Dual Nature of Thiophene Harnessed in the Design of Near-Infrared Emitters via Antiaromaticity Relief.

Near-infrared (NIR) emitters are of great interest for applications in bioimaging and modern technology. Yet the design of such materials with decent characteristics is challenging due to intrinsic limitations. In a recent article, Murai and Yamaguchi report the synthesis of NIR emitters with appreciable fluorescence quantum yields reaching 0.02 at 878 nm in CH2 Cl2 solution. The low band gaps were achieved by a new design strategy exploiting antiaromaticity relief. This concept was realized for compounds consisting of an antiaromatic azepine central ring fused to thiophene moieties. In these systems, thiophene unfolds its dual nature. On the one hand, it contributes to the high antiaromaticity of azepine; on the other hand, it exerts a stabilizing effect on azepine through the formation of a quinoid structure, which reduces its antiaromaticity and shifts the absorption and emission maxima into the NIR region.

Amber Light Control of Peptide Secondary Structure by a Perfluoroaromatic Azobenzene Photoswitch.

The incorporation of photoswitches into the molecular structure of peptides and proteins enables their dynamic photocontrol in complex biological systems. Here, a perfluorinated azobenzene derivative triggered by amber light was site-specifically conjugated to cysteines in a helical peptide by perfluoroarylation chemistry. In response to the photoisomerization (trans→cis) of the conjugated azobenzene with amber light, the secondary structure of the peptide was modulated from a disorganized into an amphiphilic helical structure.

Impact of Truncation on Optoelectronic Properties of Azaborole Helicenes.

Herein, we report configurationally stable singly-truncated (ST) and structurally flexible doubly-truncated (DT) helically chiral compounds derived from azabora[7]helicenes by a hypothetical removal of a single or two C=C double bonds. The singly-truncated constitutional isomers were synthesized from either benzoisoquinoline (BIQ) or phenantherene building blocks and the corresponding biaryls in excellent yields to give azabora[5]helicenes with a pendant phenyl ring at a sterically hindered position. These systems highlight the electronic impact of the nitrogen donor substitution position. The compounds with a disrupted BIQ moiety (STN) possess remarkable photoluminescence quantum yields of up to 0.53 in the solid state and a blue emission in solution with dissymmetry factors of up to ca. 3×10-3 . Upon cooling to 79 K all compounds exhibit phosphorescence with lifetimes of up to ca. 0.5 s. A methyl complex of azabora[7]helicene showing excellent configurational stability was used as a chiral inducer embedded in an emissive polymer (F8BT) to produce circularly polarized organic light emitting diodes with an electroluminescence dissymmetry factor gEL of up to 0.54.

Synthesis of a Blue-Emissive Azaborathia[9]helicene by Silicon-Boron Exchange from Unusual Atropisomeric Teraryls.

We report the concise synthesis and chir(optical) properties of an azaborathia[9]helicene consisting of two thienoazaborole motifs. The key intermediate, a highly congested teraryl with nearly parallel isoquinoline moieties, was generated as a mixture of atropisomers upon fusion of the central thiophene ring of the dithienothiophene moiety. These diastereomers were characterized by single crystal X-ray analysis revealing intriguing interactions in the solid state. Subsequent insertion of boron into the aromatic scaffold via silicon-boron exchange involving triisopropylsilyl groups fixed the helical geometry, thereby establishing a novel method for the preparation of azaboroles. The ligand exchange at boron in the final step afforded the blue emitter displaying a fluorescence quantum yield of 0.17 in CH2 Cl2 and excellent configurational stability. Detailed structural and theoretical investigation of unusual atropisomers and the helicene provide insights into their isomerization processes.

Electrophilic C-H Borylation of Aza[5]helicenes Leading to Bowl-Shaped Quasi-[7]Circulenes with Switchable Dynamics.

