Toxicogenomic assessment of hydroxylated metabolites of PBDEs on cetaceans: An in vitro study.

Despite their ban, polybrominated diphenyl ethers (PBDEs) are frequently detected in various environmental compartments including marine and coastal ecosystems due to their persistence, bio-accumulative, high production volumes, and widespread use. One of the major concerns from PBDEs is the transformation products, such as hydroxylated polybrominated diphenyl ethers (OH-BDEs), which are more bioactive than the parent compounds. For example, 6-hydroxy-2,2',4',4-tetrabromodiphenyl ether (6-OH-BDE-47) is a typical metabolite of PBDEs and cause endocrine system disruption, developmental toxicity, and neurotoxicity in different species. Despite being widely detected in marine environments, investigations on the toxicological mechanisms of 6-OH-BDE-47 in cetaceans remain scarce. High concentrations of PBDEs accumulate in cetaceans due to the long lifespan and large fat reserve. The accumulated PBDEs have become the major source of OH-BDEs in cetaceans. We exposed immortalized fibroblast cell lines from the skin of pygmy killer whales (PKW-LWHT) and Indo-Pacific finless porpoises (FP-LWHT) to 6-OH-BDE-47 and analyzed changes in cellular function using transcriptomic data, along with enzymatic activity. Exposure to the body-relevant body burdens of 6-OH-BDE-47 (250 and 500 ng mL-1) significantly decreased cell viability. Differentially expressed genes in FP-LWHT exposed to 6-OH-BDE-47 were primarily enriched in the pathways associated with steroid metabolism. Total cholesterol was decreased by 6-OH-BDE-47, whereas low-density lipoprotein cholesterol and triglyceride levels were significantly increased in FP-LWHT cells. In contrast, glycolysis was the main enriched function of differentially expressed genes in PKW-LWHT cells exposed to 6-OH-BDE-47, and the enzyme activity of phosphofructokinase and hexokinase was upregulated. Thus, even though the cell viability of both cell lines from these two species was significantly suppressed by 6-OH-BDE-47, the cellular response or affected cellular function was different between the Pygmy killer whale and the Indo-Pacific Finless Porpoise, suggesting a diverse response towards OH-BDEs exposure.

All-in-One 2D Molecular Crystal Optoelectronic Synapse for Polarization-Sensitive Neuromorphic Visual System.

Neuromorphic visual systems (NVSs) hold the potential to not only preserve but also enhance human visual capabilities. One such augmentation lies in harnessing polarization information from light reflected or scattered off surfaces like bees, which can disclose unique characteristics imperceptible to the human eyes. While creating polarization-sensitive optoelectronic synapses presents an intriguing avenue for equipping NVS with this capability, integrating functions like polarization sensitivity, photodetection, and synaptic operations into a singular device has proven challenging. This integration typically necessitates distinct functional components for each performance metric, leading to intricate fabrication processes and constraining overall performance. Herein, a pioneering linear polarized light sensitive synaptic organic phototransistor (OPT) based on 2D molecular crystals (2DMCs) with highly integrated, all-in-one functionality, is demonstrated. By leveraging the superior crystallinity and molecular thinness of 2DMC, the synaptic OPT exhibits comprehensive superior performance, including a linear dichroic ratio up to 3.85, a high responsivity of 1.47 × 104 A W-1, and the adept emulation of biological synapse functions. A sophisticated application in noncontact fingerprint detection achieves a 99.8% recognition accuracy, further highlights its potential. The all-in-one 2DMC optoelectronic synapse for polarization-sensitive NVS marks a new era for intelligent perception systems.

MolPackL: Quantification and Interpretation of Intermolecular Interactions Driven by Molecular Packing.

In organic optoelectronic devices, the properties of the aggregated organic materials depend not only on individual molecules or monomers but also significantly on their packing modes. Different from their inorganic counterparts linked by explicit covalent bonds, organic solids exhibit intricate and numerous intermolecular interactions (IMIs). Due to the intrinsic complexity and disorder of IMIs, identifying and understanding them is a formidable challenge in experimental, theoretical, and data-driven approaches. In this work, we constructed an innovative algorithm framework, Molecular Packing Learning (MolPackL), which can accurately quantify elusive IMIs using contact density histograms (CDHs) and efficiently extract intermolecular features for further property prediction of organic solids. It performs satisfactorily in training predictive models of IMI-related properties in molecular crystals. Particularly, the band gap predictive model based on MolPackL achieved the best-reported performance, with an MAE of 0.20 eV and an impressive R2 of 0.92. Class activation mapping (CAM) visually demonstrates MolPackL's accurate identification of effective interaction sites as the molecular packing changes. What is more, the elemental importance analysis verified that the superior score benefits from MolPackL's ability to comprehensively consider multiple influencing factors of IMIs. In summary, MolPackL provides a new framework for quantitative assessment and understanding of the effect of IMIs. The development of MolPackL marks a significant advancement in establishing predictive models of molecular aggregates, deepening the comprehension of IMIs on the material properties. Given the superior performance, we believe that MolPackL will also become a powerful tool in the design of high-performance organic optoelectronic materials.

