Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer.

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

RNA splicing modulates the postharvest physiological deterioration of cassava storage root.

Rapid postharvest physiological deterioration (PPD) of cassava (Manihot esculenta Crantz) storage roots is a major constraint that limits the potential of this plant as a food and industrial crop. Extensive studies have been performed to explore the regulatory mechanisms underlying the PPD processes in cassava to understand their molecular and physiological responses. However, the exceptional functional versatility of alternative splicing (AS) remains to be explored during the PPD process in cassava. Here, we identified several aberrantly spliced genes during the early PPD stage. An in-depth analysis of AS revealed that the abscisic acid (ABA) biosynthesis pathway might serve as an additional molecular layer in attenuating the onset of PPD. Exogenous ABA application alleviated PPD symptoms through maintaining ROS generation and scavenging. Interestingly, the intron retention transcript of MeABA1 (ABA DEFICIENT 1) was highly correlated with PPD symptoms in cassava storage roots. RNA yeast three-hybrid and RNA immunoprecipitation assays showed that the serine/arginine-rich protein MeSCL33 (SC35-like splicing factor 33) binds to the precursor mRNA of MeABA1. Importantly, overexpressing MeSCL33 in cassava conferred improved PPD resistance by manipulating the AS and expression levels of MeABA1 and then modulating the endogenous ABA levels in cassava storage roots. Our results uncovered the pivotal role of the ABA biosynthesis pathway and RNA splicing in regulating cassava PPD resistance and proposed the essential roles of MeSCL33 for conferring PPD resistance, broadening our understanding of SR proteins in cassava development and stress responses.

PSEUDO-RESPONSE REGULATOR 3b and transcription factor ABF3 modulate abscisic acid-dependent drought stress response in soybean.

The circadian system plays a pivotal role in facilitating the ability of crop plants to respond and adapt to fluctuations in their immediate environment effectively. Despite the increasing comprehension of PSEUDO-RESPONSE REGULATORs (PRRs) and their involvement in the regulation of diverse biological processes, including circadian rhythms, photoperiodic control of flowering, and responses to abiotic stress, the transcriptional networks associated with these factors in soybean (Glycine max (L.) Merr.) remain incompletely characterized. In this study, we provide empirical evidence highlighting the significance of GmPRR3b as a crucial mediator in regulating the circadian clock, drought stress response, and abscisic acid (ABA) signaling pathway in soybeans. A comprehensive analysis of DNA affinity purification sequencing and transcriptome data identified 795 putative target genes directly regulated by GmPRR3b. Among them, a total of 570 exhibited a significant correlation with the response to drought, and eight genes were involved in both the biosynthesis and signaling pathways of ABA. Notably, GmPRR3b played a pivotal role in the negative regulation of the drought response in soybeans by suppressing the expression of abscisic acid responsive element-binding factor 3 (GmABF3). Additionally, the overexpression of GmABF3 exhibited an increased ability to tolerate drought conditions, and it also restored the hypersensitive phenotype of the GmPRR3b overexpressor. Consistently, studies on the manipulation of GmPRR3b gene expression and genome editing in plants revealed contrasting reactions to drought stress. The findings of our study collectively provide compelling evidence that emphasizes the significant contribution of the GmPRR3b-GmABF3 module in enhancing drought tolerance in soybean plants. Moreover, the transcriptional network of GmPRR3b provides valuable insights into the intricate interactions between this gene and the fundamental biological processes associated with plant adaptation to diverse environmental conditions.

Single-cell transcriptome analysis of aging mouse liver.

