FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21/Nrf2 activation in a HuR-dependent m6A manner.

Doxorubicin (DOX)-induced cardiotoxicity seriously limits its clinical applicability, and no therapeutic interventions are available. Ferroptosis, an iron-dependent regulated cell death characterised by lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. N6-methyladenosine (m6A) methylation is the most frequent type of RNA modification and involved in DOX-induced ferroptosis, however, its underlying mechanism remains unclear. P21 was recently found to inhibit ferroptosis by interacting with Nrf2 and is regulated in a P53-dependent or independent manner, such as through m6A modification. In the present study, we investigated the mechanism underlying m6A modification in DOX-induced ferroptosis by focusing on P21. Our results show that fat mass and obesity-associated protein (FTO) down-regulation was associated with DOX-induced cardiotoxicity. FTO over-expression significantly improved cardiac function and cell viability in DOX-treated mouse hearts and H9C2 cells. FTO over-expression significantly inhibited DOX-induced ferroptosis, and the Fer-1 inhibition of ferroptosis significantly reduced DOX-induced cardiotoxicity. P21 was significantly upregulated by FTO and activated Nrf2, playing a crucial role in the anti-ferroptotic effect. FTO upregulated P21/Nrf2 in a P53-dependent manner by mediating the demethylation of P53 or in a P53-independent manner by mediating P21/Nrf2 directly. Human antigen R (HuR) is crucial for FTO-mediated regulation of ferroptosis and P53-P21/Nrf2. Notably, we also found that P21 inhibition in turn inhibited HuR and P53 expression, while HuR inhibition further inhibited FTO expression. RNA immunoprecipitation assay showed that HuR binds to the transcripts of FTO and itself. Collectively, FTO inhibited DOX-induced ferroptosis via P21/Nrf2 activation by mediating the m6A demethylation of P53 or P21/Nrf2 in a HuR-dependent manner and constituted a positive feedback loop with HuR and P53-P21. Our findings provide novel insight into key functional mechanisms associated with DOX-induced cardiotoxicity and elucidate a possible therapeutic approach.

Physics-Constrained Hardware-Efficient Ansatz on Quantum Computers That Is Universal, Systematically Improvable, and Size-Consistent.

Variational wave function ansätze are at the heart of solving quantum many-body problems in physics and chemistry. Previous designs of hardware-efficient ansatz (HEA) on quantum computers are largely based on heuristics and lack rigorous theoretical foundations. In this work, we introduce a physics-constrained approach for designing HEA with rigorous theoretical guarantees by imposing a few fundamental constraints. Specifically, we require that the target HEA to be universal, systematically improvable, and size-consistent, which is an important concept in quantum many-body theories for scalability but has been overlooked in previous designs of HEA. We extend the notion of size-consistency to HEA and present a concrete realization of HEA that satisfies all these fundamental constraints while only requiring linear qubit connectivity. The developed physics-constrained HEA is superior to other heuristically designed HEA in terms of both accuracy and scalability, as demonstrated numerically for the Heisenberg model and some typical molecules. In particular, we find that restoring size-consistency can significantly reduce the number of layers needed to reach a certain accuracy. In contrast, the failure of other HEA to satisfy these constraints severely limits their scalability to larger systems with more than 10 qubits. Our work highlights the importance of incorporating physical constraints into the design of HEA for efficiently solving many-body problems on quantum computers.

Application of organoids in precision immunotherapy of lung cancer (Review).