Covalent Bond Torsion-Enabled Unique Crystal-Phase Transformation of an Organic Semiconductor for Multicolor Light-Emitting Transistors.

High-mobility and color-tunable highly emissive organic semiconductors (OSCs) are highly promising for various optoelectronic device applications and novel structure-property relationship investigations. However, such OSCs have never been reported because of the great trade-off between mobility, emission color, and emission efficiency. Here, we report a novel strategy of molecular conformation-induced unique crystalline polymorphism to realize the high mobility and color-tunable high emission in a novel OSC, 2,7-di(anthracen-2-yl) naphthalene (2,7-DAN). Interestingly, 2,7-DAN has unique crystalline polymorphism, which has an almost identical packing motif but slightly different molecular conformation enabled by the small bond rotation angle variation between anthracene and naphthalene units. More remarkably, the subtle covalent bond rotation angle change leads to a big change in color emission (from blue to green) but does not significantly modify the mobility and emission efficiency. The carrier mobility of 2,7-DAN crystals can reach up to a reliable 17 cm2 V-1 s-1, which is rare for the reported high-mobility OSCs. Based on the unique phenomenon, high-performance light-emitting transistors with blue to green emission are simultaneously demonstrated in an OSC crystal. These results open a new way for designing emerging multifunctional organic semiconductors toward next-generation advanced molecular (atomic)-scale optoelectronics devices.

Cardiovascular Disease, Genetic Susceptibility, and Risk of Psychiatric Disorders and Suicide Attempt: A Community-Based Matched Cohort Study Based on the UK Biobank.

BACKGROUND: The associations between cardiovascular disease (CVD) and multiple psychiatric disorders and suicide attempt, and whether different genetic susceptibilities affect such links, have not been investigated clearly. METHODS AND RESULTS: Based on the UK Biobank, we conducted a matched cohort study involving 63 923 patients who were first hospitalized with a CVD diagnosis between 1997 and 2020, and their 127 845 matched unexposed individuals. Cox models were used to examine the subsequent risk of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress-related disorder, substance misuse, psychotic disorder, and suicide behaviors) following CVD. We further performed stratified analyses by polygenic risk score for each studied psychiatric condition to detect the possible effects of genetic susceptibility on the observed associations. We found an increased risk of any psychiatric disorders and suicide attempt among CVD patients, compared with matched unexposed individuals, particularly within 1 year following the CVD (fully adjusted hazard ratio [HR] within 1 year, 1.83 [95% CI, 1.58-2.12]; HR after 1 year, 1.24 [95% CI, 1.16-1.32]). By subtype, the risk elevations existed for any psychiatric disorders and suicide attempt following most categories of CVDs. Analyses stratified by polygenic risk score revealed little impact of genetic predisposition to studied psychiatric conditions on these observed links. CONCLUSIONS: Patients hospitalized for CVD were at increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, especially in the first year after hospitalization, irrespective of their genetic susceptibilities to studied psychiatric conditions, and these findings underscore the necessity of developing timely psychological interventions for this vulnerable population.

Large-Language-Model-Based AI Agent for Organic Semiconductor Device Research.

Large language models (LLMs) have attracted widespread attention recently, however, their application in specialized scientific fields still requires deep adaptation. Here, an artificial intelligence (AI) agent for organic field-effect transistors (OFETs) is designed by integrating the generative pre-trained transformer 4 (GPT-4) model with well-trained machine learning (ML) algorithms. It can efficiently extract the experimental parameters of OFETs from scientific literature and reshape them into a structured database, achieving precision and recall rates both exceeding 92%. Combined with well-trained ML models, this AI agent can further provide targeted guidance and suggestions for device design. With prompt engineering and human-in-loop strategies, the agent extracts sufficient information of 709 OFETs from 277 research articles across different publishers and gathers them into a standardized database containing more than 10 000 device parameters. Using this database, a ML model based on Extreme Gradient Boosting is trained for device performance judgment. Combined with the interpretation of the high-precision model, the agent has provided a feasible optimization scheme that has tripled the charge transport properties of 2,6-diphenyldithieno[3,2-b:2',3'-d]thiophene OFETs. This work is an effective practice of LLMs in the field of organic optoelectronic devices and expands the research paradigm of organic optoelectronic materials and devices.

Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.

Effective glioblastoma immune sonodynamic treatment mediated by macrophage cell membrane cloaked biomimetic nanomedicines.

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

Unraveling the crucial role of trace oxygen in organic semiconductors.