Aging has a great impact on the liver, which causes a loss of physiological integrity and an increase in susceptibility to injury, but many of the underlying molecular and cellular processes remain unclear. Here, we performed a comprehensive single-cell transcriptional profiling of the liver during aging. Our data showed that aging affected the cellular composition of the liver. The increase in inflammatory cells including neutrophils and monocyte-derived macrophages, as well as in inflammatory cytokines, could indicate an inflammatory tissue microenvironment in aged livers. Moreover, aging drove a distinct transcriptional course in each cell type. The commonly significant up-regulated genes were S100a8, S100a9, and RNA-binding motif protein 3 across all cell types. Aging-related pathways such as biosynthesis, metabolism, and oxidative stress were up-regulated in aged livers. Additionally, key ligand-receptor pairs for intercellular communication, primarily linked to macrophage migration inhibitory factor, transforming growth factor-ß, and complement signaling, were also elevated. Furthermore, hepatic stellate cells (HSCs) serve as the prominent hub for intrahepatic signaling. HSCs acquired an "activated" phenotype, which may be involved in the increased intrahepatic vascular tone and fibrosis with aging. Liver sinusoidal endothelial cells derived from aged livers were pseudocapillarized and procontractile, and exhibited down-regulation of genes involved in vascular development and homeostasis. Moreover, the aging-related changes in cellular composition and gene expression were reversed by caloric restriction. Collectively, the present study suggests liver aging is linked to a significant liver sinusoidal deregulation and a moderate pro-inflammatory state, providing a potential concept for understanding the mechanism of liver aging.

Increased regional Hurst exponent reflects response inhibition related neural complexity alterations in pediatric bipolar disorder patients during an emotional Go-Nogo task.

Fractal patterns have been shown to change in resting- and task-state blood oxygen level-dependent signals in bipolar disorder patients. However, fractal characteristics of brain blood oxygen level-dependent signals when responding to external emotional stimuli in pediatric bipolar disorder remain unclear. Blood oxygen level-dependent signals of 20 PBD-I patients and 17 age- and sex-matched healthy controls were extracted while performing an emotional Go-Nogo task. Neural responses relevant to the task and Hurst exponent of the blood oxygen level-dependent signals were assessed. Correlations between clinical indices and Hurst exponent were estimated. Significantly increased activations were found in regions covering the frontal lobe, parietal lobe, temporal lobe, insula, and subcortical nuclei in PBD-I patients compared to healthy controls in contrast of emotional versus neutral distractors. PBD-I patients exhibited higher Hurst exponent in regions that involved in action control, such as superior frontal gyrus, inferior frontal gyrus, inferior temporal gyrus, and insula, with Hurst exponent of frontal orbital gyrus correlated with onset age. The present study exhibited overactivation, increased self-similarity and decreased complexity in cortical regions during emotional Go-Nogo task in patients relative to healthy controls, which provides evidence of an altered emotional modulation of cognitive control in pediatric bipolar disorder patients. Hurst exponent may be a fractal biomarker of neural activity in pediatric bipolar disorder.

Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.

Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW-K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.

Efficient Proton Transfer and Charge Separation within Covalent Organic Frameworks via Hydrogen-Bonding Network to Boost H2O2 Photosynthesis.

Photocatalytic synthesis based on the oxygen reduction reaction (ORR) has shown great promise for H2O2 production. However, the low activity and selectivity of 2e- ORR result in a fairly low efficiency of H2O2 production. Herein, we propose a strategy to enhance the proton-coupled electron transfer (PCET) process in covalent organic frameworks (COFs), thereby significantly boosting H2O2 photosynthesis. We demonstrated that the construction of a hydrogen-bonding network, achieved by anchoring the H3PO4 molecular network on COF nanochannels, can greatly improve both proton conductivity and photogenerated charge separation efficiency of COFs. Thus, COF@H3PO4 exhibited superior photocatalytic performance in generating H2O2 without sacrificial agents, with a solar-to-chemical conversion efficiency as high as 0.69%. Results indicated that a much more localized spatial distribution of energy band charge density on COF@H3PO4 led to efficient charge separation, and the small energy barrier of the rate-limiting step from *OOH to H2O2 endowed COF@H3PO4 with higher 2e- ORR selectivity.

Research progress of the netrins and their receptors in cancer.

Netrins, a family of secreted and membrane-associated proteins, can regulate axonal guidance, morphogenesis, angiogenesis, cell migration, cell survival, and tumorigenesis. Four secreted netrins (netrin 1, 3, 4 and 5) and two glycosylphosphatidylinositols-anchored membrane proteins, netrin-G1 and G2, have been identified in mammals. Netrins and their receptors can serve as a biomarker and molecular therapeutic target for pathological differentiation, diagnosis and prognosis of malignant cancers. We review here the potential roles of the netrins family and their receptors in cancer.

HiFi long-read amplicon sequencing for full-spectrum variants of human mtDNA.

