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Aberrations in the Hedgehog (Hh) signaling pathway are significantly prevailed in various cancers, including B-cell lymphoma. A critical facet of Hh signal transduction involves the dynamic regulation of the suppressor of fused homolog (SUFU)-glioma-associated oncogene homolog (GLI) complex within the kinesin family member 7 (KIF7)-supported ciliary tip compartment. However, the specific post-translational modifications of SUFU-GLI complex within this context have remained largely unexplored. Our study reveals a novel regulatory mechanism involving prolyl 4-hydroxylase 2 (P4HA2), which forms a complex with KIF7 and is essential for signal transduction of Hh pathway. We demonstrate that, upon Hh pathway activation, P4HA2 relocates alongside KIF7 to the ciliary tip. Here, it hydroxylates SUFU to inhibit its function, thus amplifying the Hh signaling. Moreover, the absence of P4HA2 significantly impedes B lymphoma progression. This effect can be attributed to the suppression of Hh signaling in stromal fibroblasts, resulting in decreased growth factors essential for malignant proliferation of B lymphoma cells. Our findings highlight the role of P4HA2-mediated hydroxylation in modulating Hh signaling and propose a novel stromal-targeted therapeutic strategy for B-cell lymphoma.

The applications of amino acid-based polymers are impeded by their limited structure and functions. Herein, a small library of methionine-based polymers (Met-P) with programmed structure and reactive oxygen species (ROS)-responsive properties is developed for tumor therapy. The Met-P can self-assemble into sub-100 nm nanoparticles (NPs) and effectively load anticancer drugs (such as paclitaxel (PTX) (P@Met-P NPs)) via the nanoprecipitation method. The screened NPs with superior stability and high drug loading are further evaluated in vitro and in vivo. When encountering with ROS, the Met-P polymers will be oxidized and then switch from a hydrophobic to a hydrophilic state, triggering the rapid and self-accelerated release of PTX. The in vivo results indicated that the screened P@2Met10 NPs possessed significant anticancer performance and effectively alleviated the side effects of PTX. More interestingly, the blank 2Met10 NPs displayed an obvious self-tumor inhibiting efficacy. Furthermore, the other Met-P NPs (such as 2Met8, 4Met8, and 4Met10) are also found to exhibit varied self-anti-cancer capabilities. Overall, this ROS-responsive Met-P library is a rare anticancer platform with hydrophobic/hydrophilic switching, controlled drug release, and self-anticancer therapy capability. © 2024 Wiley-VCH GmbH.

Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment, and more effective treatments are urgently required. Recent studies have reported that targeted inhibition of the transcription factor cyclin dependent kinase 7 (CDK7) could effectively suppress prostate cancer progression. However, the toxicity of CDK7 inhibitors such as THZ1 is the main limitation of the clinical application. In this work, we synthesized Cys8E (C8E) nanoparticles (NPs) loaded with THZ1 (C8E@THZ1), a novel GSH-targeting and stimuli-responsive nano-delivery platform, and investigated its anti-tumor potential and biosafety properties. In vitro, C8E@THZ1 potently inhibited the proliferation and promoted the apoptosis of prostate cancer cells. On tumor-bearing mice, C8E@THZ1 inhibited tumors by up to 85%, while the damage of THZ1 to liver function was effectively avoided. These results confirmed that inhibition of CDK7 can effectively block the progression of prostate cancer, and that Cys8E NPs is a highly prospective delivery platform to promote the clinical application of CDK7 inhibitors. © 2024

Prostate cancer (PCa) with a high incidence worldwide is a serious threat to men’s health. Despite the continuous development of treatment strategies for PCa in recent years, the long-term prognosis of patients is still poor. Hence, the discovery and development of novel, secure, and efficient therapeutic approaches hold significant clinical significance. Although sorafenib (SOR) displays potential as a therapeutic option for PCa, its clinical efficacy is hindered by drug resistance, limited water solubility, and rapid metabolism. Therefore, we proposed to prepare nanoparticles (named SOR@8P4 NPs) utilizing the phenylalanine-based poly(ester amide) polymer (8P4) as the drug carrier to enhance the solubility and drug stability of SOR and improve the therapeutic targeting and bioavailability. SOR@8P4 NPs had high stability and showed acid-responsive drug release at the acidic tumor microenvironment. Additionally, SOR@8P4 NPs demonstrated more remarkable anticancer, antimetastatic, and antiproliferative abilities in vitro, compared with those of free drugs. SOR@8P4 NPs showed high tumor targeting and significantly inhibited tumor growth in vivo. In summary, the drug delivery system of SOR@8P4 NPs provides new ideas for the clinical treatment of PCa. © 2024 American Chemical Society.

A formal [4+2] cycloaddition reaction of ethynylethylene carbonates and 2-aminophenols has been developed for the synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazines bearing quaternary carbon atoms. The reaction features mild reaction conditions, good functional group compatibility and good yields. Furthermore, when using chiral PyBox ligand, this strategy could also achieve the asymmetric synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazines. Application studies indicated that the hydroxymethyl group of final products was an excellent functional group that can be further modified easily. © 2024 Wiley-VCH GmbH.

Despite the enormous developments in the asymmetric transformations of indole imine methides (IIMs), the remote asymmetric induction involving IIMs remains challenging due to the spatial interaction requirement between the substrate and catalyst. Herein we report the first catalytic asymmetric nucleophilic addition to indole imine 5-methide (5-IIM), the only topological isomer of IIMs whose asymmetric addition remains unknown. Despite the challenging remote stereocontrol, high efficiency and respectable enantioselectivity were achieved to provide access to a range of enantioenriched indole-containing triaryl alkanes. © 2024 American Chemical Society.