The intrinsic relationship between helicenes and circulenes is of fundamental interest and importance in molecular engineering. Herein, electrophilic borylation of phenanthroline-derived aza[5]helicenes is presented, resulting in the incorporation of a boryl unit into two termini of helicenes to afford quasi-[7]circulenes. Their bowl-shaped structures were determined by X-ray diffraction. UV-vis absorption and fluorescence spectroscopy, as well as electrochemical measurements and DFT calculations, gave insight into their electronic properties. Variable-temperature NMR studies and DFT calculations revealed bowl-to-bowl inversion at room temperature and bowl-to-helix equilibria at elevated temperature, highlighting the important role of B ← N bond strength in tuning their dynamic properties.

Enhanced Optical Properties of Azaborole Helicenes by Lateral and Helical Extension.

The synthesis and characterization of laterally extended azabora[5]-, -[6]- and -[7]helicenes, assembled from N-heteroaromatic and dibenzo[g,p]chrysene building blocks is described. Formally, the π-conjugated systems of the pristine azaborole helicenes were enlarged with a phenanthrene unit leading to compounds with large Stokes shifts, significantly enhanced luminescence quantum yields (Φ) and dissymmetry factors (glum ). The beneficial effect on optical properties was also observed for helical elongation. The combined contributions of lateral and helical extensions resulted in a compound showing green emission with Φ of 0.31 and |glum | of 2.2×10-3 , highest within the series of π-extended azaborahelicenes and superior to emission intensity and chiroptical response of its non-extended congener. This study shows that helical and lateral extensions of π-conjugated systems are viable strategies to improve features of azaborole helicenes. In addition, single crystal X-ray analysis of configurationally stable [6]- and -[7]helicenes was used to provide insight into their packing arrangements.

Synthesis and Strong Solvatochromism of Push-Pull Thienylthiazole Boron Complexes.

The solvatochromic behavior of two donor-π bridge-acceptor (D-π-A) compounds based on the 2-(3-boryl-2-thienyl)thiazole π-linker and indandione acceptor moiety are investigated. DFT/TD-DFT calculations were performed in combination with steady-state absorption and emission measurements, along with electrochemical studies, to elucidate the effect of two different strongly electron-donating hydrazonyl units on the solvatochromic and fluorescence behavior of these compounds. The Lippert-Mataga equation was used to estimate the change in dipole moments (Δµ) between ground and excited states based on the measured spectroscopic properties in solvents of varying polarity with the data being supported by theoretical studies. The two asymmetrical D-π-A molecules feature strong solvatochromic shifts in fluorescence of up to ~4300 cm-1 and a concomitant change of the emission color from yellow to red. These changes were accompanied by an increase in Stokes shift to reach values as large as ~5700-5800 cm-1. Quantum yields of ca. 0.75 could be observed for the N,N-dimethylhydrazonyl derivative in nonpolar solvents, which gradually decreased along with increasing solvent polarity, as opposed to the consistently reduced values obtained for the N,N-diphenylhydrazonyl derivative of up to ca. 0.20 in nonpolar solvents. These two push-pull molecules are contrasted with a structurally similar acceptor-π bridge-acceptor (A-π-A) compound.

Modular Synthesis of Organoboron Helically Chiral Compounds: Cutouts from Extended Helices.

Two types of helically chiral compounds bearing one and two boron atoms were synthesized by a modular approach. Formation of the helical scaffolds was executed by the introduction of boron to flexible biaryl and triaryl derived from small achiral building blocks. All-ortho-fused azabora[7]helicenes feature exceptional configurational stability, blue or green fluorescence with quantum yields (Φfl ) of 18-24 % in solution, green or yellow solid-state emission (Φfl up to 23 %), and strong chiroptical response with large dissymmetry factors of up to 1.12×10-2 . Azabora[9]helicenes consisting of angularly and linearly fused rings are blue emitters exhibiting Φfl of up to 47 % in CH2 Cl2 and 25 % in the solid state. As revealed by the DFT calculations, their P-M interconversion pathway is more complex than that of H1. Single-crystal X-ray analysis shows clear differences in the packing arrangement of methyl and phenyl derivatives. These molecules are proposed as primary structures of extended helices.

Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. METHODS: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. RESULTS: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. CONCLUSIONS: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Exploring the motives of Israeli Jews who were living kidney donors to strangers.

Non-directed living donors are individuals who donate a kidney to a recipient with whom they have neither a genetic nor emotional relationship. Israel legalized this type of donation in 2008. After this law was implemented, living donations significantly expanded. The aim of this article was to determine the motivations, characteristics, and perioperative experiences of non-directed living donors in Israel. Three online questionnaires (own questionnaire, Rosenberg Self-Esteem Scale (RSES), Rushton Self-Report Altruism Scale) were distributed to 180 Jewish kidney donors with the help of Matnat Chaim organization. One hundred and fifteen responses were received (69.3% response rate). The motivation for most donors (60%) was a strong willingness to help and a desire to do good. The majority of donors (78.3%) reported their health status as unchanged after donation; however, 16.5% experienced clinical problems (eg, wound infection, more pain than expected), and 5.2% experienced psychological complications. About 18% reported their health to improve after donation. Most (80%) inspired someone else to also become a kidney donor. This study breaks the myth that Jews do not support organ donation. In fact, their high level of altruism and their positive experience with donation has propelled the practice of non-directed donation in Israel.

sim1000G: a user-friendly genetic variant simulator in R for unrelated individuals and family-based designs.

BACKGROUND: Simulation of genetic variants data is frequently required for the evaluation of statistical methods in the fields of human and animal genetics. Although a number of high-quality genetic simulators have been developed, many of them require advanced knowledge in population genetics or in computation to be used effectively. In addition, generating simulated data in the context of family-based studies demands sophisticated methods and advanced computer programming. RESULTS: To address these issues, we propose a new user-friendly and integrated R package, sim1000G, which simulates variants in genomic regions among unrelated individuals or among families. The only input needed is a raw phased Variant Call Format (VCF) file. Haplotypes are extracted to compute linkage disequilibrium (LD) in the simulated genomic regions and for the generation of new genotype data among unrelated individuals. The covariance across variants is used to preserve the LD structure of the original population. Pedigrees of arbitrary sizes are generated by modeling recombination events with sim1000G. To illustrate the application of sim1000G, various scenarios are presented assuming unrelated individuals from a single population or two distinct populations, or alternatively for three-generation pedigree data. Sim1000G can capture allele frequency diversity, short and long-range linkage disequilibrium (LD) patterns and subtle population differences in LD structure without the need of any tuning parameters. CONCLUSION: Sim1000G fills a gap in the vast area of genetic variants simulators by its simplicity and independence from external tools. Currently, it is one of the few simulation packages completely integrated into R and able to simulate multiple genetic variants among unrelated individuals and within families. Its implementation will facilitate the application and development of computational methods for association studies with both rare and common variants.

Tetrahydroxy-Perylene Bisimide Embedded in a Zinc Oxide Thin Film as an Electron-Transporting Layer for High-Performance Non-Fullerene Organic Solar Cells.

By introduction of four hydroxy (HO) groups into the two perylene bisimide (PBI) bay areas, new HO-PBI ligands were obtained which upon deprotonation can complex ZnII ions and photosensitize semiconductive zinc oxide thin films. Such coordination is beneficial for dispersing PBI photosensitizer molecules evenly into metal oxide films to fabricate organic-inorganic hybrid interlayers for organic solar cells. Supported by the photoconductive effect of the ZnO:HO-PBI hybrid interlayers, improved electron collection and transportation is achieved in fullerene and non-fullerene polymer solar cell devices, leading to remarkable power conversion efficiencies of up to 15.95 % for a non-fullerene based organic solar cell.

Ultrafast Exciton Delocalization, Localization, and Excimer Formation Dynamics in a Highly Defined Perylene Bisimide Quadruple π-Stack.

