Replacing the cyano (-C[triple bond, length as m-dash]N) group to design environmentally friendly fused-ring electron acceptors.

The cyano-group (-C[triple bond, length as m-dash]N) is an electron-withdrawing group, which has been widely used to construct high-performance fused-ring electron acceptors (FREAs). Benefiting from these FREAs, the power conversion efficiency of organic solar cells has recently exceeded 18%. However, malononitrile is a highly toxic substance used to introduce -C[triple bond, length as m-dash]N during the synthesis of these FREAs. Therefore, the synthesis processes of most high-performance FREAs are typically harmful to the environment. Our previous work demonstrated that the electron-withdrawing ability of -C[triple bond, length as m-dash]N is necessary for FREAs. Thus, the use of other electron-withdrawing groups instead of -C[triple bond, length as m-dash]N to design environmentally friendly FREAs is feasible. We utilized seven electron-withdrawing groups, namely, -C[double bond, length as m-dash]NH, -N[double bond, length as m-dash]O, -CH[double bond, length as m-dash]O, -CO-CH3, -CO-OH, -CO-Cl, and -CO-Br, to replace -C[triple bond, length as m-dash]N in the commonly used acceptor Y6 to design new FREAs (Y6-CNH, Y6-NO, Y6-CHO, Y6-COCH3, Y6-COOH, Y6-COCl, and Y6-COBr). Multi-scale theoretical calculation methods were used to investigate the photoelectronic properties of these new FREAs, including energy level, absorption spectrum, exciton binding energy, and electron mobility. The results showed that Y6-CNH, Y6-COCH3 and Y6-COOH are unsuitable for use as acceptor materials because of their high frontier molecular orbital energy level and weak electron affinity. The strong absorption intensity and weak exciton binding energy of Y6-CHO, Y6-COCl, and Y6-COBr indicated that they can absorb more solar energy than Y6 and excitons are easier to separate into free charges. The electron mobility of Y6-CHO (3.53 × 10-4 cm2 V-1 s-1) was found to be approximately 28 times that of Y6-COCl (1.24 × 10-5 cm2 V-1 s-1) and Y6-COBr (1.28 × 10-5 cm2 V-1 s-1). The possible synthetic routes to Y6-CHO are environmentally friendly. Therefore, -CH[double bond, length as m-dash]O is the most suitable electron-withdrawing group for constructing high-performance environmentally friendly FREAs. This work can provide a new molecular design perspective in experimental science for developing high-performance environmentally friendly FREAs.

Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance.

Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.

Nonbonding Electron Delocalization Stabilizes the Flexible N8 Molecular Assembly.

Electron delocalization has an important impact on the physical properties of condensed materials. However, the L-electron delocalization in inorganic, especially nitrogen, compounds needs exploitation to improve the energy efficiency, safety, and environmental sustainability of high-energy-density materials (HEDMs). This Letter presents an intriguing N8 molecule, ingeniously utilizing nitrogen's L-electron delocalization. The molecule, exhibiting a unique lollipop-shaped conformation, can fold at various angles with very low energy barriers, self-assembling into environmentally stable, all-nitrogen crystals. These crystals demonstrate unparalleled stability, high energy density, low mechanical sensitivity, and optimal electronic thermal conductivity, outperforming existing HEDMs. The remarkable properties of these designed materials are attributed to two distinct delocalized systems within nitrogen's L-shell: π- and lone pair σ-electrons, which not only stabilize the molecular structure but also facilitate interconnected 3D networks of intermolecular nonbonding interactions. This work might pave the way to the experimental synthesis of environmentally stable all-nitrogen solids.

Aberrant regulation of the Rap1 small GTPase in response to escalating, intermittent stress produces hippocampal synaptic and cognitive dysfunction.

The effects of repeated stress on cognitive impairment are thought to be mediated, at least in part, by reductions in the stability of dendritic spines in brain regions critical for proper learning and memory, including the hippocampus. Small GTPases are particularly potent regulators of dendritic spine formation, stability, and morphology in hippocampal neurons. Through the use of small GTPase protein profiling in mice, we identify increased levels of synaptic Rap1 in the hippocampal CA3 region in response to escalating, intermittent stress. We then demonstrate that increased Rap1 in the CA3 is sufficient in and of itself to produce stress-relevant dendritic spine and cognitive phenotypes. Further, using super-resolution imaging, we investigate how the pattern of Rap1 trafficking to synapses likely underlies its effects on the stability of select dendritic spine subtypes. These findings illuminate the involvement of aberrant Rap1 regulation in the hippocampus in contributing to the psychobiological effects of stress.

Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function.