Revealing the oxidation behavior of superalloys is crucial for optimizing material properties and extending service life. This study investigated the oxidation behavior of superalloy GH4738 under stress states at 850 degrees C. High-throughput specimens were fabricated to withstand different stresses at the same time. Isothermal oxidation samples were analyzed using the mass gain method to obtain oxidation kinetic curves. The results show that the external stress below 200 MPa could improve the oxidation resistance of the GH4738. With tensile stress increasing, the oxide layer becomes thinner, denser and more complete, while internal oxidation decreases. The tensile stress alters the structure of the external oxide layer from a two-layer to a three-layer configuration. The Cr2O3 oxide layer inhibits the outward diffusion of Ti, leading to Ti enrichment at the oxide-matrix interface and altering the oxidation mechanism of GH4738., Funding Agencies|Shandong Provincial Natural Science Foundation for Youths; National Key R&D Program of China [2021YFB3700401]; Zhejiang Provincial Natural Science Foundation [LQ21E030002]; Youth Innovation team Project of Higher Education Institutions in Shandong Province [2022KJ272]; [ZR2022QE234]

The coalescence of stellar-mass primordial black holes (PBHs) might explain some of the gravitation waves (GWs) events detected by LIGO-Virgo-KAGRA. On the other hand, observational hints for supermassive PBHs (SMPBHs) have been accumulated. Thus it can be expected that stellar-mass PBHs might be gravitationally bounded to SMPBHs ($\sim10^{6}-10^9M_\odot$) in the early Universe, and both constituted primordial extreme mass-ratio inspirals (EMRIs). In this work, we initiate the study of the merger rate for primordial EMRIs. The corresponding intrinsic EMRI rate at low redshift may be comparable to that of astrophysical model, $10-10^4$yr$^{-1}$, which the space-based detector LISA has the capability to detect, but significantly raises with redshift. Though equal mass binaries also inevitably form, we find that under certain conditions the primordial EMRIs can be the most prevalent GW sources, and thus potentially a new probe to PBH., Comment: 23 pages, 6 figures

Qian-Qian Liao,1,* Yan-Ju Mo,2,* Ke-Wei Zhu,3,4,* Feng Gao,2 Bin Huang,2 Peng Chen,4 Feng-Tian Jing,5 Xuan Jiang,6 Hong-Zhen Xu,1 Yan-Feng Tang,7 Li-Wei Chu,8 Hai-Ling Huang,1 Wen-Li Wang,8 Fang-Ning Wei,9 Dan-Dan Huang,9 Bin-Jing Zhao,9 Jia Chen,9 Hao Zhang1 1Department of Pharmacy, People’s Hospital of Guilin, Guilin, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, People’s Hospital of Guilin, Guilin, People’s Republic of China; 3GuangZhou BaiYunShan Pharmaceutical Holdings CO.,LTD. BaiYunShan Pharmaceutical General Factory, Guangzhou, People’s Republic of China; 4Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 5Department of Respiratory Medicine, Xing An County People’ Hospital, Guilin, People’s Republic of China; 6Department of Hospital Infection Management, People’s Hospital of Guilin, Guilin, People’s Republic of China; 7Department of Geriatrics, People’s Hospital of Guilin, Guilin, People’s Republic of China; 8Department of Laboratory Medicine, People’s Hospital of Guilin, Guilin, People’s Republic of China; 9School of Clinical Pharmacy, Guilin Medical University, Guilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke-Wei Zhu, GuangZhou BaiYunShan Pharmaceutical Holdings CO.,LTD. BaiYunShan Pharmaceutical General Factory, No. 88 Yunxiang Road Tonghe Street, Baiyun District, Guangzhou, Guangdong Province, 510515, People’s Republic of China, Tel +86-020-87062636, Fax +86-020-87095309, Email zhukew2018@outlook.comPurpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD

This report investigates the mechanism of photochemical Povarov-type reactions of N,N-dialkylanilines and maleimides in polar solvents (DMF or dioxane) in the presence of light. Fundamental aspects of the electron donor-acceptor (EDA) photoactivation pathway proposed to underpin this chemistry are examined through integrated experimental and computational studies. This approach provided evidence supporting the involvement of an EDA complex in facilitating this chemistry via a reaction mechanism that does not involve a triplet manifold. Most notably, our findings indicate that relying solely on UV-vis absorption spectroscopic data to either account for or predict reactivity in synthetic experiments may not always provide the complete picture. More specifically, this relates to considering UV-vis absorption spectroscopic data, calculated values for association constants (K-EDA) and molar extinction coefficients (epsilon), with the reactivity observed in associated synthetic reactions in practice.

Demonstrated here is an asymmetric nucleophilic addition via primary activation of para-quinone methides (p-QMs) based on a chiral phosphoric acid catalytic system. In sharp contrast to previous CPA-based bifunctional activation processes that all required the nucleophiles to have an effective hydrogen bond donor unit (e.g., OH, NH), here no such unit is required in the nucleophile. N-protected indole nucleophiles were successfully utilized for the synthesis of chiral tetraarylmethanes with high efficiency and enantioselectivity under mild conditions. Therefore, this protocol significantly expanded the scope of asymmetric transformations of p-QMs. © 2024 The Royal Society of Chemistry.

Recent advances in representation learning have demonstrated the significance of multimodal alignment. The Dual Cross-modal Information Disentanglement (DCID) model, utilizing a unified codebook, shows promising results in achieving fine-grained representation and cross-modal generalization. However, it is still hindered by equal treatment of all channels and neglect of minor event information, resulting in interference from irrelevant channels and limited performance in fine-grained tasks. Thus, in this work, We propose a Training-free Optimization of Codebook (TOC) method to enhance model performance by selecting important channels in the unified space without retraining. Additionally, we introduce the Hierarchical Dual Cross-modal Information Disentanglement (H-DCID) approach to extend information separation and alignment to two levels, capturing more cross-modal details. The experiment results demonstrate significant improvements across various downstream tasks, with TOC contributing to an average improvement of 1.70% for DCID on four tasks, and H-DCID surpassing DCID by an average of 3.64%. The combination of TOC and H-DCID further enhances performance, exceeding DCID by 4.43%. These findings highlight the effectiveness of our methods in facilitating robust and nuanced cross-modal learning, opening avenues for future enhancements. The source code and pre-trained models can be accessed at https://github.com/haihuangcode/TOC_H-DCID.