In immunotherapy, the immune system is modulated in order to treat cancer. Traditional two dimensional in vitro models and in vivo animal models are insufficient to simulate the complex tumor microenvironment (TME) in the original tumor. As tumor immunotherapy involves the immune system, additional tumor mimic models, such as patient-derived organoids, are required for the evaluation of the efficacy of immunotherapy. Furthermore, non-tumor components and host tumor cells in the TME may interact to promote cancer incidence, progression, drug resistance and metastasis. It is possible to produce organoid models for lung cancer by retaining endogenous stromal components (e.g., multiple immune cell types), supplying cancer-associated fibroblasts and exogenous immune cells, constructing tumor vasculature and adding other biological or chemical components that emulate the TME. Therefore, the lung cancer organoid culture platform may facilitate preclinical testing of immunotherapy drugs for lung cancer by mimicking immunotherapy responses. The present review summarizes current lung cancer organoid culture methods for TME modeling and discusses the use of lung cancer-derived organoids for the detection of lung cancer immunotherapy and individualized cancer immunotherapy.

Time-Dependent Density Matrix Renormalization Group Method for Quantum Transport with Phonon Coupling in Molecular Junction.

Quantum transport in molecular junctions has attracted great attention. The charge motion in a molecular junction can cause geometric deformation, leading to strong electron phonon coupling, which was often overlooked. We have formulated a nearly exact method to assess the time-dependent current and occupation number in the molecular junction modeled by the electron-phonon coupled bridge state using the time-dependent density matrix renormalization group (TD-DMRG) method. The oscillation period and amplitude of the current are found to be dependent on the electron phonon coupling strength and energy level alignment with the electrodes. In an attempt to better understand these phenomena, we have devised a new approximation that explains the bistability phenomenon and the behavior of steady currents in the strong electron-phonon coupling regime. Comparisons have been made with the multilayer-multiconfiguration time-dependent Hartree (ML-MCTDH) method and the analytical result in the purely electronic limit. Furthermore, we explore the entropy of different orderings, extending to the electron phonon model problems. Regarding finite temperature, the thermal Bogoliubov transformation of both fermions and bosons is used and compared with imaginary time evolution results.

lnc-HC ameliorates steatosis by promoting miR-130b-3p biogenesis and the assembly of an RNA-induced silencing complex.

Hepatic lipid deposition is the main cause of non-alcoholic fatty liver disease (NAFLD). Our previous study identified that lnc-HC prevents NAFLD by increasing the expression of miR-130b-3p. In the present study, we show that lnc-HC, an lncRNA derived from hepatocytes, positively controls miR-130b-3p maturation at multiple levels and contributes to its action by enhancing the assembly of an RNA-induced silencing complex (RISC). lnc-HC negatively regulates the downstream target genes of miR-130b-3p, including peroxisome proliferator-activated receptor gamma (PPARγ) and acyl-CoA synthetase long-chain family member 1 and 4 (Acsl1 and Acsl4, respectively), thus suppressing hepatic lipid droplet accumulation. Mechanistically, lnc-HC enhanced the promoter activity of miR-130b-3p by positively regulating the expression of transcription factors MAF bZIP transcription factor B (Mafb) and Jun proto-oncogene (Jun). Then, lnc-HC contributed the processing step of primary (pri-) miR-130b and strengthened the interaction between Drosha enzyme and the 5'-flanking sequence of pri-miR-130b to produce more precursor transcripts. Through direct binding with the chaperone heat shock protein 90 alpha family class A member 1 (HSP90AA1), lnc-HC contributed to RISC assembly, which was composed of HSP90AA1, argonaute RISC catalytic component 2 (AGO2) and miR-130b-3p. In a high-fat, high-cholesterol-induced hepatic lipid disorder E3 model, we confirmed that the hepatic expression of lnc-HC/miR-130b-3p negatively correlated with that of the target genes and was closely associated with liver triglycerides concentration. These findings provide a deeper understanding of the regulatory roles of lnc-HC in hepatic lipid metabolism and NAFLD development.

Developing a Core Outcome Set for Assessing Clinical Safety Outcomes of Prostate Cancer in Clinical Trials of Traditional Chinese Medicine: Protocol for a Mixed Methods Study.