An adequately designed, bay-tethered perylene bisimide (PBI) dimer Bis-PBI was synthesized by Pd/Cu-catalyzed Glaser-type oxidative homocoupling of the respective PBI building block. This newly synthesized PBI dimer self-assembles exclusively and with high binding constants of up to 106 M-1 into a discrete π-stack of four chromophores. Steady-state absorption and emission spectra show the signatures of H-type excitonic coupling among the dye units. Broadband fluorescence upconversion spectroscopy (FLUPS) reveals an ultrafast dynamics in the optically excited state. An initially coherent Frenkel exciton state that is delocalized over the whole quadruple stack rapidly (τ = ∼200 fs) loses its coherence and relaxes into an excimer state. Comparison with Frenkel exciton dynamics in PBI dimeric and oligomeric H-aggregates demonstrates that in the quadruple stack coherent exciton propagation is absent due to its short length of aggregates, thereby it has only one relaxation pathway to the excimer state. Furthermore, the absence of pump-power dependence in transient absorption experiments suggests that multiexciton cannot be generated in the quadruple stack, which is in line with time-resolved fluorescence measurements.

Multivariate joint frailty model for the analysis of nonlinear tumor kinetics and dynamic predictions of death.

The Response Evaluation Criteria in Solid Tumors are used as standard guidelines for the clinical evaluation of cancer treatments. The assessment is based on the anatomical tumor burden: change in size of target lesions and evolution of nontarget lesions (NTL). Despite unquestionable advantages of this standard tool, Response Evaluation Criteria in Solid Tumors are subject to some limitations such as categorization of continuous tumor size or negligence of its longitudinal trajectory. In particular, it is of interest to capture its nonlinear shape and model it simultaneously with recurrent progressions of NTL and overall survival. We propose a multivariate nonlinear mechanistic joint frailty model for longitudinal data, recurrent events, and a terminal event. In the model, the tumor size trajectory is described using an ordinary differential equation that accounts for the natural growth and treatment-induced decline. We perform a simulation study to validate the method and apply the model to a phase III clinical trial in colorectal cancer. In the results of the analysis, we determine on which component, tumor size, NTL, or death the treatment acts mostly and perform dynamic predictions of death. We compare the model with other models that consider parametric functions or splines for the tumor size trajectory in terms of goodness of fit and predictive accuracy.

n-Channel Organic Semiconductors Derived from Air-Stable Four-Coordinate Boron Complexes of Substituted Thienylthiazoles.

Three acceptor-π-bridge-acceptor (A-π-A) molecules derived from 2-(3-boryl-2-thienyl)thiazole have been synthesized and thoroughly characterized. Incorporation of a B-N unit into thienylthiazole and attachment of suitable acceptor moieties allowed to obtain ambient-stable A-π-A molecules with low-lying LUMO levels. Their potential for applications in organic electronics was tested in vacuum-deposited organic thin film transistors (OTFT). The OTFT device based on boryl-thienylthiazole and 1,1-dicyanomethylene-3-indanone (DCIND) acceptor moieties showed an electron mobility of ≈1.4×10-2  cm2 V-1 s-1 in air, which is the highest electron mobility reported to date for organoboron small molecules. Conversely, the device employing the malononitrile (MAL) derivative as an active layer did not show any charge transport behavior. As suggested by single crystal X-ray analysis of indandione (IND) and MAL derivatives, the enhanced mobility of IND (and DCIND) in comparison to the MAL molecule can be attributed to the effective two-dimensional π-stacking in the solid state imparted by the acceptor moieties with an extended π-surface.

A Crystalline π-Stack Containing Five Stereoisomers: Insights into Conformational Isomorphism, Chirality Inversion, and Disorder.