In the field of large language models (LLMs), aligning models with the diverse preferences of users is a critical challenge. Direct Preference Optimization (DPO) has played a key role in this area. It works by using pairs of preferences derived from the same prompts, and it functions without needing an additional reward model. However, DPO does not fully reflect the complex nature of human learning, which often involves understanding contrasting responses to not only identical but also similar questions. To overcome this shortfall, we propose Relative Preference Optimization (RPO). RPO is designed to discern between more and less preferred responses derived from both identical and related prompts. It introduces a contrastive weighting mechanism, enabling the tuning of LLMs using a broader range of preference data, including both paired and unpaired sets. This approach expands the learning capabilities of the model, allowing it to leverage insights from a more varied set of prompts. Through empirical tests, including dialogue and summarization tasks, and evaluations using the AlpacaEval2.0 leaderboard, RPO has demonstrated a superior ability to align LLMs with user preferences and to improve their adaptability during the training process. Our code can be viewed at https://github.com/yinyueqin/relative-preference-optimization

In this paper, we present ControlSpeech, a text-to-speech (TTS) system capable of fully cloning the speaker's voice and enabling arbitrary control and adjustment of speaking style, merely based on a few seconds of audio prompt and a simple textual style description prompt. Prior zero-shot TTS models and controllable TTS models either could only mimic the speaker's voice without further control and adjustment capabilities or were unrelated to speaker-specific voice generation. Therefore, ControlSpeech focuses on a more challenging new task-a TTS system with controllable timbre, content, and style at the same time. ControlSpeech takes speech prompts, content prompts, and style prompts as inputs and utilizes bidirectional attention and mask-based parallel decoding to capture corresponding codec representations in a discrete decoupling codec space. Moreover, we discovered the issue of text style controllability in a many-to-many mapping fashion and proposed the Style Mixture Semantic Density (SMSD) model to resolve this problem. SMSD module which is based on Gaussian mixture density networks, is designed to enhance the fine-grained partitioning and sampling capabilities of style semantic information and generate speech with more diverse styles. In terms of experiments, we make available a controllable model toolkit called ControlToolkit with a new style controllable dataset, some replicated baseline models and propose new metrics to evaluate both the control capability and the quality of generated audio in ControlSpeech. The relevant ablation studies validate the necessity of each component in ControlSpeech is necessary. We hope that ControlSpeech can establish the next foundation paradigm of controllable speech synthesis. The relevant code and demo are available at https://github.com/jishengpeng/ControlSpeech .

Diffusion-based text-to-image generation models trained on extensive text-image pairs have shown the capacity to generate photorealistic images consistent with textual descriptions. However, a significant limitation of these models is their slow sample generation, which requires iterative refinement through the same network. In this paper, we enhance Score identity Distillation (SiD) by developing long and short classifier-free guidance (LSG) to efficiently distill pretrained Stable Diffusion models without using real training data. SiD aims to optimize a model-based explicit score matching loss, utilizing a score-identity-based approximation alongside the proposed LSG for practical computation. By training exclusively with fake images synthesized with its one-step generator, SiD equipped with LSG rapidly improves FID and CLIP scores, achieving state-of-the-art FID performance while maintaining a competitive CLIP score. Specifically, its data-free distillation of Stable Diffusion 1.5 achieves a record low FID of 8.15 on the COCO-2014 validation set, with a CLIP score of 0.304 at an LSG scale of 1.5, and a FID of 9.56 with a CLIP score of 0.313 at an LSG scale of 2. We will make our PyTorch implementation and distilled Stable Diffusion one-step generators available at https://github.com/mingyuanzhou/SiD-LSG

Deep clustering as an important branch of unsupervised representation learning focuses on embedding semantically similar samples into the identical feature space. This core demand inspires the exploration of contrastive learning and subspace clustering. However, these solutions always rely on the basic assumption that there are sufficient and category-balanced samples for generating valid high-level representation. This hypothesis actually is too strict to be satisfied for real-world applications. To overcome such a challenge, the natural strategy is utilizing generative models to augment considerable instances. How to use these novel samples to effectively fulfill clustering performance improvement is still difficult and under-explored. In this paper, we propose a novel Generative Calibration Clustering (GCC) method to delicately incorporate feature learning and augmentation into clustering procedure. First, we develop a discriminative feature alignment mechanism to discover intrinsic relationship across real and generated samples. Second, we design a self-supervised metric learning to generate more reliable cluster assignment to boost the conditional diffusion generation. Extensive experimental results on three benchmarks validate the effectiveness and advantage of our proposed method over the state-of-the-art methods.

We introduce Score identity Distillation (SiD), an innovative data-free method that distills the generative capabilities of pretrained diffusion models into a single-step generator. SiD not only facilitates an exponentially fast reduction in Fr\'echet inception distance (FID) during distillation but also approaches or even exceeds the FID performance of the original teacher diffusion models. By reformulating forward diffusion processes as semi-implicit distributions, we leverage three score-related identities to create an innovative loss mechanism. This mechanism achieves rapid FID reduction by training the generator using its own synthesized images, eliminating the need for real data or reverse-diffusion-based generation, all accomplished within significantly shortened generation time. Upon evaluation across four benchmark datasets, the SiD algorithm demonstrates high iteration efficiency during distillation and surpasses competing distillation approaches, whether they are one-step or few-step, data-free, or dependent on training data, in terms of generation quality. This achievement not only redefines the benchmarks for efficiency and effectiveness in diffusion distillation but also in the broader field of diffusion-based generation. The PyTorch implementation is available at https://github.com/mingyuanzhou/SiD, Comment: ICML 2024, PyTorch implementation: https://github.com/mingyuanzhou/SiD

Graph Transformer, due to its global attention mechanism, has emerged as a new tool in dealing with graph-structured data. It is well recognized that the global attention mechanism considers a wider receptive field in a fully connected graph, leading many to believe that useful information can be extracted from all the nodes. In this paper, we challenge this belief: does the globalizing property always benefit Graph Transformers? We reveal the over-globalizing problem in Graph Transformer by presenting both empirical evidence and theoretical analysis, i.e., the current attention mechanism overly focuses on those distant nodes, while the near nodes, which actually contain most of the useful information, are relatively weakened. Then we propose a novel Bi-Level Global Graph Transformer with Collaborative Training (CoBFormer), including the inter-cluster and intra-cluster Transformers, to prevent the over-globalizing problem while keeping the ability to extract valuable information from distant nodes. Moreover, the collaborative training is proposed to improve the model's generalization ability with a theoretical guarantee. Extensive experiments on various graphs well validate the effectiveness of our proposed CoBFormer., Comment: Accepted by ICML 2024 (Camera-Ready)