BACKGROUND: Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS). METHODS: In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and to compare the mtDNA variant detection efficacy. RESULTS: Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs). CONCLUSIONS: LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.

Nomogram predicts survival and surgical benefits for patients with breast cancer with initial bone metastasis: A population-based study.

BACKGROUND: Primary stage IV breast cancer is associated with a poor prognosis. At present, the value of local surgical treatment for patients with stage IV breast cancer remains uncertain; therefore, treatment principles remain controversial. Because of the high heterogeneity of these patients, it is often difficult to evaluate their prognoses. As a result, this study aimed to establish a prognostic nomogram to evaluate the prognosis of patients with breast cancer experiencing primary bone metastasis. METHODS: The clinical characteristics and follow-up data of patients with primary breast cancer and bone metastasis from 2010 to 2018 were collected from the Surveillance, Epidemiology, and End Results database and from 2013 to 2021 at the Peking Union Medical College Hospital. Patients were divided into training and validation groups. Multivariate Cox regression analysis was used to identify the independent prognostic variables for predicting cancer-specific survival (CSS). On the basis of these independent risk factors, a nomogram was developed and used calibration curves to evaluate its accuracy. Patients were divided into three risk groups according to their scores and surgery-related survival curves plotted using the log-rank test. RESULTS: Overall, 6372 patients were included, with 6319 from the Surveillance, Epidemiology, and End Results database and 53 from the Peking Union Medical College Hospital Breast Surgery Department. Multivariate analysis showed that age, race, marital status, grade, tumor stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, and burden of other metastatic lesions were all associated with CSS. Based on these results, a nomogram that predicted the 1-, 3-, and 5-year CSS rates in patients with primary breast cancer and bone metastasis (concordance index > 0.69) was developed. After dividing patients into low-risk, high-risk, or super-high-risk groups based on nomogram scoring criteria, survival analysis revealed that patients in the low- and high-risk groups had significant survival benefits from primary focal surgery. CONCLUSION: Independent risk factors for primary breast cancer in patients with bone metastasis were analyzed and a nomogram established to predict CSS. The prognostic tool derived in this study can assist clinicians in predicting the survival and surgical benefits of these patients through scoring, thereby providing further guidance for treatment strategies.

Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer.

PURPOSE: In the present study, we addressed the inconsistency between the testing criteria and diverse phenotypes for germline TP53 mutation in patients with breast cancer in the Chinese population. METHOD: We proposed a new added item (synchronous or metachronous bilateral breast cancer) as one of the testing criteria (aimed at high-penetrance breast cancer susceptibility genes) and applied it for determining TP53 germline mutation status in 420 female patients with breast cancer using multigene panel-based next-generation sequencing, Sanger sequencing, and mass spectrometry. RESULTS: We found that 1.4% of patients carried a pathogenic or likely pathogenic germline TP53 mutation. Compared with BRCA mutation carriers (8.0%) and non-carriers (7.1%), TP53 mutation carriers (33.3%) developed breast cancer earlier. The majority of TP53 mutation carriers (66.7%) developed breast cancer after age 30 and had bilateral breast cancer (33.3%). Pedigree investigation of four TP53 carriers and a patient with a TP53 variant of unknown significance revealed that neither of their parents harbored the same mutations as the probands, indicating that the mutations might occur de novo. CONCLUSION: Our study revealed distinguishing features of TP53 carriers among Chinese women with breast cancer, which is inconsistent with the currently used testing criteria; therefore, the newly proposed testing criteria may be more appropriate.

Growth of Size-Tunable Ag2O Polyhedra and Revelation of Their Bulk and Surface Lattices.

By primarily adjusting the reagent amounts, particularly the volume of AgNO3 solution introduced, Ag2O cubes with decreasing sizes from 440 to 79 nm, octahedra from 714 to 106 nm, and rhombic dodecahedra from 644 to 168 nm are synthesized. 733 nm cuboctahedra are also prepared for structural analysis. With in-house X-ray diffraction (XRD) peak calibration, shape-related peak shifts are recognizable. Synchrotron XRD measurements at 100 K reveal the presence of bulk and surface layer lattices. Bulk cell constants also deviate slightly. They show a negative thermal expansion behavior with shrinking cell constants at higher temperatures. The Ag2O crystals exhibit size- and facet-dependent optical properties. Bandgaps red-shift continuously with increasing particle sizes. Optical facet effect is also observable. Moreover, synchrotron XRD peaks of a mixture of Cu2O rhombicuboctahedra and edge- and corner-truncated cubes exposing all three crystal faces can be deconvoluted into three components with the bulk and the [111] microstrain phase as the major component. Interestingly, while the unheated Cu2O sample shows clear diffraction peak asymmetry, annealing the sample to 450 K yields nearly symmetric peaks even when returning the sample to room temperature, meaning even moderately high temperatures can permanently change the crystal lattice.