BACKGROUND: Among the common malignant tumors in men worldwide, the incidence of prostate cancer ranks second to lung cancer. This disease will bring an economic burden to patients and their families and can reduce the quality of life of patients. Researchers have conducted numerous clinical trials on the efficacy and safety of different interventions in the treatment of prostate cancer with traditional Chinese medicine (TCM) combined with standard treatment regimens. However, the currently published clinical trials exhibit inconsistent and irregular reporting of outcome measures. OBJECTIVE: The objective of this paper is to emphasize the need for a core outcome set (COS) to facilitate future prostate cancer research, aiming to improve the quality of trials and generate high-quality evidence. METHODS: This mixed methods project has three phases, as follows: (1) a scoping review of the literature to identify outcomes that have been reported in clinical trials and systematic reviews of interventions involving TCM for the treatment of prostate cancer as well as a qualitative component using interviews to obtain the views of patients with prostate cancer, their families, and their caregivers who have a history of TCM treatment; (2) a Delphi survey among stakeholders to prioritize the core outcomes-Participants will include traditional Chinese and Western medicine clinicians in prostate cancer-related directions, nurses, and methodology experts who will participate in 2 rounds of the Delphi method expert consultation to score each outcome in the list of outcome indicators; and (3) a face-to-face consensus meeting to discuss and agree on the final COS for the application of TCM in the treatment of prostate cancer. RESULTS: The protocol has been registered in PROSPERO (CRD42022356184) before the start of the review process, and we will initiate the review on August 1, 2023; results should be expected by September 1, 2023. The Delphi survey among stakeholders is expected to start in October 2023. CONCLUSIONS: The development of a core outcome set for assessing clinical safety outcomes of prostate cancer in clinical trials of TCM will provide a significant first step to assist Chinese doctors, researchers, and policy makers. TRIAL REGISTRATION: PROSPERO CRD42022356184; https://tinyurl.com/ysakz74r. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46794.

Minimizing non-radiative decay in molecular aggregates through control of excitonic coupling.

The widely known "Energy Gap Law" (EGL) predicts a monotonically exponential increase in the non-radiative decay rate (knr) as the energy gap narrows, which hinders the development of near-infrared (NIR) emissive molecular materials. Recently, several experiments proposed that the exciton delocalization in molecular aggregates could counteract EGL to facilitate NIR emission. In this work, the nearly exact time-dependent density matrix renormalization group (TD-DMRG) method is developed to evaluate the non-radiative decay rate for exciton-phonon coupled molecular aggregates. Systematical numerical simulations show, by increasing the excitonic coupling, knr will first decrease, then reach a minimum, and finally start to increase to follow EGL, which is an overall result of two opposite effects of a smaller energy gap and a smaller effective electron-phonon coupling. This anomalous non-monotonic behavior is found robust in a number of models, including dimer, one-dimensional chain, and two-dimensional square lattice. The optimal excitonic coupling strength that gives the minimum knr is about half of the monomer reorganization energy and is also influenced by system size, dimensionality, and temperature.

Surface Defect Detection for Automated Tape Laying and Winding Based on Improved YOLOv5.

To address the issues of low detection accuracy, slow detection speed, high missed detection rate, and high false detection rate in the detection of surface defects on pre-impregnated composite materials during the automated tape laying and winding process, an improved YOLOv5 (You Only Look Once version 5) algorithm model was proposed to achieve the high-precision, real-time detection of surface defects. By leveraging this improvement, the necessity for frequent manual interventions, inspection interventions, and subsequent rework during the automated lay-up process of composite materials can be significantly reduced. Firstly, to improve the detection accuracy, an attention mechanism called "CA (coordinate attention)" was introduced to enhance the feature extraction ability, and a Separate CA structure was used to improve the detection speed. Secondly, we used an improved loss function "SIoU (SCYLLA-Intersection over Union) loss" to replace the original "CIoU (Complete-Intersection over Union) loss", which introduced an angle loss as a penalty term to consider the directional factor and improve the stability of the target box regression. Finally, Soft-SIoU-NMS was used to replace the original NMS (non-maximum suppression) of YOLOv5 to improve the detection of overlapping defects. The results showed that the improved model had a good detection performance for surface defects on pre-impregnated composite materials during the automated tape laying and winding process. The FPS (frames per second) increased from 66.7 to 72.1, and the mAP (mean average precision) of the test set increased from 92.6% to 97.2%. These improvements ensured that the detection accuracy, as measured by the mAP, surpassed 95%, while maintaining a detection speed of over 70 FPS, thereby meeting the requirements for real-time online detection.