AIMS: More than one-third of type 2 long QT syndrome (LQT2) patients carry KCNH2 non-missense variants that can result in haploinsufficiency (HI), leading to mechanistic loss-of-function. However, their clinical phenotypes have not been fully investigated. The remaining two-thirds of patients harbour missense variants, and past studies uncovered that most of these variants cause trafficking deficiency, resulting in different functional changes: either HI or dominant-negative (DN) effects. In this study, we examined the impact of altered molecular mechanisms on clinical outcomes in LQT2 patients. METHODS AND RESULTS: We included 429 LQT2 patients (234 probands) carrying a rare KCNH2 variant from our patient cohort undergoing genetic testing. Non-missense variants showed shorter corrected QT (QTc) and less arrhythmic events (AEs) than missense variants. We found that 40% of missense variants in this study were previously reported as HI or DN. Non-missense and HI-groups had similar phenotypes, while both exhibited shorter QTc and less AEs than the DN-group. Based on previous work, we predicted the functional change of the unreported variants-whether they cause HI or DN via altered functional domains-and stratified them as predicted HI (pHI)- or pDN-group. The pHI-group including non-missense variants exhibited milder phenotypes compared to the pDN-group. Multivariable Cox model showed that the functional change was an independent risk of AEs (P = 0.005). CONCLUSION: Stratification based on molecular biological studies enables us to better predict clinical outcomes in the patients with LQT2.

Fermented milk is consumed worldwide because of its nutritious and healthful qualities. Although it is somewhat sour, causing some to dislike it, few studies have examined taste aspects of its ingredients. Wild-type mice and T1R3-GFP-KO mice lacking sweet/umami receptors were tested with various taste components (sucrose, galactose, lactose, galacto-oligosaccharides, fructo-oligosaccharides, l- and d-lactic acid) using 48 h two-bottle tests and short-term lick tests. d-lactic acid levels were measured after the ingestion of d- or; l-lactic acid or water to evaluate d-lactic acidosis. In wild-type mice, for the sweet ingredients the number of licks increased in a concentration-dependent manner, but avoidance was observed at higher concentrations in 48 h two-bottle tests; the sour ingredients d- and l-lactic acid showed concentration-dependent decreases in preference in both short- and long-term tests. In 48 h two-bottle tests comparing d- and l-lactic acid, wild-type but not T1R3-GFP-KO mice showed higher drinking rates for l-lactic acid. d-lactic acidosis did not occur and thus did not contribute to this preference. These results suggest that intake in short-term lick tests varied by preference for each ingredient, whereas intake variation in long-term lick tests reflects postingestive effects. l-lactic acid may have some palatable taste in addition to sour taste.

The introduction of vehicle automation, shared mobility, and vehicle electrification will bring about changes in urban transportation, land use, energy, and the environment. The accurate estimation of these effects is therefore essential for sustainable urban development. However, existing research on estimating the energy and environmental effects of shared autonomous electric vehicles generally ignores the interaction between land-use and transportation systems. This study, therefore, analyzes the long-term effects of shared autonomous vehicles (SAVs) from the perspective of land use and transportation integration. Different SAV pricing scenarios are also developed to explore the optimal pricing strategy for low carbon–oriented SAVs. Moreover, the study has further assessed the effect of vehicle electrification on vehicle emissions and energy consumption. The results have shown a nonlinear relationship between SAV fares and their transportation, land-use, energy, and environmental effects. Under an appropriate pricing strategy, SAV deployment could reduce PM2.5 emission and energy consumption by 56–64% and 53–61%, respectively. With the further introduction of vehicle electrification, these can rise to 76% and 74%.

Fermented milk is consumed worldwide because of its nutritious and healthful qualities. Although it is somewhat sour, causing some to dislike it, few studies have examined taste aspects of its ingredients. Wild-type mice and T1R3-GFP-KO mice lacking sweet/umami receptors were tested with various taste components (sucrose, galactose, lactose, galacto-oligosaccharides, fructo-oligosaccharides, l- and d-lactic acid) using 48 h two-bottle tests and short-term lick tests. d-lactic acid levels were measured after the ingestion of d- or; l-lactic acid or water to evaluate d-lactic acidosis. In wild-type mice, for the sweet ingredients the number of licks increased in a concentration-dependent manner, but avoidance was observed at higher concentrations in 48 h two-bottle tests; the sour ingredients d- and l-lactic acid showed concentration-dependent decreases in preference in both short- and long-term tests. In 48 h two-bottle tests comparing d- and l-lactic acid, wild-type but not T1R3-GFP-KO mice showed higher drinking rates for l-lactic acid. d-lactic acidosis did not occur and thus did not contribute to this preference. These results suggest that intake in short-term lick tests varied by preference for each ingredient, whereas intake variation in long-term lick tests reflects postingestive effects. l-lactic acid may have some palatable taste in addition to sour taste.

The construction of medium-sized ring compounds has been a prominent research area in synthetic chemistry. In this study, we developed a tandem strategy that combines allylic amination and ring-opening of oxetanes to synthesize medium-sized heterocycles. Specifically, N-aryl oxetan-3-amines undergo allylic amination with zwitterionic pi-allylpalladium, followed by intramolecular ring-opening, resulting in the formation of medium-sized heterocycles. Notably, we are able to achieve the synthesis of 7-8 membered heterocycles with moderate to good yields by employing different types of zwitterionic pi-allylpalladium species. In this study, a tandem strategy has been developed for the synthesis of medium-sized heterocycles from oxetanes through the allylic amination/ring-opening of oxetanes.

