Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer.

Despite the development of highly effective therapies for the treatment of estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current therapies requires the development of novel therapeutic strategies. Herein, we report the discovery of ERD-1233 as a potent and orally efficacious ERα degrader designed using the PROTAC technology. ERD-1233 was developed based on Lasofoxifene as the ER binding moiety and a novel cereblon ligand through extensive optimization of the linker. ERD-1233 potently and effectively reduces the ERα protein in vitro and achieves excellent oral bioavailability in mice and rats. Oral administration of ERD-1233 effectively reduces ER protein in ER+ tumors and achieves tumor regression in the ER wild-type MCF-7 xenograft tumor model and strong tumor growth inhibition in the ESR1Y537S mutated model in mice. Our data demonstrate that ERD-1233 is a promising ER PROTAC degrader for extensive evaluation as a new therapy for the treatment of ER+ human breast cancer.

In Situ Synthesis of Copper-Based Metal-Organic Frameworks with Ligand Defects for Electrochemical Reduction of CO2 into C2 Products.

Electrochemical reduction of CO2 into high-value-added products is a potential approach to solving environmental problems but is limited by poor product selectivity and low efficiency. Metal-organic framework (MOF) materials have been considered one of the most promising catalysts, but their application is limited by complicated preparation processes, especially during the synthesis of organic ligands. In this work, a new three-dimensional Cu-MOF (JXUST-301) with high porosity was constructed based on the naphthalene diimide (NDI) ligand. Furthermore, JXUST-301 with ligand defects (JXUST-301D) originating from the missing NDI unit was synthesized via an in situ reaction. The presence of ligand defects endows JXUST-301D with a better CO2RR performance with a FEC2 of 56.7% and a jC2 of -162.4 mA cm-2. Mechanistic studies revealed that the hierarchical pore structure and amino sites are created from the absence of the NDI unit, which promotes the exposure of catalytically active sites and CO2 enrichment. Furthermore, the electronic structure of the Cu sites is modulated to upshift the d-band center, facilitating chemical adsorption and activation of key reaction intermediates. This work provides new insight into the in situ preparation of efficient Cu-MOF catalysts by introducing defects for the CO2RR.

UCLN: Toward the Causal Understanding of Brain Disorders With Temporal Lag Dynamics.

Resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a powerful tool for exploring interactions among brain regions. A growing body of research is actively investigating various computational approaches for estimating causal effects among brain regions. Compared to traditional methods, causal relationship reveals the causal influences among distinct brain regions, offering a deeper understanding of brain network dynamics. However, existing methods either neglect the concept of temporal lag across brain regions or set the temporal lag value to a fixed value. To address this limitation, we propose a Unified Causal and Temporal Lag Network (termed UCLN) that jointly learns the causal effects and temporal lag values among brain regions. Our method effectively captures variations in temporal lag between distant brain regions by avoiding the predefined lag value across the entire brain. The brain networks obtained are directed and weighted graphs, enabling a more comprehensive disentanglement of complex interactions. In addition, we also introduce three guiding mechanisms for efficient brain network modeling. The proposed method outperforms state-of-the-art approaches in classification accuracy on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our findings indicate that the method not only achieves superior classification but also successfully identifies crucial neuroimaging biomarkers associated with the disease.

Scalable Fabrication of High-Performance Perovskite Solar Cell Modules by Mediated Vapor Deposition.

Perovskite solar cells (PSCs) can enable renewable electricity generation at low levelized costs, subject to the invention of an economically feasible technology for their large-scale fabrication, like vapor deposition. This approach is effective for the fabrication of small area (<1 cm2) PSCs, but its scale-up to produce high-efficiency larger area modules has been limited by a severe imbalance between the vapor-solid reaction kinetics and the mass-transport of the volatile ammonium salt precursor. In this study, an amidine-based low-dimensional perovskite is introduced as an intermediate of the solid-vapor reaction to help resolve this limitation. This improves reaction pathway produces unique vertically monolithic grains with no detectable horizontal boundaries, which is used to produce 1.0 cm2 PSCs with an efficiency of 22.1%, as well as 12.5 and 48 cm2 modules delivering 21.1% and 20.1% efficiency, respectively. The modules retain ≈85% of their initial performance after 900 h of continuous operation (ISOS-L-1 protocol) and ≈100% after 2800 h of storage in an ambient environment (ISOS-D-1 protocol).

Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function.

The role of gut microbiota (GM) dysbiosis in the pathogenesis of depression has received widespread attention, but the mechanism remains elusive. Corticosterone (CORT)-treated mice showed depression-like behaviors, reduced hippocampal neurogenesis, and altered composition of the GM. Fecal microbial transplantation from CORT-treated mice transferred depression-like phenotypes and their dominant GM to the recipients. Fecal metabolic profiling exposed remarkable increase of gut ceramides in CORT-treated and recipient mice. Oral gavage with Bifidobacterium pseudolongum and Lactobacillus reuteri could induce elevations of gut ceramides in mice. Ceramides-treated mice showed depressive-like phenotypes, significant downregulation of oxidative phosphorylation-associated genes, and hippocampal mitochondrial dysfunction. Our study demonstrated a link between chronic exposure to CORT and its impact on GM composition, which induces ceramides accumulation, ultimately leading to hippocampal mitochondrial dysfunction. This cascade of events plays a critical role in reducing adult hippocampal neurogenesis and is strongly associated with the development of depression-like behaviors.

Sustainable development of fishery resources: Precipitation of protein from surimi rinsing wastewater by low-temperature plasma.

This study aimed to determine the impact of low-temperature plasma (LTP) on the protein stability and composition in surimi rinsing wastewater (SRW). When SRW (300 mL) was treated with LTP at a power of 420 W and a flow rate of 1.1 L/min for 106 s, the protein precipitation was 76.04 %, the pH was close to the estimated value of the isoelectric point (pI). In comparison with the pI precipitation treatment, non-precipitated proteins in the SRW after LTP precipitation treatment showed significant changes in amino acids susceptible to oxidation but had minor changes in the hydrophobic amino acid content. LTP showed a markedly differentiated response to the different protein types in the SRW, increasing the relative amounts of several enzyme proteins in the non-precipitated protein. The combined effect of the active ingredients provided by LTP on protein conformation and hydrophobic interactions may be responsible for this 'screening' phenomenon.

Learnable Brain Connectivity Structures for Identifying Neurological Disorders.

Brain networks/graphs have been widely recognized as powerful and efficient tools for identifying neurological disorders. In recent years, various graph neural network models have been developed to automatically extract features from brain networks. However, a key limitation of these models is that the inputs, namely brain networks/graphs, are constructed using predefined statistical metrics (e.g., Pearson correlation) and are not learnable. The lack of learnability restricts the flexibility of these approaches. While statistically-specific brain networks can be highly effective in recognizing certain diseases, their performance may not exhibit robustness when applied to other types of brain disorders. To address this issue, we propose a novel module called Brain Structure Inference (termed BSI), which can be seamlessly integrated with multiple downstream tasks within a unified framework, enabling end-to-end training. It is highly flexible to learn the most beneficial underlying graph structures directly for specific downstream tasks. The proposed method achieves classification accuracies of 74.83% and 79.18% on two publicly available datasets, respectively. This suggests an improvement of at least 3% over the best-performing existing methods for both tasks. In addition to its excellent performance, the proposed method is highly interpretable, and the results are generally consistent with previous findings.

