Conspectus Chromophore aggregates are capable of a wide variety of excited-state dynamics that are potentially of great use in optoelectronic devices based on organic molecules. For example, singlet ...fission, the process by which a singlet exciton is down converted into two triplet excitons, holds promise for extending the efficiency of solar cells, while other processes, such as excimer formation, are commonly regarded as parasitic pathways or traps. Other processes, such as symmetry-breaking charge transfer, where the excited dimer charge separates into a radical ion pair, can be both a trap and potentially useful in devices, depending on the context. Thus, an understanding of the precise mechanisms of each of these processes is vital to designing tailor-made organic chromophores for molecular optoelectronics. These excited-state phenomena have each been well-studied in recent years and show tantalizing connections as the molecular systems and environments are subtly changed. These seemingly disparate phenomena can be described within the same unifying framework, where each case can be represented as one point in continuum of mixed states. The coherent mixed state is observed experimentally, and it collapses to each of the limiting cases under well-defined conditions. This framework is especially useful in demonstrating the connections between these different states so that we can determine the factors that control their evolution and may ultimately guide the state mixtures to the product state of choice. The emerging picture shows that tuning the electronic coupling through proper arrangement of the chromophores must accompany environmental tuning of the chromophore energies to produce a fully mixed state. Changes in either of these quantities leads to evolution of the admixture and ultimately collapsing the superposition onto a given state, producing one of the photophysical pathways discussed above. In our laboratory, we are utilizing covalent dimers to precisely arrange the chromophores in rigid, well-defined geometries to systematically study the factors that determine the degree of state mixing and its fate. We interrogate these dynamics with transient absorption spectroscopy from the UV continuously into the mid-infrared, along with time-resolved Raman and emission and magnetic resonance spectroscopies to build a complete and detailed molecular level picture of the dynamics of these dimers. The knowledge gained from dimer studies can also be applied to the understanding the dynamics in extended molecular solids. The insight afforded by these studies will help guide the creation of new designer chromophores with control over the fate of the excited state.
Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it ...comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform ...genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.
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•Diffuse large B cell lymphoma (DLBCL) consists of seven genetic subtypes•The LymphGen algorithm classifies a DLBCL biopsy into one or more genetic subtypes•The genetic subtypes have distinct clinical outcomes and pathway dependencies•The genetic subtypes will aid the development of rationally targeted therapy of DLBCL
Wright et al. identify seven genetic subtypes of diffuse large B cell lymphoma (DLBCL) with distinct outcomes and therapeutic vulnerabilities. The LymphGen probabilistic classification tool that can classify a DLBCL biopsy into the genetic subtypes is developed, which could be used for precision medicine trials.
Understanding the photophysics and photochemistry of molecular π-stacked chromophores is important for utilizing them as functional photonic materials. However, these investigations have been mostly ...limited to covalent molecular dimers, which can only approximate the electronic and vibronic interactions present in the higher oligomers typical of functional organic materials. Here we show that a comparison of the excited-state dynamics of a covalent slip-stacked perylenediimide dimer (2) and trimer (3) provides fundamental insights into electronic state mixing and symmetry-breaking charge separation (SB-CS) beyond the dimer limit. We find that coherent vibronic coupling to high-frequency modes facilitates ultrafast state mixing between the Frenkel exciton (FE) and charge-transfer (CT) states. Subsequently, solvent fluctuations and interchromophore low-frequency vibrations promote CT character in the coherent FE/CT mixed state. The coherent FE/CT mixed state persists in 2, but, in 3, low-frequency vibronic coupling collapses the coherence, resulting in ultrafast SB-CS between the distal perylenediimide units.
Signals emanating from the B‐cell receptor (BCR) promote proliferation and survival in diverse forms of B‐cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally ...effective in treating lymphoma, but often fail to produce durable responses in diffuse large B‐cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen‐dependent and antigen‐independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF‐κB activity in the activated B‐cell‐like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.
Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated ...B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
► Lenalidomide kills ABC DLBCLs by decreasing expression of IRF4 and SPIB ► IRF4 and SPIB maintain ABC DLBCL viability ► IRF4 and SPIB block toxic IFNβ production while enhancing prosurvival NF-κB activity ► Lenalidomide and BCR pathway drugs synergize to inhibit IRF4 and kill ABC DLBCLs
Acting as hosts, cationic cyclophanes, consisting of π-electron-poor bipyridinium units, are capable of entering into strong donor–acceptor interactions to form host–guest complexes with various ...guests when the size and electronic constitution are appropriately matched. A synthetic protocol has been developed that utilizes catalytic quantities of tetrabutylammonium iodide to make a wide variety of cationic pyridinium-based cyclophanes in a quick and easy manner. Members of this class of cationic cyclophanes with boxlike geometries, dubbed Ex n Box m 4+ for short, have been prepared by altering a number of variables: (i) n, the number of “horizontal” p-phenylene spacers between adjoining pyridinium units, to modulate the “length” of the cavity; (ii) m, the number of “vertical” p-phenylene spacers, to modulate the “width” of the cavity; and (iii) the aromatic linkers, namely, 1,4-di- and 1,3,5-trisubstituted units for the construction of macrocycles (ExBoxes) and macrobicycles (ExCages), respectively. This Account serves as an exploration of the properties that emerge from these structural modifications of the pyridinium-based hosts, coupled with a call for further investigation into the wealth of properties inherent in this class of compounds. By variation of only the aforementioned components, the role of these cationic receptors covers ground that spans (i) synthetic methodology, (ii) extraction and sequestration, (iii) catalysis, (iv) molecular electronics, (v) physical organic chemistry, and (vi) supramolecular chemistry. Ex 1 Box 4+ (or simply ExBox 4+ ) has been shown to be a multipurpose receptor capable of binding a wide range of polycyclic aromatic hydrocarbons (PAHs), while also being a suitable component in switchable mechanically interlocked molecules. Additionally, the electronic properties of some host–guest complexes allow the development of artificial photosystems. Ex 2 Box 4+ boasts the ability to bind both π-electron-rich and -poor aromatic guests in different binding sites located within the same cavity. ExBox 2 4+ forms complexes with C60 in which discrete arrays of aligned fullerenes result in single cocrystals, leading to improved material conductivities. When the substitution pattern of the Ex n Box 4+ series is changed to 1,3,5-trisubstituted benzenoid cores, the hexacationic cagelike compound, termed ExCage 6+ , exhibits different kinetics of complexation with guests of varying sizesa veritable playground for physical organic chemists. The organization of functionality with respect to structure becomes valuable as the number of analogues continues to grow. With each of these minor structural modifications, a wealth of properties emerge, begging the question as to what discoveries await and what properties will be realized with the continued exploration of this area of supramolecular chemistry based on a unique class of receptor molecules.
Singlet exciton fission (SF) in organic chromophore assemblies results in the conversion of one singlet exciton (S1) into two triplet excitons (T1), provided that the overall process is exoergic, ...i.e., E(S1) > 2E(T1). We report on SF in thin polycrystalline films of two terrylene-3,4:11,12-bis(dicarboximide) (TDI) derivatives 1 and 2, which crystallize into two distinct π-stacked structures. Femtosecond transient absorption spectroscopy (fsTA) reveals a charge-transfer state preceding a 190% T1 yield in films of 1, where the π-stacked TDI molecules are rotated by 23° along an axis perpendicular to their π systems. In contrast, when the TDI molecules are slip-stacked along their N–N axes in films of 2, fsTA shows excimer formation, followed by a 50% T1 yield.
Quantum teleportation transfers the quantum state of a system over an arbitrary distance from one location to another through the agency of quantum entanglement. Because quantum teleportation is ...essential to many aspects of quantum information science, it is important to establish this phenomenon in molecular systems whose structures and properties can be tailored by synthesis. Here, we demonstrate electron spin state teleportation in an ensemble of covalent organic donor-acceptor-stable radical (D-A-R
) molecules. Following preparation of a specific electron spin state on R
in a magnetic field using a microwave pulse, photoexcitation of A results in the formation of an entangled electron spin pair D
-A
. The spontaneous ultrafast chemical reaction D
-A
-R
→ D
-A-R
constitutes the Bell state measurement step necessary to carry out spin state teleportation. Quantum state tomography of the R
and D
spin states using pulse electron paramagnetic resonance spectroscopy shows that the spin state of R
is teleported to D
with high fidelity.
Multiple myeloma is a common hematological malignancy of plasma cells, the terminally differentiated B cells that secrete antibodies as part of the adaptive immune response. Significant progress has ...been made in treating multiple myeloma, but this disease remains largely incurable, and most patients will eventually suffer a relapse of disease that becomes refractory to further therapies. Moreover, a portion of patients with multiple myeloma present with disease that is refractory to all treatments from the initial diagnosis, and no current therapeutic approaches can help. Therefore, the task remains to advance new therapeutic strategies to help these vulnerable patients. One strategy to meet this challenge is to unravel the complex web of pathogenic signaling pathways in malignant plasma cells and use this information to design novel precision medicine strategies to assist these patients most at risk.
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