Unified Definition of Exciton Coherence Length for Exciton-Phonon Coupled Molecular Aggregates.

Exciton coherence length (ECL) characterizes the spatial extent of coherently delocalized excited states of molecular aggregates. Constructive/destructive superpositions of coherent molecular dipoles lead to superradiance/subradiance, where the radiative rate is enhanced/suppressed compared to that of a single molecule. Longer ECLs correspond to faster/slower radiative rates for superradiant/subradiant aggregates. However, previous ECL definitions fail to produce monotonic relationships when exciton-phonon coupling is considered, even for simple 1D exciton-phonon systems. This problem is exacerbated for 2D aggregates with both constructive and destructive superpositions. In this Letter, we propose a novel ECL definition by virtue of sum rule for oscillator strengths, ensuring a bijective and monotonic relationship between ECL and radiative rate for both 1D/2D superradiant and subradiant aggregates. Using numerically accurate time-dependent matrix product states, we study large-scale, exciton-phonon coupled 2D aggregates and predict the existence of maximum superradiance at finite temperature, in contrast to the previously believed 1/T law. Our results provide new insights into the design and optimization of efficient light emitting materials.

Computational Method for Evaluating the Thermoelectric Power Factor for Organic Materials Modeled by the Holstein Model: A Time-Dependent Density Matrix Renormalization Group Formalism.

Organic/polymeric materials are of emerging importance for thermoelectric conversion. The soft nature of these materials implies strong electron-phonon coupling, often leading to carrier localization. This poses great challenges for the conventional Boltzmann transport description based on relaxation time approximation and band structure calculations. In this work, combining the Kubo formula with the finite-temperature time-dependent density matrix renormalization group (FT-TD-DMRG) in the grand canonical ensemble, we developed a nearly exact algorithm to calculate the thermoelectric power factor PF = α2 σ, where α is the Seebeck coefficient and σ is the electrical conductivity, and apply the algorithm to Holstein Hamiltonian with electron-phonon coupling to model organic materials. Our algorithm can provide a unified description covering the weak coupling limit described by the bandlike Boltzmann transport to the strong coupling hopping limit.

Hybrid Quantum-Classical Boson Sampling Algorithm for Molecular Vibrationally Resolved Electronic Spectroscopy with Duschinsky Rotation and Anharmonicity.

Using a photonic quantum computer for boson sampling has demonstrated a tremendous advantage over classical supercomputers. It is highly desirable to develop boson sampling algorithms for realistic scientific problems. In this work, we propose a hybrid quantum-classical sampling (HQCS) algorithm to calculate the optical spectrum for complex molecules considering Duschinsky rotation effects and anharmonicity. The classical sum-over-states method for this problem has a computational complexity that exponentially increases with system size. The HQCS algorithm creates an intermediate harmonic potential energy surface (PES) to bridge the initial and final PESs. The magnitude and sign of the overlap between the initial and the intermediate state are estimated by boson sampling and classical algorithms, respectively. The overlap between the intermediate and the final state is efficiently evaluated by classical algorithms. The feasibility of HQCS is demonstrated in calculations of the emission spectrum of a Morse model as well as the pyridine molecule.

On the fly swapping algorithm for ordering of degrees of freedom in density matrix renormalization group.