Based on a halopalladation strategy, we successfully developed a haloesterification reaction of propargylic amides to synthesize a diverse range of 5-(halomethylene)oxazolidine-2,4-diones. This reaction demonstrates good yield and compatibility with various functional groups. Notably, the halogen atoms present in the resulting products can be readily substituted by other functional groups, highlighting the versatility and appeal of this method. Additionally, we have achieved the successful cyclizative dimerization of propargylic amides to produce bisoxazolidine-2,4-dione derivatives. Based on a halopalladation strategy, we successfully developed a haloesterification reaction of propargylic amides to synthesize a diverse range of 5-(halomethylene)oxazolidine-2,4-diones.

Direct arylation of the benzylic C-(sp(3))-H bond is one of the most straightforward strategies for the construction of multi-aryl methanes, owing to the extraordinary step and atom economy. In this paper, we developed the first metal-free arylation of the C-(sp(3))-H bond in 3-methylindoles, thereby providing rapid access to a range of diaryl- and triarylmethanes with two indole rings. Mechanistically, 3-indole imine methide serves as the key intermediate. Water plays a crucial role in this process, likely serving as a proton shuttle to facilitate the key 1,3-proton transfer step in this reaction and, thus, enhance the reaction efficiency.

Recently, observational hints for supermassive black holes have been accumulating, which has inspired ones to wonder: Can primordial black holes (PBHs) be supermassive, in particular with the mass $M\gtrsim 10^{9}M_\odot$? A supercritical bubble (with an inflating baby universe inside it) that nucleated during inflation can develop into a PBH in our observable Universe. Here, we find that when the inflaton slowly passes by a neighboring vacuum, the nucleating rate of supercritical bubbles would inevitably attain a peak, so the mass distribution of multiverse PBHs, and the mass of peak can be up to $M\gtrsim 10^{11}M_\odot$. Thus our mechanism naturally provides a primordial origin of supermassive BHs., Comment: 15 pages, 4 figures

Oral delivery of proteins has opened a new perspective for the treatment of different diseases. However, advances of oral protein formulation are usually hindered by protein susceptibility and suboptimal absorption in the gastrointestinal tract (GIT). Polymeric nano drug delivery systems are considered revolutionary candidates to solve these issues, which can be preferably tunable against specific delivery challenges. Herein, a tailored family of lysine-based poly(ester amide)s (Lys-aaPEAs) is designed as a general oral protein delivery platform for efficient protein loading and protection from degradation. Insulin, as a model protein, can achieve effective internalization by epithelial cells and efficient transport across the intestinal epithelium layer into the systemic circulation, followed by controlled release in physiological environments. After the oral administration of insulin carried by Lys-aaPEAs with ornamental hyaluronic acid (HA), mice with type 1 diabetes mellitus showed an acceptable hypoglycemic effect with alleviated complications. A successful oral insulin delivery is associated with patient comfort and convenience and simultaneously avoids the risk of hypoglycemia compared with injections, which is of great feasibility for daily diabetes therapy. More importantly, this versatile Lys-aaPEAs polymeric library can be recognized as a universal vehicle for oral biomacromolecule delivery, providing more possibilities for treating various diseases.

We consider a bottleneck system in a state of disequilibrium, in which commuters are heterogeneous in the values of travel time and schedule delays. Three representative dynamical systems are used to formulate the day-to-day departure time choice of commuters, and a Walrasian toll charge scheme is utilized to control the evolutionary process of traffic flows. The toll charge scheme is anonymous; that is, toll charges are identical for all user classes, and the scheme's implementation does not need to resort to information on the values of travel time and schedule delays. We find that the system optimum (SO) flow pattern can be achieved at the stationary state under the implementation of the toll charge scheme. The equivalence between the stationary state and the SO, the existence of the toll charge for achieving the SO, and the convergence of day-to-day traffic flows to the SO under the implementation of the toll charge scheme are theoretically proved. The distributions of traffic flows and toll charges at the SO state during morning rush hour are analytically shown. The application of the toll charge scheme to a network with multiple trip origins is presented. The effectiveness of the toll charge scheme for achieving the SO is also examined by numerical analyses.

Ligand-directed divergent synthesis (LDS) is an importantsynthetictool for the preparation of structurally diverse organic moleculeswithout tedious steps to modify substrates. Herein, we introduce therealization of 3,4-, 1,2-, and 1,4-cyclization of benzo[d]isothiazole-1,1-dioxide-fused azadienes (BDAs) through LDS, leadingto tetrahydro-2H-pyrans, oxazinanes, and tetrahydro-2H-1,5-oxazocines, respectively. Using phosphinooxazoline(PHOX) ligands, we have developed a [4 + 2] cycloaddition betweenBDAs and substituted 2-alkylidenetrimethylene carbonates, providingaccess to multi-substituted chiral tetrahydro-2H-pyransin good yields with excellent enantio-, diastereo-, and regioselectivities.

A tandem allylic amination/oxa-Michael addition of vinyl methylene cyclic carbonates (VMCCs) has been developed to construct heterocycles by single palladium catalysis or palladium-organo relay catalysis. In this process, the bisnucleophiles first underwent regioselective allylic amination, and then the second nucleophilic group further completed the hetero-Michael addition reaction to form a series of heterocycles. Among them, the chiral 3,4-dihydro-2H-benzo[b][1,4]oxazines could be produced in medium to high yield with good enantioselectivity under a palladium-organo relay catalysis.

The main goal of distribution network (DN) expansion planning is essentially to achieve minimal investment constrained with specified reliability requirements. The reliability-constrained distribution network planning (RcDNP) problem can be cast an instance of mixed-integer linear programming (MILP) which involves ultra-heavy computation burden especially for large scale DNs. In this paper, we propose a parallel computing-based acceleration algorithm for solve RcDNP problem. The RcDNP is decomposed into a backbone grid and several lateral grid problems with coordination. Then a parallelizable augmented Lagrangian algorithm with acceleration strategy is developed to solve the coordination planning problems. In this method, the lateral grid problems are solved in parallel through coordinating with the backbone grid planning problem. To address the presence of nonconvexity, Gauss-Seidel iteration is adopted on the convex hull of the feasible region constructed by the decomposition method. Under mild conditions, the optimality and convergence of this algorithm is proven. The numerical tests show the proposed method can significantly reduce the computation time and make the RcDNP applicable for real-world problems.