An unprecedented crystal-packing arrangement of a tetramethoxy-bay-substituted perylene bisimide (PBI) consists of three crystallographically independent molecules, that is, an achiral (AC) PBI of saddle-shaped geometry along with two pairs of propeller-like twisted (P)- and (M)-enantiomeric PBI frameworks. All these five conformations are observed within a single π-stack revealing an intriguing packing sequence with an inversion of chirality from P to M via AC. Nudged elastic band calculations for the isolated molecule show that AC is a local minimum of the P to M interconversion path. In addition, two minor conformations were observed in the crystal, one of which resembles a transition-state molecule. Theoretical studies of dimeric and trimeric stacks reveal that the coexistence of all these structures in the crystal lattice is aided by the strong dispersion interactions between PBI cores and perfectly interdigitated dodecyl chains which stabilize energetically higher conformations.

Direct Observation of Excimer-Mediated Intramolecular Electron Transfer in a Cofacially-Stacked Perylene Bisimide Pair.

We have elucidated excimer-mediated intramolecular electron transfer in cofacially stacked PBIs tethered by two phenylene-butadiynylene loops. The electron transfer between energetically equivalent PBIs is revealed by the simultaneous observation of the PBI radical anion and cation bands in the transient absorption spectra. The fluorescence decay time of the excimer states is in good agreement with the rise time of PBI radical bands in transient absorption spectra suggesting that the electron transfer dynamics proceed via the excimer state. We can conclude that the excimer state effectuates the efficient charge transfer in the cofacially stacked PBI dimer.

Joint model for left-censored longitudinal data, recurrent events and terminal event: Predictive abilities of tumor burden for cancer evolution with application to the FFCD 2000-05 trial.

In oncology, the international WHO and RECIST criteria have allowed the standardization of tumor response evaluation in order to identify the time of disease progression. These semi-quantitative measurements are often used as endpoints in phase II and phase III trials to study the efficacy of new therapies. However, through categorization of the continuous tumor size, information can be lost and they can be challenged by recently developed methods of modeling biomarkers in a longitudinal way. Thus, it is of interest to compare the predictive ability of cancer progressions based on categorical criteria and quantitative measures of tumor size (left-censored due to detection limit problems) and/or appearance of new lesions on overall survival. We propose a joint model for a simultaneous analysis of three types of data: a longitudinal marker, recurrent events, and a terminal event. The model allows to determine in a randomized clinical trial on which particular component treatment acts mostly. A simulation study is performed and shows that the proposed trivariate model is appropriate for practical use. We propose statistical tools that evaluate predictive accuracy for joint models to compare our model to models based on categorical criteria and their components. We apply the model to a randomized phase III clinical trial of metastatic colorectal cancer, conducted by the Fédération Francophone de Cancérologie Digestive (FFCD 2000-05 trial), which assigned 410 patients to two therapeutic strategies with multiple successive chemotherapy regimens.

An efficient synthesis of porphyrins with different meso substituents that avoids scrambling in aqueous media.

We have developed new conditions that afford regioisomerically pure trans-A2B2-, A3B-, and trans-AB2C-porphyrins bearing aryl and arylethynyl substituents. The porphyrins were prepared by the acid-catalyzed condensation of dipyrromethanes with aldehydes followed by oxidation with p-chloranil or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Optimal conditions for the condensation were identified after examining various reaction parameters such as solvent composition, acid concentration, and reaction time. The conditions identified (for aromatic aldehydes: EtOH/H2O 4:1, [DPM] = 4 mM, [aldehyde] = 4 mM, [HCl] = 38 mM, 16 h; for arylethynyl aldehydes: THF/H2O 2:1, [DPM] = 13 mM, [aldehyde] = 13 mM, [HCl] = 150 mM, 3 h) resulted in the formation of porphyrins in yields of 9-38% without detectable scrambling. This synthesis is compatible with diverse functionalities such as ester or nitrile. In total, 20 new trans-A2B2-, A3B-, and trans-AB2C-porphyrins were prepared. The scope and limitations of the two sets of reaction conditions have been explored. The methodological advantage of this approach is its straightforward access to building blocks and the formation of the porphyrin core in higher yields than by any other methodology and by using environmentally benign and nonhazardous chemicals.