Density matrix renormalization group (DMRG) and its time-dependent variants have found widespread applications in quantum chemistry, includingab initioelectronic structure of complex bio-molecules, spectroscopy for molecular aggregates, and charge transport in bulk organic semiconductors. The underlying wavefunction ansatz for DMRG, matrix product state (MPS), requires mapping degrees of freedom (DOF) into a one-dimensional topology. DOF ordering becomes a crucial factor for DMRG accuracy. In this work, we propose swapping neighboring DOFs during the DMRG sweeps for DOF ordering, which we term 'on the fly swapping' (OFS) algorithm. We show that OFS is universal for both static and time-dependent DMRG with minimum computational overhead. Examples are given for one dimensional antiferromagnetic Heisenberg model,ab initioelectronic structure of N2molecule, and the S1/S2internal conversion dynamics of pyrazine molecule. It is found that OFS can indeed improve accuracy by finding better DOF ordering in all cases.

Pdcd4 promotes lipid deposition by attenuating PPARα-mediated fatty acid oxidation in hepatocytes.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. The involvement of programmed cell death 4 (Pdcd4) in inflammation and metabolic diseases has been widely reported. However, the precise regulatory role of Pdcd4 in hepatocytic lipid metabolism and NAFLD is not well known. RESEARCH DESIGN AND METHODS: We established a high-fat diet-induced NAFLD (HFD-NAFLD) rat model and a free fatty acids (FFAs)-treated cell model, and analyzed the expression and distribution of PDCD4. The lentivirus for Pdcd4 knockout and the vector for Pdcd4 overexpression were used to alter Pdcd4 expression in BRL 3A cells. Thereafter, lipid accumulation, FA metabolic gene expression, and peroxisome proliferator-activated receptor alpha (Pparα)-dependent peroxisomal ß-oxidation-related gene expression, especially that of the critical transcription factors and enzymes acyl-CoA oxidases 1-3 (Acox1-3), were detected both at the mRNA and protein levels. RESULTS: PDCD4 expression increased and it was mainly distributed in hepatocyte nuclei of the HFD-NAFLD rats. as well as the FFAs-treated CBRH-7919 and BRL 3A cell lines. Pdcd4 knockout significantly suppressed FFAs-induced lipid accumulation, and Pdcd4 overexpression accelerated FFAs-induced lipid accumulation in hepatocytes. Mechanistically, Pdcd4 negatively regulated the expression Pparα and Acox1-3. In addition, rescue experiments confirmed that Pparα knockdown could attenuate the expression of Acox1-3 in Pdcd4 knockout cells, which ultimately restored lipid deposition to normal levels. PPARα expression decreased in the liver of the HFD-NAFLD rats. The enrichment of PDCD4 in hepatocyte nuclei correlated with lower PPARα expression after FFAs treatment in vitro. CONCLUSION: Our results indicate that the abundance of PDCD4 under high-fat conditions facilitates hepatocellular lipid accumulation by decreasing PPARα-dependent FA peroxisomal ß-oxidation.

Prevalence and Factors Associated With Suicidal Ideation in Medical Students With Migraine.

Background: The association between migraine and suicide ideation has been identified. However, the predictive factors of suicidal ideation are still controversial and whether migraine with aura can serve as an independent associated factor is uncertain. This manuscript studied the association between migraine with aura and suicidal ideation and explored the predictive factors for suicidal ideation. Methods: We surveyed 9,057 medical students and included 579 medical students with migraine into our study population. All students completed the General Situation Questionnaire, the Verified Headache Questionnaire, Hamilton Anxiety Scale (24 items), Hamilton Depression Scale (24 items), 36-item Health Survey Brief (SF-36), Headache Impact Text-6 (HIT-6), Test Anxiety Scale (TAS), and Pittsburgh Sleep Quality Index (PSQI). Suicidal ideation was measured by the Self-rating Idea of Suicide Scale (SIOSS). Results: Out of the 579 migraine medical college students, 562 (age 19.6 ± 1.6; 448 women and 114 men) were included in the final study. The positive rate of suicidal ideation was 13.7%. Compared with students suffering from migraine without aura, those having migraine with aura had higher suicidal ideation (p < 0.015). After adjusting for demographic factors and headache characteristics, migraine with aura was found to be independently associated with suicidal ideation. Other independent associated factors include anxiety, depression, test anxiety, sleep, headache, and quality of life. Among these various factors, high quality of life was found to play a protective role against suicidal ideation. Conclusions: Migraine with aura is independently associated with suicidal ideation. Furthermore, anxiety, depression, text anxiety, poor sleep quality, and headache frequency are associated with suicidal ideation among medical college students with migraine.