Lang Wang,1,2,&ast; Zhiqi Zhang,1,3,&ast; Xingxiang Chen,1 Fang Yu,4 Hai Huang,4 Xue Shen,4 Yujie Tan,4 Qingqing Wu4 1Department of Microbiology and Immunology, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, People’s Republic of China; 2Hunan University of Medicine, Huaihua, People’s Republic of China; 3Taian City Central Hospital Affiliated to Qingdao University, Taian, People’s Republic of China; 4Center of Clinical Laboratory, the Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingqing Wu, Center of Clinical Laboratory, the Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China, Email wuqingqing@gmc.edu.cnPurpose: The study aimed to investigate the relationship between the expression of PD-1 and CTLA-4 on the surface of peripheral blood T lymphocyte subsets in patients with sepsis and the severity and prognosis of the disease.Patients and Methods: The study included patients with sepsis who were admitted to the intensive care unit. The expression of PD-1 and CTLA-4 on T lymphocyte subsets was detected by flow cytometry, and the severity of sepsis was assessed using the SOFA score.Results: The expression of PD-1 on CD4+T cells, PD-1 on Tregs, and CTLA-4 on Tregs increased with the severity of the disease (P< 0.05). Multivariate logistic regression analysis showed that PD-1 expression on CD4+T cells, CTLA-4 expression on Tregs, and the SOFA score were independent risk factors for 28-day mortality in patients with sepsis (P< 0.05). The area under the curve of the SOFA score combined with the expression of PD-1 on CD4+T cells and CTLA-4 on Treg cells was significantly higher than any single indicator (P< 0.05). Patients with high expression of PD-1 on CD4+T cells (> 31.25%) and CTLA-4 on Tregs (> 12.64%) had a lower 28-day survival rate (P< 0.05).Conclusion: The i

An organocatalytic enantioselective formal hydroarylation of 2-vinyl indoles for the preparation of enantioenriched 2,3′-bis(indolyl)methanes bearing an all-carbon quaternary stereocenter is described. This reaction features mild conditions, low catalyst loading, excellent efficiency and enantioselectivity. The obtained products showed promising anticancer activity. © 2023 American Chemical Society.

Jianyi Li,1,* Keke Li,2,* Yukun Du,1,* Xiaojie Tang,3,* Chenjing Liu,1 Shannan Cao,3 Baomeng Zhao,2 Hai Huang,3 Hongri Zhao,3 Weiqing Kong,1 Tongshuai Xu,3 Cheng Shao,1 Jiale Shao,1 Guodong Zhang,4 Hongbo Lan,5 Yongming Xi1 1Department of Orthopaedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Yantai Campus of Binzhou Medical University, Yantai, People’s Republic of China; 3Yantai Affiliated Hospital of Binzhou Medical University, Yantai, People’s Republic of China; 4Tengzhou Central People’s Hospital, Tengzhou, People’s Republic of China; 5Shandong Engineering Research Center for Additive Manufacturing Qingdao University of Technology, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongming Xi, Department of Orthopaedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China, Email xym700118@163.com Hongbo Lan, Shandong Engineering Research Center for Additive Manufacturing Qingdao University of Technology, Qingdao, 266520, People’s Republic of China, Email hblan99@126.comBackground: Successful treatment of infectious bone defect remains a major challenge in the orthopaedic field. At present, the conventional treatment for infectious bone defects is surgical debridement and long-term systemic antibiotic use. It is necessary to develop a new strategy to achieve effective bone regeneration and local anti-infection for infectious bone defects.Methods: Firstly, vancomycin / poly (lactic acid-glycolic acid) sustained release microspheres (VAN/PLGA-MS) were prepared. Then, through the dual-nozzle 3D printing technology, VAN/PLGA-MS was uniformly loaded into the pores of nano-hydroxyapatite (n-HA) and polylactic acid (PLA) scaffolds printed in a certain proportion, and a composite scaffold (VAN/MS-PLA/n-HA) was designed, which can not only promote bon

The introduction of vehicle automation, shared mobility, and vehicle electrification will bring about changes in urban transportation, land use, energy, and the environment. The accurate estimation of these effects is therefore essential for sustainable urban development. However, existing research on estimating the energy and environmental effects of shared autonomous electric vehicles generally ignores the interaction between land-use and transportation systems. This study, therefore, analyzes the long-term effects of shared autonomous vehicles (SAVs) from the perspective of land use and transportation integration. Different SAV pricing scenarios are also developed to explore the optimal pricing strategy for low carbon–oriented SAVs. Moreover, the study has further assessed the effect of vehicle electrification on vehicle emissions and energy consumption. The results have shown a nonlinear relationship between SAV fares and their transportation, land-use, energy, and environmental effects. Under an appropriate pricing strategy, SAV deployment could reduce PM2.5 emission and energy consumption by 56–64% and 53–61%, respectively. With the further introduction of vehicle electrification, these can rise to 76% and 74%.

The bubbles that nucleated during slow-roll inflation can be supercritical, i.e. their radii are larger than the Hubble horizon of de Sitter spacetime inside the bubble (an inflating baby universe inside it), and thus naturally develop to the supermassive primordial black holes (SMPBHs) with a multi-peaks mass function. In this paper, we further investigate relevant phenomenology. After slow-roll inflation ended, the bubbles may be not only supercritical, but also subcritical. It is showed that it seems unlikely for the subcritical bubbles to collapse to SMPBHs. Theoretically, however, before they collapsed such bubbles might have a probability of up-tunnelling to the supercritical ones and thus contribute to SMPBHs. We present a mechanism for the origin of initial clustering of SMPBHs, which can significantly magnify the merger rate of SMPBH binaries, and show the possibility that the merging of such SMPBH binaries explains recent NANOGrav signal., Comment: 39 pages, 11 figures