A Patient With Hepatocellular Carcinoma and Lung Metastasis Successfully Underwent Curative Surgery Following the Downstaging Treatment: A Case Report.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Hepatic resection constitutes the major curative treatment option, but a significant proportion of patients are not surgical candidates on initial evaluation. Along with the development of novel therapeutic strategies including targeted therapies and immunotherapies, a few HCCs can achieve tumor downstaging and be curatively resected. A 52-year-old man was diagnosed with HCC with portal vein invasion and extensive pulmonary and lymph node metastasis. Transarterial chemoembolization (TACE) in conjunction with donafenib and sintilimab was given. Primary tumors in the liver largely shrank with almost complete elimination of the lung metastases following treatment. The patient subsequently underwent curative surgery for HCC, and the pathological examination revealed complete necrosis of the tumor. Targeted immunotherapy was continued after surgery and no disease progression was found on the latest follow-up. Advanced HCC with distant metastasis might have an excellent response to combination therapy of TACE with tyrosine kinase-targeted inhibitors and PD-1 blocker, and achieve opportunity for curative surgery. This efficacy may be associated with the remodeling of immune microenvironment and angiogenesis. HCC is extremely heterogeneous, and the response to therapeutics varies among patients. There is a lack of useful biomarkers to predict therapeutic efficacy, which needs further studies.

Efficient dry reforming of methane realized by photoinduced acceleration of oxygen migration rate.

Methane dry reforming (DRM) can consume greenhouse gases (CH4 and CO2) to produce valuable Fischer-Tropsch syngas (CO and H2). However, conventional thermally driven DRM consume large amounts of energy and face problems such as catalyst sintering and carbon deposition leading to insufficient catalytic activity. In this study, a photothermal synergistic TiO2/CeO2/Ru catalyst with high efficiency was designed. Under the light condition, the yields of H2 and CO reached 496.3 mmol g-1 h-1 and 522.4 mmol g-1 h-1, respectively. In addition, the catalyst demonstrated excellent stability after 100 h cyclic stability test. In-situ X-ray photoelectron spectroscopy (IS-XPS) and density functional theory (DFT) calculations revealed that the heterojunction interface formed by TiO2/CeO2/Ru is favourable for capturing photogenerated electrons and suppressing the recombination rate of photons and holes, thus improving the photocatalytic performance. Furthermore, light-induced metal-to-metal charge transfer (MMCT) accelerated oxygen migration, which not only improved the catalytic activity, but also suppressed the formation of carbon deposits on the catalyst surface, thereby enhancing the cycling stability. This study explores the mechanism of photothermally synergistic DRM, which provides a new pathway for the efficient use of solar energy.

Exploring autism via the retina: Comparative insights in children with autism spectrum disorder and typical development.

Autism spectrum disorder (ASD) is a widely recognized neurodevelopmental disorder, yet the identification of reliable imaging biomarkers for its early diagnosis remains a challenge. Considering the specific manifestations of ASD in the eyes and the interconnectivity between the brain and the eyes, this study investigates ASD through the lens of retinal analysis. We specifically examined differences in the macular region of the retina using optical coherence tomography (OCT)/optical coherence tomography angiography (OCTA) images between children diagnosed with ASD and those with typical development (TD). Our findings present potential novel characteristics of ASD: the thickness of the ellipsoid zone (EZ) with cone photoreceptors was significantly increased in ASD; the large-caliber arteriovenous of the inner retina was significantly reduced in ASD; these changes in the EZ and arteriovenous were more significant in the left eye than in the right eye. These observations of photoreceptor alterations, vascular function changes, and lateralization phenomena in ASD warrant further investigation, and we hope that this work can advance interdisciplinary understanding of ASD.

In-Doped ZnO Electron Transport Layer for High-Efficiency Ultrathin Flexible Organic Solar Cells.

Sol-gel processed zinc oxide (ZnO) is one of the most widely used electron transport layers (ETLs) in inverted organic solar cells (OSCs). The high annealing temperature (≈200 °C) required for sintering to ensure a high electron mobility however results in severe damage to flexible substrates. Thus, flexible organic solar cells based on sol-gel processed ZnO exhibit significantly lower efficiency than rigid devices. In this paper, an indium-doping approach is developed to improve the optoelectronic properties of ZnO layers and reduce the required annealing temperature. Inverted OSCs based on In-doped ZnO (IZO) exhibit a higher efficiency than those based on ZnO for a range of different active layer systems. For the PM6:L8-BO system, the efficiency increases from 17.0% for the pristine ZnO-based device to 17.8% for the IZO-based device. The IZO-based device with an active layer of PM6:L8-BO:BTP-eC9 exhibits an even higher efficiency of up to 18.1%. In addition, a 1.2-micrometer-thick inverted ultrathin flexible organic solar cell is fabricated based on the IZO ETL that achieves an efficiency of 17.0% with a power-per-weight ratio of 40.4 W g-1, which is one of the highest efficiency for ultrathin (less than 10 micrometers) flexible organic solar cells.