Blockade of PI3K/AKT signaling pathway by Astragaloside IV attenuates ulcerative colitis via improving the intestinal epithelial barrier.

BACKGROUND: The specific pathogenesis of UC is still unclear, but it has been clear that defects in intestinal barrier function play an important role in it. There is a temporary lack of specific drugs for clinical treatment. Astragaloside IV (AS-IV) is one of the main active ingredients extracted from Astragalus root and is a common Chinese herbal medicine for the treatment of gastrointestinal diseases. This study aimed to determine whether AS-IV has therapeutic value for DSS or LPS-induced intestinal epithelial barrier dysfunction in vivo and in vitro and its potential molecular mechanisms. METHODS: The intestinal tissues from UC patients and colitis mice were collected, intestinal inflammation was observed by colonoscopy, and mucosal barrier function was measured by immunofluorescence staining. PI3K/AKT signaling pathway activator YS-49 and inhibitor LY-29 were administered to colitic mice to uncover the effect of this pathway on gut mucosal barrier modulation. Then, network pharmacology was used to screen Astragaloside IV (AS-IV), a core active component of the traditional Chinese medicine Astragalus membranaceus. The potential of AS-IV for intestinal barrier function repairment and UC treatment through blockade of the PI3K/AKT pathway was further confirmed by histopathological staining, FITC-dextran, transmission electron microscopy, ELISA, immunofluorescence, qRT-PCR, and western blotting. Finally, 16 S rRNA sequencing was performed to uncover whether AS-IV can ameliorate UC by regulating gut microbiota homeostasis. RESULTS: Mucosal barrier function was significantly damaged in UC patients and murine colitis, and the activated PI3K/AKT signaling pathway was extensively involved. Both in vivo and vitro showed that the AS-IV-treated group significantly relieved inflammation and improved intestinal epithelial permeability by inhibiting the activation of the PI3K/AKT signaling pathway. In addition, microbiome data found that gut microbiota participates in AS-IV-mediated intestinal barrier recovery as well. CONCLUSIONS: Our study highlights that AS-IV exerts a protective effect on the integrality of the mucosal barrier in UC based on the PI3K/AKT pathway, and AS-IV may serve as a novel AKT inhibitor to provide a potential therapy for UC.

Exploring functional genes' correlation with (S)-equol concentration and new daidzein racemase identification.

With its estrogenic activity, (S)-equol plays an important role in maintaining host health and preventing estrogen-related diseases. Exclusive production occurs through the transformation of soy isoflavones by intestinal bacteria, but the reasons for variations in (S)-equol production among different individuals and species remain unclear. Here, fecal samples from humans, pigs, chickens, mice, and rats were used as research objects. The concentrations of (S)-equol, along with the genetic homology and evolutionary relationships of (S)-equol production-related genes [daidzein reductase (DZNR), daidzein racemase (DDRC), dihydrodaidzein reductase (DHDR), tetrahydrodaidzein reductase (THDR)], were analyzed. Additionally, in vitro functional verification of the newly identified DDRC gene was conducted. It was found that approximately 40% of human samples contained (S)-equol, whereas 100% of samples from other species contained (S)-equol. However, there were significant variations in (S)-equol content among the different species: rats > pigs > chickens > mice > humans. The distributions of the four genes displayed species-specific patterns. High detection rates across various species were exhibited by DHDR, THDR, and DDRC. In contrast, substantial variations in detection rates among different species and individuals were observed with respect to DZNR. It appears that various types of DZNR may be associated with different concentrations of (S)-equol, which potentially correspond to the regulatory role during (S)-equol synthesis. This enhances our understanding of individual variations in (S)-equol production and their connection with functional genes in vitro. Moreover, the newly identified DDRC exhibits higher potential for (S)-equol synthesis compared to the known DDRC, providing valuable resources for advancing in vitro (S)-equol production. IMPORTANCE: (S)-equol ((S)-EQ) plays a crucial role in maintaining human health, along with its known capacity to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. However, factors affecting individual variations in (S)-EQ production and the underlying regulatory mechanisms remain elusive. This study examines the association between functional genes and (S)-EQ production, highlighting a potential correlation between the DZNR gene and (S)-EQ content. Various types of DZNR may be linked to the regulation of (S)-EQ synthesis. Furthermore, the identification of a new DDRC gene offers promising prospects for enhancing in vitro (S)-EQ production.