The probability that the primordial black hole (PBH) binaries formed in the early Universe can be affected by the Hubble expansion of background, which is non-negligible when the number density of PBHs is very low (it is actually this case for supermassive PBHs). In this paper, taking into account the effect of cosmic expansion on the comoving distance of PBH pairs, we worked out the merger rate of PBHs with any extended mass function. The torques by all PBHs and linear density perturbations are also considered. It is found that the merger rate of PBH, $M\gtrsim 10^6M_\odot$, binaries is significantly lower for $f_\text{pbh}\lesssim 0.01$ than expected., Comment: 16 pages, 5 figures

Androgen deprivation therapy is administered to suppress the growth of prostate cancer (PCa). However, some cells continue to proliferate independent of hormones, leading to the development of castration-resistant prostate cancer (CRPC). Overexpression of the epidermal growth factor receptor (EGFR) has been observed in CRPC and is associated with an unfavorable prognosis. Gefitinib (GEF) is an EGFR inhibitor used to treat patients with CRPC. Nevertheless, some clinical studies have reported that gefitinib does not result in prostate-specific antigen (PSA) or objectively measurable CRPC reactions. This lack of response may be attributed to the limited solubility in water, high side effects, low tumor aggregation, and insufficient tumor-specific reactions of GEF. In order to tackle these obstacles, we present a practical and efficient approach to administer GEF, encompassing the utilization of biocompatible nanostructures as a vehicle for drug delivery to augment its bioaccessibility and curative potency. Despite their small particle size, poly(d,l-lactide-co-glycolide) acid nanoparticles (PLGA NPs) exhibit a high drug-loading capacity, low toxicity, biocompatibility, biodegradability, and minimal immunogenicity. The drug delivery efficiency can be improved by employing GEF@PLGA NPs, which could also enhance drug cytotoxicity and impede the advancement of prostate cancer. Moreover, through experiments in vivo, it has been verified that GEF@PLGA NPs exhibit selective accumulation in the tumor and effectively restrain tumor growth. Therefore, the GEF@PLGA NPs hold great promise for the treatment of PCa. © 2024 The Royal Society of Chemistry.

The Pd-catalyzed dipolar cycloaddition represents a significant synthetic strategy for the construction of useful heterocyclic compounds. This study developed the dipolar [4+2] and [6+2] cycloaddition reactions of benzo[d]isothiazole 1,1-dioxides (BDs) leading to the synthesis of BD-fused 1,3-oxazinane and 1,3-oxazocane derivatives, respectively. In particular, the synthesis of BD-fused 1,3-oxazinanes demonstrated regio- and enantioselective characteristics, resulting in products with good yields, enantioselectivity and regioselectivity (if applicable). Furthermore, the [6+2] cycloaddition reaction developed in this work represented the first strategy for the synthesis of medium-sized ring compounds based on BDs. © 2023 SIOC, CAS, Shanghai, & WILEY-VCH GmbH.

Herein we employed ethynylethylene carbonates (EECs) to achieve formal [4 + 1] and [3 + 3] cycloaddition with cyclic 1,3-dicarbonyl compounds. On one hand, EECs with styryl substitution could undergo a remotely controlled enantioselective [4 + 1] cycloaddition reaction. This reaction exhibits good chemoselectivity, regioselectivity, and enantioselectivity. In addition, a [3 + 3] cycloaddition reaction of EECs with cyclic 1,3-dicarbonyl compounds was also achieved, leading to a series of 4H-pyrans with impressive chemoselectivity and enantioselectivity. © 2023 American Chemical Society.

The expansion of optoelectronic devices on photonic integration platforms has led to significant growth in the field of photonic computing. Photonic integrated circuits have facilitated the creation of ultrafast artificial neural networks, forming the basis for a novel category of information processing devices. Their application extends to diverse domains such as medical diagnosis, language models, telecommunications, quantum computing, and the metaverse, addressing the escalating demands of machine learning and artificial intelligence (AI). In contrast, conventional electronics faces challenges in latency, crosstalk, and energy consumption. Neuromorphic photonics emerges as a compelling solution, featuring sub-nanosecond latencies, minimal heat dissipation, and high parallelism, expanding the scope of AI and Optical Neural Networks. This review explores recent advances in integrated photonic neuromorphic systems, focusing on materials and device engineering breakthroughs needed to overcome existing challenges. Examining various technologies in AI accelerators, from traditional optics to PICs, we assess energy efficiency through operations per joule and compute density in operations per squared millimeter per second. A comparative analysis highlights crucial technical aspects, emphasizing nanophotonic components like VCSEL lasers, optical interconnects, nanocavity resonators, and frequency microcombs. These components showcase recent breakthroughs in photonic engineering and materials science, enabling the creation of customized neuromorphic systems for AI tasks. Despite progress, current technologies face obstacles in achieving photonic AI accelerators with computing speed and energy efficiencies reaching the petaOPS range. The review explores potential future approaches in new devices, fabrication, materials, scalability, and integration to enhance critical performance metrics., Comment: 39 pages,17 figures

In this paper, we highlight a problem of evaluation metrics adopted in the open-vocabulary segmentation. That is, the evaluation process still heavily relies on closed-set metrics on zero-shot or cross-dataset pipelines without considering the similarity between predicted and ground truth categories. To tackle this issue, we first survey eleven similarity measurements between two categorical words using WordNet linguistics statistics, text embedding, and language models by comprehensive quantitative analysis and user study. Built upon those explored measurements, we designed novel evaluation metrics, namely Open mIoU, Open AP, and Open PQ, tailored for three open-vocabulary segmentation tasks. We benchmarked the proposed evaluation metrics on 12 open-vocabulary methods of three segmentation tasks. Even though the relative subjectivity of similarity distance, we demonstrate that our metrics can still well evaluate the open ability of the existing open-vocabulary segmentation methods. We hope that our work can bring with the community new thinking about how to evaluate the open ability of models. The evaluation code is released in github.