Single-cell RNA sequencing reveals the heterogeneity and interactions of immune cells and Müller glia during zebrafish retina regeneration.

ABSTRACT: Inflammation plays a crucial role in the regeneration of fish and avian retinas. However, how inflammation regulates Müller glia (MG) reprogramming remains unclear. Here, we used single-cell RNA sequencing to investigate the cell heterogeneity and interactions of MG and immune cells in the regenerating zebrafish retina. We first showed that two types of quiescent MG (resting MG1 and MG2) reside in the uninjured retina. Following retinal injury, resting MG1 transitioned into an activated state expressing known reprogramming genes, while resting MG2 gave rise to rod progenitors. We further showed that retinal microglia can be categorized into three subtypes (microglia-1, microglia-2, and proliferative) and pseudotime analysis demonstrated dynamic changes in microglial status following retinal injury. Analysis of cell-cell interactions indicated extensive crosstalk between immune cells and MG, with many interactions shared among different immune cell types. Finally, we showed that inflammation activated Jak1-Stat3 signaling in MG, promoting their transition from a resting to an activated state. Our study reveals the cell heterogeneity and crosstalk of immune cells and MG in zebrafish retinal repair, and may provide valuable insights into future mammalian retina regeneration.

Effect of sodium metabisulfite-mediated self-assembly on the quality of silver carp myofibrillar protein-EGCG composite gels.

Myofibrillar protein (MP) gels are susceptible to oxidation, which can be prevented by complexing with hydrophilic polyphenols, but may cause gel deterioration. Sodium metabisulfite (Na2S2O5) has been used to induce self-assembly of MP and analyze the impact of self-assembly on the quality of composite gels containing high amounts of (-)-epigallocatechin gallate (EGCG). Hydrophobic forces were confirmed as the main driver of self-assembly. Self-assembly reduced the size of the MP-EGCG complex to approximately 670 nm and increased the gel's hydrophobic force by approximately 3.6-fold. The maximum hardness of the Na2S2O5-treated MP-EGCG composite gel was 52.43 g/kg, which was approximately 49% greater than pure MP gel. After oxidative treatment, the Na2S2O5-treated MP-EGCG composite gel had considerably lower carbonyl and dityrosine levels (2.47-µmol/g protein and 450 a.u.) than the control (8.37-µmol/g protein and 964 a.u.). Therefore, Na2S2O5 shows potential as a cost-effective additive for alleviating MP limitations in the food industry.

Transcriptomic profiling across human serotonin neuron differentiation via the FEV reporter system.

BACKGROUND: The detailed transcriptomic profiles during human serotonin neuron (SN) differentiation remain elusive. The establishment of a reporter system based on SN terminal selector holds promise to produce highly-purified cells with an early serotonergic fate and help elucidate the molecular events during human SN development process. METHODS: A fifth Ewing variant (FEV)-EGFP reporter system was established by CRISPR/Cas9 technology to indicate SN since postmitotic stage. FACS was performed to purify SN from the heterogeneous cell populations. RNA-sequencing analysis was performed for cells at four key stages of differentiation (pluripotent stem cells, serotonergic neural progenitors, purified postmitotic SN and purifed mature SN) to explore the transcriptomic dynamics during SN differentiation. RESULTS: We found that human serotonergic fate specification may commence as early as day 21 of differentiation from human pluripotent stem cells. Furthermore, the transcriptional factors ZIC1, HOXA2 and MSX2 were identified as the hub genes responsible for orchestrating serotonergic fate determination. CONCLUSIONS: For the first time, we exposed the developmental transcriptomic profiles of human SN via FEV reporter system, which will further our understanding for the development process of human SN.