Optoelectronic properties of semiconductors are significantly modified by impurities at trace level. Oxygen, a prevalent impurity in organic semiconductors (OSCs), has long been considered charge-carrier traps, leading to mobility degradation and stability problems. However, this understanding relies on the conventional deoxygenation methods, by which oxygen residues in OSCs are inevitable. It implies that the current understanding is questionable. Here, we develop a non-destructive deoxygenation method (i.e., de-doping) for OSCs by a soft plasma treatment, and thus reveal that trace oxygen significantly pre-empties the donor-like traps in OSCs, which is the origin of p-type characteristics exhibited by the majority of these materials. This insight is completely opposite to the previously reported carrier trapping and can clarify some previously unexplained organic electronics phenomena. Furthermore, the de-doping results in the disappearance of p-type behaviors and significant increase of n-type properties, while re-doping (under light irradiation in O2) can controllably reverse the process. Benefiting from this, the key electronic characteristics (e.g., polarity, conductivity, threshold voltage, and mobility) can be precisely modulated in a nondestructive way, expanding the explorable property space for all known OSC materials.

Quantitative image analysis of intracellular protein translocation in 3-dimensional tissues for pharmacodynamic studies of immunogenic cell death.

A recent development in cancer chemotherapy is to use cytotoxics to induce tumor-specific immune response through immunogenic cell death (ICD). In ICD, calreticulin is translocated from endoplasmic reticulum to cell membrane (ecto-CRT) which serves as the 'eat-me-signal' to antigen-presenting cells. Ecto-CRT measurements, e.g., by ecto-CRT immunostaining plus flow cytometry, can be used to study the pharmacodynamics of ICD in single cells, whereas ICD studies in intact 3-dimensional tissues such as human tumors require different approaches. The present study described a method that used (a) immunostaining with fluorescent antibodies followed by confocal microscopy to obtain the spatial locations of two molecules-of-interest (CRT and a marker protein WGA), and (b) machine-learning (trainable WEKA segmentation) and additional image processing tools to locate the target molecules, remove the interfering signals in the nucleus, cytosol and extracellular space, enable the distinction of the inner and outer edges of the cell membrane and thereby identify the cells with ecto-CRT. This method, when applied to 3-dimensional human bladder cancer cell spheroids, yielded drug-induced ecto-CRT measurements that were qualitatively comparable to the flow cytometry results obtained with single cells disaggregated from spheroids. This new method was applied to study drug-induced ICD in short-term cultures of surgical specimens of human patient bladder tumors.

Superhydrophilic Triazine-Based Covalent Organic Frameworks via Post-Modification of FeOOH Clusters for Boosted Photocatalytic Performance.

The triazine-based covalent organic frameworks (tCOF), an intriguing subtype of COFs, are expected as highly promising photocatalysts for various photocatalytic applications owing to their fully conjugated structures and nitrogen-rich skeletons. However, the inherent hydrophobicity and fast recombination of photoexcited electron-hole pairs are two main factors hindering the application of tCOF in practical photocatalytic reactions. Here, a post-synthetic modification strategy to fabricate superhydrophilic tCOF-based photocatalysts is demonstrated by in situ growing FeOOH clusters on TaTz COF (TaTz-FeOOH) for efficient photocatalytic oxidation of various organic pollutants. The strong polar FeOOH endows TaTz-FeOOH with good hydrophilic properties. The well-defined heterogeneous interface between FeOOH and TaTz allows the photoelectrons generated by TaTz to be consumed by Fe (III) to transform into Fe (II), synergistically promoting the separation of holes and the generation of free radicals. Compared with the unmodified TaTz, the optimized TaTz-FeOOH (1%) shows excellent photocatalytic performance, where the photocatalytic degrade rate (k) of rhodamine B is increased by about 12 times, and the degradation rate is maintained at 99% after 5 cycles, thus achieving efficient removal of quinolone antibiotics from water. This study provides a new avenue for the development of COF-based hydrophilic functional materials for a wide range of practical applications.

Ultrahigh-gain organic transistors based on van der Waals metal-barrier interlayer-semiconductor junction.

Intrinsic gain is a vital figure of merit in transistors, closely related to signal amplification, operation voltage, power consumption, and circuit simplification. However, organic thin-film transistors (OTFTs) targeted at high gain have suffered from challenges such as narrow subthreshold operating voltage, low-quality interface, and uncontrollable barrier. Here, we report a van der Waals metal-barrier interlayer-semiconductor junction-based OTFT, which shows ultrahigh performance including ultrahigh gain of ~104, low saturation voltage, negligible hysteresis, and good stability. The high-quality van der Waals-contacted junctions are mainly attributed to patterning EGaIn liquid metal electrodes by low-energy microfluidic processes. The wide-bandgap semiconductor Ga2O3 as barrier interlayer is achieved by in situ surface oxidation of EGaIn electrodes, allowing for an adjustable barrier height and expected thermionic emission properties. The organic inverters with a high gain of 5130 and a simplified current stabilizer are further demonstrated, paving a way for high-gain and low-power organic electronics.

