Weakly bound anionic systems present a new domain for negative ion spectroscopy. Here we report on a multifaceted study of the CH2CN- dipole-bound state, employing high-resolution photoelectron spectroscopy from 130 different wavelengths, velocity-map imaging at threshold, and laser scanning photodetachment experiments. This uncovers a wide variety of different vibrational and rotational autodetaching resonances. By examination of both sides of the problem, absorption from the anion to the dipole-bound state and vibrational/rotational autodetachment to the neutral, a complete model of the dipole-bound chemistry is formed. Precise values for the electron affinity EA = 12468.9(1) cm-1, dipole binding energy DBE = 40.2(3) cm-1, and anion inversion splitting ω5 = 115.9(2) cm-1 are obtained. This model is then employed to study possible astronomical implications, revealing good agreement between the K = 1 ← 0 CH2CN- dipole transition and the λ8040 diffuse interstellar band.

Large, Tunable, and Reversible pH Changes by Merocyanine Photoacids.

Molecular photoswitches capable of generating precise pH changes will allow pH-dependent processes to be controlled remotely and noninvasively with light. We introduce a series of new merocyanine photoswitches, which deliver reversible bulk pH changes up to 3.2 pH units (pH 6.5 to pH 3.3) upon irradiation with 450 nm light, displaying tunable and predictable timescales for thermal recovery. We present models to show that the key parameters for optimizing the bulk pH changes are measurable: the solubility of the photoswitch, the acidity of the merocyanine form, the thermal equilibrium position between the spiropyran and the merocyanine isomers, and the increased acidity under visible light irradiation. Using ultrafast transient absorption spectroscopy, we determined the quantum yields for the ring-closing reaction and found that the lifetimes of the transient cis-merocyanine isomers ranged from 30 to 550 ns. Quantum yields did not appear to be a limitation for bulk pH switching. The models we present use experimentally determined parameters and are, in principle, able to predict the change in pH obtained for any related merocyanine photoacid.

Singlet Fission in Concentrated TIPS-Pentacene Solutions: The Role of Excimers and Aggregates.

The excited-state dynamics of 6,13-bis(triisopropylsilylethynyl)pentacene is investigated to determine the role of excimer and aggregate formation in singlet fission in high-concentration solutions. Photoluminescence spectra were measured by excitation with the evanescent wave in total internal reflection, in order to avoid reabsorption effects. The spectra over nearly two magnitudes of concentration were nearly identical, with no evidence for excimer emission. Time-correlated single-photon counting measurements confirm that the fluorescence lifetime shortens with concentration. The observed rate constant grows at high concentrations, and this effect is modeled in terms of the hard-sphere radial distribution function. NMR measurements confirm that aggregation takes place with a binding constant of between 0.14 and 0.43 M-1. Transient absorption measurements are consistent with a diffusive encounter mechanism for singlet fission, with hints of more rapid singlet fission in aggregates at the highest concentration measured. These data show that excimers do not play the role of an emissive intermediate in exothermic singlet fission in solution and that, while aggregation occurs at higher concentrations, the mechanism of singlet fission remains dominated by diffusive encounters.

Diagnosis and Management of Monoclonal Gammopathy and Smoldering Multiple Myeloma.

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. This review summarizes the current diagnosis treatment guidelines for MGUS and SMM and highlights recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Quantum-Induced Symmetry Breaking in the Deuterated Dihydroanthracenyl Radical.

The hydrogen-atom adduct with anthracene, 9-dihydroanthracenyl radical (C14H11), and its deuterated analogue have been identified by laser spectroscopy coupled to time-of-flight mass spectrometry, supported by time-dependent density functional theory calculations. The electronic spectrum of 9-dihydroanthracenyl radical exhibits an origin band at 19115 cm-1 and its ionization energy was determined to be 6.346(1) eV. The spectra reveal a low-frequency vibrational progression corresponding to a mode described by a butterfly inversion. In the deuterated analogue, a zero-point-energy imbalance along this coordinate is found to lead to a doubling of the observed spectral lines in the progression. This is attributed to quantum-induced symmetry breaking as previously observed in isotopologues of CH5+.

Quality of care for cardiovascular disease prevention in rheumatoid arthritis: compliance with hyperlipidemia screening guidelines.

Objective: To evaluate compliance with hyperlipidaemia screening guidelines for cardiovascular disease prevention in RA compared with the general population. Methods: We conducted a longitudinal study of a population-based RA cohort including all prevalent cases in British Columbia between 1996 and 2006, followed up until 2010, with matched general population controls. Using administrative data, we measured compliance with general population guidelines (testing lipids every 5 years for women ⩾50 and men ⩾40), after excluding individuals with previous diabetes, coronary artery disease or hyperlipidaemia. Compliance was measured as the proportion of 5-year eligibility periods with one or more lipid test. Compliance rates in RA and controls were compared by Chi-square test. Odds ratio (95% CI) of compliance in RA (vs controls) was estimated using generalized estimating equation models, adjusting for age and sex. Mean compliance rate per patient was also calculated and compared using Mann-Whitney U test. Results: Analyses included 5587 RA individuals and 5613 controls, contributing 6993 and 7208 5-year eligibility periods, respectively. Lipids were measured in 56.6 and 59.5% of eligibility periods in RA and controls, respectively [adjusted odds ratio (95% CI): 0.97 (0.90, 1.06)]. Screening improved over time in RA relative to the general population, but remained suboptimal even after 2003, at 65.8%. Mean (s.d.) compliance rate per patient was 56.6 (47.2)% for RA and 59.5 (46.6)% for controls. Family physicians ordered almost all the lipid tests. Conclusion: Compliance with general population guidelines for hyperlipidaemia screening in RA was poor and did not differ from the general population, despite a higher risk of cardiovascular diseases.