Ordered Perovskite Structure with Functional Units for High Performance and Stable Solar Cells.

Ion migration is one of the most critical challenges that affects the stability of metal-halide perovskite solar cells (PSCs). However, the current arsenal of available strategies for solving this issue is limited. Here, novel perovskite active layers following the concept of ordered structures with functional units (OSFU) to intrinsically suppress ion migration, in which a three-dimensional (3D) perovskite layer is deposited by vapor deposition for light absorption and a 2D layer is deposited by solution process for ion inhibition, are constructed. As a promising result, the activation energy of ion migration increases from 0.36 eV for the conventional perovskite to 0.54 eV for the OSFU perovskite. These devices exhibit substantially enhanced operational stability in comparison with the conventional ones, retaining >85% of their initial efficiencies after 1200 h under ISOS-L-1. Moreover, the OSFU devices show negligible fatigue behavior with a robust performance under light/dark cycling aging test (ISOS-LC-1 protocol), which demonstrates the promising application of functional motif theory in this field.

Facile preparation of a water-based antireflective SiO2 film with high transmittance for perovskite solar cells.

The synthesis of anti-reflective (AR) films has been increasingly focused on environmental friendliness and cost efficiency in order to realize green and sustainable development. Herein, a novel strategy for preparing a nanoporous SiO2 AR film with high transmittance by a sol-gel process is proposed based on a sodium silicate aqueous solution. Sodium ions in the as-prepared SiO2 AR film can be effectively removed by a facile washing process, and thus its refractive index can be regulated. Moreover, the pH value of the sol has a huge effect on the structure and properties of the SiO2 AR film. As a result, the AR film exhibited a high transmittance increase of 4.10% at 550 nm and an average transmittance increase by 3.51% in the wavelength range of 380-1100 nm compared with blank glass. In addition, the obtained water-based SiO2 AR film exhibited hydrophilicity and the water contact angle (WCA) can be regulated from 61° to 8.4°. When the AR film was applied to the upper surface of perovskite solar cells, the photoelectric conversion efficiency (PCE) revealed an improvement of 1.44% compared with the PCE of perovskite solar cells without the AR film. Therefore, this work can provide a facile and effective method to prepare water-based antireflective films with high transmittance for solar cells.

Two-Dimensional SnS Mediates NiFe-LDH-Layered Electrocatalyst toward Boosting OER Activity for Water Splitting.

NiFe-layered double hydroxides (NiFe-LDHs), as promising electrocatalysts, have received significant research attention for hydrogen and oxygen generation through water splitting. However, the slow oxidation kinetics of NiFe-LDH, due to the limited number of active sites and the low conductivity, hinders the improvement of the water-splitting efficiency. Therefore, to overcome the obstacles, two-dimensional (2D) SnS was first explored to tailor the prepared NiFe-LDH via the hydrothermal method. A NiFe-LDH/SnS heterojunction is built, which is observed from the microstructural investigations. SnS incorporation could greatly improve the conductivity of the NiFe-LDH sheets, which was reflected by the reduced charge transfer resistance. Moreover, SnS layers modulated the electronic environment around the active sites, favoring the adsorption of intermediates during the oxygen evolution reaction (OER) process, which was verified by density functional theory calculations. A synergistic effect induced by the NiFe-LDH/SnS heterostructure promoted the OER activities in electrical, electronic, and energetic aspects. Consequently, the as-prepared NiFe-LDH/SnS electrocatalyst greatly improved the electrocatalytic performance, exhibiting 20% and 27% reductions in the overpotential and Tafel slope compared with those of pristine NiFe-LDH, respectively. The results provide a strategy for regulating NiFe-based electrocatalysts by using emerging 2D materials to enhance water-splitting efficiency.

Enhancing the Quality of Low-Salt Silver Carp (Hypophthalmichthys molitrix) Surimi Gel Using Psyllium Husk Powder: An Orthogonal Experimental Approach.