Functional Covalent Organic Framework (COF) Nanoparticles for Biomimic Mineralization and Bacteria Inhabitation.

Biomimic mineralization of hard tissues with hierarchical structures is a challenging task, while designing multifunctional materials possessing both the ability of biomimic mineralization and drug delivery is even more difficult. Herein, inspired by the multilevel structure and mineralization ability of amelogenin, a novel carboxyl-functionalized covalent organic framework (COF) nanosphere material was designed and synthesized, which exhibited a significant biomimetic remineralization ability as demonstrated on SiO2 glass, Ti6Al4V, and an acid-etched enamel surface. Furthermore, the nanoporous structure also enables the COF nanospheres to serve as a drug delivery system for the controlled release of antibacterial drugs. This work provides a promising strategy for the design of multifunctional biomimic materials.

Oxygen-Induced Lattice Strain for High-Performance Organic Transistors with Enhanced Stability.

Integrating the merits of low cost, flexibility, and large-area processing, organic semiconductors (OSCs) are promising candidates for the next-generation electronic materials. The mobility and stability are the key figures of merit for its practical application. However, it is greatly challenging to improve the mobility and stability simultaneously owing to the weak interactions and poor electronic coupling between OSCs molecules. Here, an oxygen-induced lattice strain (OILS) strategy is developed to achieve OSCs with both high mobility and high stability. Utilizing the strategy, the maximum mobility of dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT) organic field-effect transistor (OFET) rises to 15.3 cm2  V-1  s-1 and the contact resistance lowers to 25.5 Ω cm. Remarkably, the thermal stability of DNTT is much improved, and a record saturated power density of ≈3.4 × 104  W cm-2 is obtained. Both the experiments and theoretical calculations demonstrate that the lattice compressive strain induced by oxygen is responsible for their high performance and stability. Furthermore, the universality of the strategy is manifested in both n-type and p-type small OSCs. This work provides a novel strategy to improve both the mobility and the stability of OSCs, paving the way for the practical applications of organic devices.

Oxygen-Induced Barrier Lowering for High-Performance Organic Field-Effect Transistors.

Organic field-effect transistors (OFETs) have the advantages of low-cost, large-area processing and could be utilized in a variety of emerging applications. However, the generally large contact resistance (Rc) limits the integration and miniaturization of OFETs. The Rc is difficult to reduce due to an incompatibility between obtaining strong orbit coupling and the barrier height reduction. In this study, we developed an oxygen-induced barrier lowering strategy by introducing oxygen (O2) into the nanointerface between the electrodes and organic semiconductors layer and achieved an ultralow channel width-normalized Rc (Rc·W) of 89.8 Ω·cm and a high mobility of 11.32 cm2 V-1 s-1. This work demonstrates that O2 adsorbed at the nanointerface of metal-semiconductor contact can significantly reduce the Rc from both experiments and theoretical simulations and provides guidance for the construction of high-performance OFETs, which is conducive to the integration and miniaturization of OFETs.

Cancer cell-mitochondria hybrid membrane coated Gboxin loaded nanomedicines for glioblastoma treatment.

Glioblastoma (GBM) remains the most lethal malignant tumours. Gboxin, an oxidative phosphorylation inhibitor, specifically restrains GBM growth by inhibiting the activity of F0F1 ATPase complex V. However, its anti-GBM effect is seriously limited by poor blood circulation, the blood brain barrier (BBB) and non-specific GBM tissue/cell uptake, leading to insufficient Gboxin accumulation at GBM sites, which limits its further clinical application. Here we present a biomimetic nanomedicine (HM-NPs@G) by coating cancer cell-mitochondria hybrid membrane (HM) on the surface of Gboxin-loaded nanoparticles. An additional design element uses a reactive oxygen species responsive polymer to facilitate at-site Gboxin release. The HM camouflaging endows HM-NPs@G with unique features including good biocompatibility, improved pharmacokinetic profile, efficient BBB permeability and homotypic dual tumour cell and mitochondria targeting. The results suggest that HM-NPs@G achieve improved blood circulation (4.90 h versus 0.47 h of free Gboxin) and tumour accumulation (7.73% ID/g versus 1.06% ID/g shown by free Gboxin). Effective tumour inhibition in orthotopic U87MG GBM and patient derived X01 GBM stem cell xenografts in female mice with extended survival time and negligible side effects are also noted. We believe that the biomimetic Gboxin nanomedicine represents a promising treatment for brain tumours with clinical potential.