Exploration of differentially-expressed exosomal mRNAs, lncRNAs and circRNAs from serum samples of gallbladder cancer and xantho-granulomatous cholecystitis patients.

Gallbladder cancer (GBC) is the most common biliary tract malignancy worldwide. Although a growing number of studies have explored the mechanism of GBC, thus far, few molecules have been discovered that can be utilized as specific biomarkers for the early diagnosis and therapeutic treatment of GBC. Recent studies have shown that exosomes not only participate in the progression of tumors, but also carry specific information that can define multiple cancer types. The present study investigated the expression profiles of coding (or messenger) ribonucleic acids (mRNAs) and non-coding RNAs (ncRNAs, including long non-coding RNAs [lncRNAs] and circular RNAs [circRNAs]) in plasma-derived exosomes from GBC patients. Using high-throughput RNA sequencing and subsequent bioinformatic analysis, a number of differentially expressed (DE) mRNAs, lncRNAs, and circRNAs were identified in GBC exosomes, compared to their expressions in xantho-granulomatous cholecystitis (XGC) exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses were then conducted to investigate the potential functions of these DE RNAs. Furthermore, the interaction networks and competing endogenous RNA networks of these DE RNAs and their target genes were investigated, revealing a complex regulatory network among mRNAs and ncRNAs. In summary, this study demonstrates the diagnostic value of plasma-derived exosomes in GBC and provides a new perspective on the mechanism of GBC.

Chebyshev Matrix Product States with Canonical Orthogonalization for Spectral Functions of Many-Body Systems.

We propose a method to calculate the spectral functions of many-body systems by Chebyshev expansion in the framework of matrix product states coupled with canonical orthogonalization (coCheMPS). The canonical orthogonalization can improve the accuracy and efficiency significantly because the orthogonalized Chebyshev vectors can provide an ideal basis for constructing the effective Hamiltonian in which the exact recurrence relation can be retained. In addition, not only the spectral function but also the excited states and eigenenergies can be directly calculated, which is usually impossible for other MPS-based methods such as time-dependent formalism or correction vector. The remarkable accuracy and efficiency of coCheMPS over other methods are demonstrated by calculating the spectral functions of spin chain and ab initio hydrogen chain. For the first time we demonstrate that Chebyshev MPS can be used to deal with ab initio electronic Hamiltonian effectively. We emphasize the strength of coCheMPS to calculate the low excited states of systems with sparse discrete spectrum. We also caution the application for electron-phonon systems with dense density of states.

Evaluating the anharmonicity contributions to the molecular excited state internal conversion rates with finite temperature TD-DMRG.

In this work, we propose a new method to calculate molecular nonradiative electronic relaxation rates based on the numerically exact time-dependent density matrix renormalization group theory. This method could go beyond the existing frameworks under the harmonic approximation (HA) of the potential energy surface (PES) so that the anharmonic effect could be considered, which is of vital importance when the electronic energy gap is much larger than the vibrational frequency. We calculate the internal conversion (IC) rates in a two-mode model with Morse potential to investigate the validity of HA. We find that HA is unsatisfactory unless only the lowest several vibrational states of the lower electronic state are involved in the transition process when the adiabatic excitation energy is relatively low. As the excitation energy increases, HA first underestimates and then overestimates the IC rates when the excited state PES shifts toward the dissociative side of the ground state PES. On the contrary, HA slightly overestimates the IC rates when the excited state PES shifts toward the repulsive side. In both cases, a higher temperature enlarges the error of HA. As a real example to demonstrate the effectiveness and scalability of the method, we calculate the IC rates of azulene from S1 to S0 on the ab initio anharmonic PES approximated by the one-mode representation. The calculated IC rates of azulene under HA are consistent with the analytically exact results. The rates on the anharmonic PES are 30%-40% higher than the rates under HA.