Low-salt surimi production is crucial as it addresses health concerns related to sodium intake while maintaining the quality and shelf-life of seafood products. This research focused on optimizing the gelation conditions for silver carp surimi with the addition of psyllium husk powder at low salt concentrations (0.5% and 1%, w/w) to investigate the effects of psyllium husk powder concentration, temperature, and time on gel strength and water-holding capacity. The quality was assessed in terms of gel strength and water-holding capacity. Following a single-factor exploration, a three-level orthogonal experiment was designed to evaluate the influence of these three variables using a combined scoring system. Results indicated that psyllium husk powder levels between 0.1% and 0.3% (w/w) enhanced gel strength and water-holding capacity. The optimal conditions were identified as follows: 1% (w/w) NaCl with 0.2% (w/w) psyllium husk powder for 2.5 h at 35 °C, and 0.5% (w/w) NaCl with 0.3% (w/w) psyllium husk powder for 3 h at 35 °C. Texture profile analysis revealed that psyllium husk powder increased the hardness of the surimi gel, promoting myosin cross-linking and denser gel structure. Compared to traditional surimi gel, which relies on ionic bonds, the optimized gel showed higher levels of disulfide cross-linking and enhanced hydrophobic interactions, resulting in a stronger gel structure. Sensory evaluation suggested that surimi gels with psyllium husk powder were perceived as better than those without psyllium husk powder. The study concludes that selecting the appropriate psyllium husk powder quantity and thermal processing conditions based on salt concentration can significantly improve the quality of low-salt surimi gels. Error analysis using one-way ANOVA was performed on all experimental data and (p < 0.05) indicated the significant difference.

Qubit Count Reduction by Orthogonally Constrained Orbital Optimization for Variational Quantum Excited-State Solvers.

We propose a state-averaged orbital optimization scheme for improving the accuracy of excited states of the electronic structure Hamiltonian for use on near-term quantum computers. Instead of parameterizing the orbital rotation operator in the conventional fashion as an exponential of an antihermitian matrix, we parameterize the orbital rotation as a general partial unitary matrix. Whereas conventional orbital optimization methods minimize the state-averaged energy using successive Newton steps of the second-order Taylor expansion of the energy, the method presented here optimizes the state-averaged energy using an orthogonally constrained gradient projection method that does not require any expansion approximations. Through extensive benchmarking of the method on various small molecular systems, we find that the method is capable of producing more accurate results than fixed basis FCI while simultaneously using fewer qubits. In particular, we show that for H2, the method is capable of matching the accuracy of FCI in the cc-pVTZ basis (56 qubits) while only using 14 qubits.

Evolution analysis of low-carbon cooperation of service providers based on Moran process in cloud manufacturing.

Low-carbon cooperation among cloud manufacturing service providers is one way to achieve carbon peak and neutrality. Such cooperation is related to the benefits to service providers adopting low-carbon strategies and stochastic factors such as government low-carbon policies, providers' environmental awareness, and demanders' low-carbon preferences. Focusing on the evolutionary process of service providers' low-carbon strategy selection under uncertain factors, a stochastic evolutionary game model is constructed based on the Moran process, and the equilibrium conditions for low-carbon cooperation among providers are analyzed under benefit-dominated and stochastic factor-dominated situations. Through numerical simulation, the effects of the cloud platform's cost-sharing coefficient for low-carbon investment, matching growth rate, carbon trading price, and group size on providers' low-carbon strategy evolution are analyzed. The research results show that increasing the cloud platform's low-carbon cost-sharing, carbon trading price, and group size can promote low-carbon cooperation among service providers. With greater low-carbon investment costs and greater stochastic factor interference, the providers' enthusiasm for low-carbon cooperation decreases. This study fills the research gap in the low-carbon cooperation evolution of cloud manufacturing providers based on the stochastic evolutionary game and provides decision-making suggestions for governments and cloud platforms to encourage provider participation in low-carbon cooperation and for providers to adopt low-carbon strategies.