Humans watch more than a billion hours of video per day. Most of this video was edited manually, which is a tedious process. However, AI-enabled video-generation and video-editing is on the rise. Building on text-to-image models like Stable Diffusion and Imagen, generative AI has improved dramatically on video tasks. But it's hard to evaluate progress in these video tasks because there is no standard benchmark. So, we propose a new dataset for text-guided video editing (TGVE), and we run a competition at CVPR to evaluate models on our TGVE dataset. In this paper we present a retrospective on the competition and describe the winning method. The competition dataset is available at https://sites.google.com/view/loveucvpr23/track4., Comment: Project page: https://sites.google.com/view/loveucvpr23/track4

Fine-tuning large pre-trained computer vision models is infeasible for resource-limited users. Visual prompt learning (VPL) has thus emerged to provide an efficient and flexible alternative to model fine-tuning through Visual Prompt as a Service (VPPTaaS). Specifically, the VPPTaaS provider optimizes a visual prompt given downstream data, and downstream users can use this prompt together with the large pre-trained model for prediction. However, this new learning paradigm may also pose security risks when the VPPTaaS provider instead provides a malicious visual prompt. In this paper, we take the first step to explore such risks through the lens of backdoor attacks. Specifically, we propose BadVisualPrompt, a simple yet effective backdoor attack against VPL. For example, poisoning $5\%$ CIFAR10 training data leads to above $99\%$ attack success rates with only negligible model accuracy drop by $1.5\%$. In particular, we identify and then address a new technical challenge related to interactions between the backdoor trigger and visual prompt, which does not exist in conventional, model-level backdoors. Moreover, we provide in-depth analyses of seven backdoor defenses from model, prompt, and input levels. Overall, all these defenses are either ineffective or impractical to mitigate our BadVisualPrompt, implying the critical vulnerability of VPL.

Large language models (LLMs) have demonstrated superior performance compared to previous methods on various tasks, and often serve as the foundation models for many researches and services. However, the untrustworthy third-party LLMs may covertly introduce vulnerabilities for downstream tasks. In this paper, we explore the vulnerability of LLMs through the lens of backdoor attacks. Different from existing backdoor attacks against LLMs, ours scatters multiple trigger keys in different prompt components. Such a Composite Backdoor Attack (CBA) is shown to be stealthier than implanting the same multiple trigger keys in only a single component. CBA ensures that the backdoor is activated only when all trigger keys appear. Our experiments demonstrate that CBA is effective in both natural language processing (NLP) and multimodal tasks. For instance, with $3\%$ poisoning samples against the LLaMA-7B model on the Emotion dataset, our attack achieves a $100\%$ Attack Success Rate (ASR) with a False Triggered Rate (FTR) below $2.06\%$ and negligible model accuracy degradation. Our work highlights the necessity of increased security research on the trustworthiness of foundation LLMs., Comment: To Appear in Findings of the Association for Computational Linguistics: NAACL 2024, June 2024

B(C6F5)3was found to catalyze an unusual double reduction of oxetanes by hydrosilane with aryl migration via neighboring group participation. Control experiments suggested that the phenonium ion serves as the key intermediate. Minor modification of this protocol also led to simple hydrosilylative opening of oxetanes.

How the spacetime evolved non-perturbatively in a landscape with multiple anti-de Sitter (AdS) vacua, which is theoretically well-motivated, has always been a matter of concern. As a step towards this issue, we perform (3+1)D numerical relativity simulations for the inhomogeneous universe in an AdS landscape, and find that large inhomogeneity of scalar field can develop into not only sphere-like bubbles, but also novel tube-like structures. It is observed that the bubble or tube wall (across the potential barrier) likely inflates as a quasi-dS space, while the different regions separated by the walls are in different AdS vacua and will collapse towards singularity., Comment: 7 pages, 6 figures + references

Existing studies on neural architecture search (NAS) mainly focus on efficiently and effectively searching for network architectures with better performance. Little progress has been made to systematically understand if the NAS-searched architectures are robust to privacy attacks while abundant work has already shown that human-designed architectures are prone to privacy attacks. In this paper, we fill this gap and systematically measure the privacy risks of NAS architectures. Leveraging the insights from our measurement study, we further explore the cell patterns of cell-based NAS architectures and evaluate how the cell patterns affect the privacy risks of NAS-searched architectures. Through extensive experiments, we shed light on how to design robust NAS architectures against privacy attacks, and also offer a general methodology to understand the hidden correlation between the NAS-searched architectures and other privacy risks., Comment: Accepted by CCS 2022

While asymmetric insertion of metal carbenes into H-X (X = C, N, O, etc.) bonds has been well-established, asymmetric control over free carbenes is challenging due to the presence of strong background reactions and lack of any anchor for a catalyst interaction. Here we have achieved the first photo-induced metal-free asymmetric H-X bond insertion of this type. With visible light used as a promoter and a chiral phosphoric acid used as a catalyst, alpha-diazoesters and aryl amines underwent smooth N-H bond insertion to form enantioenriched alpha-aminoesters with high efficiency and good enantioselectivity under mild conditions. Key to the success was the use of DMSO as an additive, which served to rapidly capture the highly reactive free carbene intermediate to form a domesticated sulfoxonium ylide.

Prostate cancer (PCa) is the second most common malignant tumor among males. Traditional treatments for PCa, which include surgery and endocrine therapy, have shown limited success, and more effective therapies are needed. Cisplatin (DDP) is an approved chemotherapeutic drug that causes DNA damage in cancer, whereas AZD7762, an inhibitor of CHK1, can significantly inhibit DNA repair. The effective therapeutic combination of cisplatin and the DNA damage response inhibitor AZD7762 has been considered to be a potential solution to the resistance to cisplatin and the adverse reactions that occur in many cancers. However, the co-transmission of cisplatin and AZD7762 and the unsatisfactory tumor-targeting efficacy of this therapy remain problems to be solved. Here, we confirmed the combined therapeutic efficacy of cisplatin and AZD7762 in PCa. Furthermore, we show that the glutathione-targeted Cys8E nanoparticles we synthesized, which have high drug-loading capacity, remarkable stability, and satisfactory release efficiency, enhanced the therapeutic efficacy of this treatment and reduced the required dosages of these drugs both in vitro and in vivo. Overall, we propose combination therapy of cisplatin and AZD7762 for PCa and facilitate it using Cys8E nanoparticles, which allow for better drug loading release, higher release efficiency, and more accurate tumor-targeting efficacy. (C) 2022 Author(s).