The role of Pleistocene dispersal in shaping species richness of sky island wintergreens from the Himalaya-Hengduan Mountains.

In addition to topography and climate, biogeographic dispersal has been considered to influence plant diversity in the Himalaya-Hengduan Mountains (HHM), yet, the mode and tempo of sky island dispersal and its influence on species richness has been little explored. Through phylogenetic analysis of Gaultheria ser. Trichophyllae, a sky island alpine clade within the HHM, we test the hypothesis that dispersal has affected current local species richness. We inferred the dynamics of biogeographic dispersal with correlation tests on direction, distance, occurrence time, and regional species richness. We found that G. ser. Trichophyllae originated at the end of the Miocene and mostly dispersed toward higher longitudes (eastward). In particular, shorter intra-regional eastward dispersals and longer inter-regional westward dispersals were most frequently observed. We detected a prevalence of eastward intra-region dispersals in both glacial periods and interglacials. These dispersals may have been facilitated by the reorganization of paleo-drainages and monsoon intensification through time. We suggest that the timing of dispersal corresponding to glacial periods and the prevalence of intra-region dispersal, rather than dispersal frequency, most influenced the pattern of species richness of G. ser. Trichophyllae. This study facilitates a more comprehensive understanding of biodiversity in the sky islands within the HHM.

AMPK activator 991 specifically activates SnRK1 and thereby affects seed germination in rice.

Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) and AMP-activated protein kinase (AMPK) are highly conserved. Compound 991 is an AMPK activator in mammals. However, whether 991 also activates SnRK1 remains unknown. The addition of 991 significantly increased SnRK1 activity in desalted extracts from germinating rice seeds in vitro. To determine whether 991 has biological activity, rice seeds were treated with different concentrations of 991. Germination was promoted at low concentrations but inhibited at high concentrations. The effects of 991 on germination were similar to those of OsSnRK1a overexpression. To explore whether 991 affects germination by specifically affecting SnRK1, germination of an snrk1a mutant and the wild type under 1 µM 991 treatment was compared. The snrk1a mutant was insensitive to 991. Phosphoproteomic analysis showed that the differential phosphopeptides induced by 991 and OsSnRK1a overexpression largely overlapped. Furthermore, SnRK1 might regulate rice germination in a dosage-dependent manner by regulating the phosphorylation of three phosphosites, namely S285-PIP2;4, S1013-SOS1, and S110-ABI5. These results indicate that 991 is a specific SnRK1 activator in rice. The promotion and inhibition of germination by 991 also occurred in wheat seeds. Thus, 991 is useful for exploring SnRK1 function and the chemical regulation of growth and development in crops.

Overcrowded 14,14'-Bidibenzo[a,j]anthracenes: Challenges in Syntheses and Atypical Property of Lacking Symmetry-Breaking Charge Transfer (SBCT).

14,14'-Bidibenzo[a,j]anthracenes (BDBAs) were prepared by iridium-catalyzed annulation of 5,5'-biterphenylene with alkynes. The molecular geometries of overcrowded BDBAs were verified by X-ray crystallography. The two dibenzo[a,j]anthryl moieties are connected through the sterically hindered 14 positions, resulting in highly distorted molecular halves. The conformation with a small twist angle between two molecular halves can minimize steric conflicts between the substituents at 1 and 13 positions and the carbon atoms of the central axis, as well as steric clashes between those substituents. One such example is octafluoro-substituted BDBA, where the interplanar angle between two anthryl moieties is approximately 31° (currently the lowest reported value, cf. 81° in 9,9'-bianthracene). The intramolecular interactions and electronic couplings between two molecular halves resulted in upfield 1H NMR signals, redshifted absorption and emission bands, and a reduced HOMO-LUMO gap. Photodynamic investigations on BDBAs indicated that the formation of the conventional symmetry-breaking charge transfer (SBCT) state was suspended by restricted rocking around the central C-C bond. Such a mechanism associated with this highly constrained conformation was examined for the first time.