The effects of repeated stress on cognitive impairment are thought to be mediated, at least in part, by reductions in the stability of dendritic spines in brain regions critical for proper learning and memory, including the hippocampus. Small GTPases are particularly potent regulators of dendritic spine formation, stability, and morphology in hippocampal neurons. Through the use of small GTPase protein profiling in mice, we identify increased levels of synaptic Rap1 in the hippocampal CA3 region in response to escalating, intermittent stress. We then demonstrate that increased Rap1 in the CA3 is sufficient in and of itself to produce stress-relevant dendritic spine and cognitive phenotypes. Further, using super-resolution imaging, we investigate how the pattern of Rap1 trafficking to synapses likely underlies its effects on the stability of select dendritic spine subtypes. These findings illuminate the involvement of aberrant Rap1 regulation in the hippocampus in contributing to the psychobiological effects of stress.

Pharmacist-Led Management Improves Treatment Adherence and Quality of Life in Opioid-Tolerant Patients With Cancer Pain: A Randomized Controlled Trial.

INTRODUCTION: Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life. METHODS: Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035). RESULTS: In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522). CONCLUSIONS: Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03455023.

Functionalizing triptycene to create 3D high-performance non-fullerene acceptors.

Non-fullerene acceptors have been widely investigated for organic solar cells (OSCs). In particular, fused-ring electron acceptors (FREAs), composed of two strongly electron-withdrawing end groups connected by a planar fused-ring core, have been successfully applied to develop high-performance OSCs (>16%). In this work, we proposed two novel 3D FREAs named BFT-3D and BFTT-3D, which can reduce the formation of crystalline domains and increase the interface with donors to promote exciton separation. These 3D FREAs consist of three strongly electron-withdrawing end groups linked by a central triptycene hub to form a three-bladed propeller nanostructure. In comparison with high-performance FREA (ITOIC-2F), these FREAs have stronger absorption intensity and smaller exciton binding energy. These findings demonstrated that these three-bladed propeller-shaped FREAs can absorb abundant energy from sunlight to generate excitons, easily separate excitons to free electrons and holes, and reduce the recombination of excitons. In addition, the electron mobility of BFT-3D (8.4 × 10-4 cm2 V-1 s-1) is higher than that of BFTT-3D (1.0 × 10-4 cm2 V-1 s-1), which indicated that the appropriate 3D core structure was conducive to the electron mobility of the three-bladed propeller-shaped FREAs. It can effectively improve the current density to enhance the performance of OSCs. These findings will provide new perspectives for experimental scientists to synthesize high-performance FREAs.

MicroRNA­671­3p regulates the development of knee osteoarthritis by targeting TRAF3 in chondrocytes.

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation and joint inflammation. A previous study showed that microRNA (miR)­671­3p is involved in the development of OA, however, its function and molecular target in chondrocytes during the pathogenesis of OA remain to be fully elucidated. In the present study, miR­671­3p was significantly downregulated in knee OA cartilage tissues compared with normal cartilage tissues. The expression levels of pro­inflammatory cytokines, including interleukin (IL)­1ß, IL­6, IL­8 and tumor necrosis factor (TNF)­α, in the knee OA cartilage tissues were significantly higher than those in the normal cartilage tissues. Through gain­of­function and loss­of­function experiments, miR­671­3p was shown to significantly affect matrix synthesis gene expression, cell proliferation, apoptosis and inflammation in chondrocytes from patients with OA. Subsequent bioinformatics analysis identified potential target sites of the miR­671­3p located in the 3'untranslated region of TNF receptor­associated factor (TRAF3). The results of a dual­luciferase reporter assay showed that TRAF3 is a target gene of miR­671­3p. Western blot analysis demonstrated that miR­671­3p inhibited the gene expression of TRAF3. Furthermore, the restoration of TRAF3 markedly abrogated the effect of miR­671­3p. Taken together, the present study suggests that miR­671­3p may be important in the pathogenesis of OA through targeting TRAF3 and regulating chondrocyte apoptosis and inflammation, which may be a potential molecular target for OA treatment.

miR-29a inhibits adhesion, migration, and invasion of osteosarcoma cells by suppressing CDC42.

Osteosarcoma is one of the most common tumors of the bone in children and adolescents worldwide. The relapse and metastasis of osteosarcoma are a major therapeutic challenge. Recently, several metastasis regulators, including miRNAs, kinases, and lncRNAs, were reported in osteosarcoma. Identifying novel regulators of metastasis will be useful to explore novel biomarkers for osteosarcoma. The present study showed miR-29a overexpression significantly inhibited HOS and MG-63 cell adhesion, invasion, and migration. About 70% of the wound area was repaired by migrating cells after 24 h in the control group, and only 50% of the wound area was repaired in the miR-29a overexpression group. The numbers of invading cells were decreased by 40% and 50% in HOS and MG-63 cells transfected with miR-29a, respectively, compared with the negative control group. Moreover, the present study validated that CDC42 was a direct target of miR-29a in OS cells. In conclusion, miR-29a may serve as a therapeutic target for osteosarcoma.