A general charge transport picture for organic semiconductors with nonlocal electron-phonon couplings.

The nonlocal electron-phonon couplings in organic semiconductors responsible for the fluctuation of intermolecular transfer integrals has been the center of interest recently. Several irreconcilable scenarios coexist for the description of the nonlocal electron-phonon coupling, such as phonon-assisted transport, transient localization, and band-like transport. Through a nearly exact numerical study for the carrier mobility of the Holstein-Peierls model using the matrix product states approach, we locate the phonon-assisted transport, transient localization and band-like regimes as a function of the transfer integral (V) and the nonlocal electron-phonon couplings (ΔV), and their distinct transport behaviors are analyzed by carrier mobility, mean free path, optical conductivity and one-particle spectral function. We also identify an "intermediate regime" where none of the established pictures applies, and the generally perceived hopping regime is found to be at a very limited end in the proposed regime paradigm.

Intermolecular Charge-Transfer-Induced Strong Optical Emission from Herringbone H-Aggregates.

Luminescence in molecular aggregates can be quenched either by intermolecular charge transfer or by forming a dipole-forbidden lower Frenkel exciton in H-aggregate. Taking intermolecular charge transfer and excitonic coupling into a three-state model through localized diabatization, we demonstrate that the low-lying intermolecular charge-transfer state could couple with the upper bright Frenkel exciton to form dipole-allowed S1 that lies below the dark state, which accounts for the recent experimentally discovered strong luminescence in organic light-emitting transistors (OLETs) system with DPA and dNaAnt herringbone aggregates. The condition of forming such bright state is that the electron and hole transfer integrals, te and th, are of the same sign, and should be notably larger than the excitonic coupling (J), that is , te × th > 2J2. This theoretical finding not only rationalizes recent experiments but unravels an exciting scenario where strong luminescence and high charge mobilities become compatible, which is a preferable condition for both OLETs and electrically pumped lasing.

Induction of PDCD4 by albumin in proximal tubule epithelial cells potentiates proteinuria-induced dysfunctional autophagy by negatively targeting Atg5.

Autophagy dysfunction is a hallmark of type 1 diabetes. However, the precise molecular mechanism of proteinuria-induced dysfunctional autophagy remains unclear. Herein, we investigated the role of programmed cell death 4 (PDCD4) in the regulation of autophagy in the pathogenesis of diabetic kidney disease (DKD) in vivo and in vitro. RT-qPCR, immunohistochemistry (IHC), and western blotting demonstrated an upregulation of Pdcd4 mRNA and protein in streptozotocin (STZ)-induced DKD rats, as compared to the control. In addition, IHC and western blotting of a unilateral ureteral obstruction mouse model showed an upregulation of PDCD4 in the disease group, as compared to their respective controls. IHC analysis of kidney biopsy samples of human DKD patients showed an upregulation of PDCD4 compared to the control. Western blotting of the STZ-induced DKD rat tissues displayed a low microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, as compared to the control. It was found that albumin overload in cultured PTECs upregulated the expression of PDCD4 and p62 and decreased the expression of LC3-II and autophagy-related 5 (Atg5) proteins. The knockout of Pdcd4 in cultured PTECs could reduce albumin-induced dysfunctional autophagy, as evidenced by the recovery of Atg5 and LC3-II protein. The forced expression of PDCD4 could further suppress the expression of the crucial autophagy-related gene Atg5. Evidence suggests that endogenous PDCD4 promotes proteinuria-induced dysfunctional autophagy by negatively regulating Atg5. Therefore, PDCD4 may be a potential therapeutic target in DKD.