CBe2 H5 - : Unprecedented 2σ/2π Double Aromaticity and Dynamic Structural Fluxionality in a Planar Tetracoordinate Carbon Cluster.

A 14-electron ternary anionic CBe2 H5 - cluster containing a planar tetracoordinate carbon (ptC) atom is designed herein. Remarkably, it can be stabilized by only two beryllium atoms with both π-acceptor/σ-donor properties and two hydrogen atoms, which means that the conversion from planar methane (transition state) to ptC species (global minimum) requires the substitution of only two hydrogen atoms. Moreover, two ligand H atoms exhibit alternate rotation, giving rise to interesting dynamic fluxionality in this cluster. The electronic structure analysis reveals the flexible bonding positions of ligand H atoms due to C-H localized bonds, highlighting the rotational fluxionality in the cluster, and two CBe2 3c-2e delocalized bonds endow its rare 2σ/2π double aromaticity. Unprecedentedly, the fluxional process exhibits a conversion in the type of bonding (σ bond↔π bond), which is an uncommon fluxional mechanism. The cluster can be seen as an attempt to apply planar hypercoordinate carbon species to molecular motors.

A New Series of Sandwich-Type 5,5'-Biterphenylenes: Synthetic Challenge, Structural Uniqueness and Photodynamics.

A new series of biaryls, bi-linear-terphenylenes (BLTPs), were prepared using the tert-butyllithium-mediated cyclization as the key synthetic step. The three-dimensional structures of the studied compounds were verified using X-ray crystallography and DFT calculations. Tetraaryl(ethynyl)-substituted BLTPs are highly crowded molecules, and the internal rotation around the central C-C bond is restricted due to a high barrier (>50 kcal/mol). These structures contain several aryl/terphenylenyl/aryl sandwiches, where the through-space π-π (TSPP) interactions are strongly reflected in the shielding of 1 H NMR chemical shifts, reduction of oxidation potentials, increasing aromaticity of the central six-membered ring and decreasing antiaromaticity of the four-membered rings in a terphenylenyl moiety based on NICS(0) and iso-chemical shielding surfaces. Despite the restricted C-C bond associated intramolecular TSPP interactions for BLTPs in the ground state, to our surprise, the electronic coupling between two linear terphenylenes (LTPs) in BLTPs in the excited state is weak, so that the excited-state behavior is dominated by the corresponding monomeric LTPs. In other words, all BLTPs undergo ultrafast relaxation dynamics via strong exciton-vibration coupling, acting as a blue-light absorber with essentially no emission.

Dynamic Structural Fluxionality in a Planar Tetracoordinate Carbon Cluster Stabilized by Boron Ligands.

The design of boron-based molecular rotors stems from boron-carbon binary clusters containing multiple planar hypercoordinate carbons (phCs, such as C2B8). However, the design of boron-coordinated phCs is challenging due to boron's tendency to occupy hypercoordinate centers more than carbon. Although this challenge has been addressed, the designed clusters of interest have not exhibited dynamic fluxionality similar to that of the initial C2B8. To address this issue, we report a σ/π doubly aromatic CB2H5+ cluster, the first global minimum containing a boron-coordinated planar tetracoordinate carbon atom with dynamic fluxionality. Dynamics simulations show that two ligand H atoms exhibit alternate rotation, resulting in an intriguing dynamic fluxionality in this cluster. Electronic structure analysis reveals the flexible bonding positions of the ligand H atoms because they do not participate in π delocalized bonding nor bond to any other non-carbon atom, highlighting this rotational fluxionality. Unprecedentedly, the fluxional process involves not only the usual conversion of the number of bonding atoms, but also the type of bonding (3c π bonds ↔ 4c σ bonds), which is an uncommon fluxional mechanism. The cluster represents an effort to apply phC species to molecular machines.