Synthesis of Biheteroaryls by Pd-Catalyzed Homocoupling of Heteroaryl Bromides.

Symmetrical biheteroaryl compounds, such as bypyridines and bipyrazoles, are important ligands in transition-metal catalysis. They also serve as synthetic precursors of photo catalysts/sensitizers, bioactive agents, and energetic materials. To facilitate the concise synthesis of these useful structures, an efficient Pd-catalyzed homocoupling of heteroaryl bromides has been successfully established using the electron-rich and sterically hindered monophosphorus ligand BIDIME. The coupling protocol features a tandem Miyaura borylation/Suzuki coupling sequence and exhibits unprecedented tolerance of a wide range of heteroaryl bromides, providing a series of symmetrical biheteroaryls in moderate to good yields. Notably, the use of the corresponding polymeric ligand, PolyBIDIME, enabled the recycling of a palladium catalyst, demonstrating the potential of the homocoupling in practical applications.

Chiral Polymeric Diamine Ligands for Iridium-Catalyzed Asymmetric Transfer Hydrogenation.

A series of polymeric chiral diamine ligands are developed by diboron-templated asymmetric reductive couplings, and their iridium complexes Ir-polydiamines are efficient and recyclable catalysts for asymmetric transfer hydrogenation (ATH) of functionalized ketones, affording a series of optically active secondary alcohols in excellent enantioselectivities (up to 99% ee) and unprecedentedly high total TONs (12,000, six cycles). Ir-polydiamine catalysts with longer chains offered higher reactivities, providing a plausible deactivation mechanism and practical solutions of ATH for vitamin B5 and phenylephrine.

Water isotope ratios reflect convection intensity rather than rain type proportions in the pantropics.

Against the traditional view, a recently published theory argued that isotope ratios are higher in convective precipitation but lower in stratiform precipitation and proposed that isotope ratios reflect rain type proportions. This theory has been widely cited despite some early reservations. Whether the theory represents a faithful reflection of signals of water isotope ratios remains unclear. Here, we reassess its validity from different timescales and broader observations from the pantropics. Unexpectedly, our findings contradict the theory on daily, monthly, and even annual timescales. Pantropical precipitation isotope ratios remain strongly correlated to convection intensity but are independent of rain type proportions because stratiform precipitation isotope ratios cover a large range of values. We find that the theory has many serious weaknesses related to preferential data selection and suggest that new theories need to be validated at more locations on different timescales before gaining widespread acceptance.

Ginsenoside Re inhibits non-small cell lung cancer progression by suppressing macrophage M2 polarization induced by AMPKα1/STING positive feedback loop.

Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.

Outpatient reception via collaboration between nurses and a large language model: a randomized controlled trial.

Reception is an essential process for patients seeking medical care and a critical component influencing the healthcare experience. However, current communication systems rely mainly on human efforts, which are both labor and knowledge intensive. A promising alternative is to leverage the capabilities of large language models (LLMs) to assist the communication in medical center reception sites. Here we curated a unique dataset comprising 35,418 cases of real-world conversation audio corpus between outpatients and receptionist nurses from 10 reception sites across two medical centers, to develop a site-specific prompt engineering chatbot (SSPEC). The SSPEC efficiently resolved patient queries, with a higher proportion of queries addressed in fewer rounds of queries and responses (Q&Rs; 68.0% ≤2 rounds) compared with nurse-led sessions (50.5% ≤2 rounds) (P = 0.009) across administrative, triaging and primary care concerns. We then established a nurse-SSPEC collaboration model, overseeing the uncertainties encountered during the real-world deployment. In a single-center randomized controlled trial involving 2,164 participants, the primary endpoint indicated that the nurse-SSPEC collaboration model received higher satisfaction feedback from patients (3.91 ± 0.90 versus 3.39 ± 1.15 in the nurse group, P < 0.001). Key secondary outcomes indicated reduced rate of repeated Q&R (3.2% versus 14.4% in the nurse group, P < 0.001) and reduced negative emotions during visits (2.4% versus 7.8% in the nurse group, P < 0.001) and enhanced response quality in terms of integrity (4.37 ± 0.95 versus 3.42 ± 1.22 in the nurse group, P < 0.001), empathy (4.14 ± 0.98 versus 3.27 ± 1.22 in the nurse group, P < 0.001) and readability (3.86 ± 0.95 versus 3.71 ± 1.07 in the nurse group, P = 0.006). Overall, our study supports the feasibility of integrating LLMs into the daily hospital workflow and introduces a paradigm for improving communication that benefits both patients and nurses. Chinese Clinical Trial Registry identifier: ChiCTR2300077245 .

Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species.

BACKGROUND: Vorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30-35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies. PURPOSE: This study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it. METHODS AND RESULTS: In this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rß with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo. CONCLUSION: Our study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL.

Synergistic Regulation of Targeted Organelles in Tumor Cells to Promote Photothermal-Immunotherapy Using Intelligent Core-Satellite-Like Nanoparticles for Effective Treatment of Breast Cancer.

The normal operation of organelles is critical for tumor growth and metastasis. Herein, an intelligent nanoplatform (BMAEF) is fabricated to perform on-demand destruction of mitochondria and golgi apparatus, which also generates the enhanced photothermal-immunotherapy, resulting in the effective inhibition of primary and metastasis tumor. The BMAEF has a core of mesoporous silica nanoparticles loaded with brefeldin A (BM), which is connected to ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) and folic acid co-modified gold nanoparticles (AEF). During therapy, the BMAEF first accumulates in tumor cells via folic acid-induced targeting. Subsequently, the schiff base/ester bond cleaves in lysosome to release brefeldin A and AEF with exposed EGTA. The EGTA further captures Ca2+ to block ion transfer among mitochondria, endoplasmic reticulum, and golgi apparatus, which not only induced dysfunction of mitochondria and golgi apparatus assisted by brefeldin A to suppress both energy and material metabolism against tumor growth and metastasis, but causes AEF aggregation for tumor-specific photothermal therapy and photothermal assisted immunotherapy. Moreover, the dysfunction of these organelles also stops the production of BMI1 and heat shock protein 70 to further enhance the metastasis inhibition and photothermal therapy, which meanwhile triggers the escape of cytochrome C to cytoplasm, leading to additional apoptosis of tumor cells.

The Realities and Needs of Nursing Assistants Caring for Disabled Patients with Fecal Incontinence During Hospitalization: A Qualitative Study.

Objective: To explore the experience, role, and needs of medical nursing assistants during hospitalization in patients with incapacitated fecal incontinence. Methods: Qualitative study using reflexive thematic analysis. Semi-structured interviews were conducted with 21 medical nursing assistants from three hospitals in Southern China. Results: Four themes were constructed from the data: (1) Role perception. All participants described the multiple roles they played during care and knowledge and familiarity with the roles were seen as providing high-quality care to patients. (2) Career cognition. Overall, participants had a positive view of nurse assistants as a career. They believed that nursing experience was more important than training. (3) emotional belonging. The multiple roles of medical nursing assistants give them very mixed emotions. (4) Potential needs. Participants reported that the fatigue of repeatedly scrubbing and cleaning stools, the negative emotions that could not be faced and resolved, and their special status made them overwhelmed, potentially reflecting that they needed more support. Conclusions: This study highlights the roles, experiences, confusions, and needs of nursing assistants in caring for patients with disabling fecal incontinence. Suggested areas for improvement include the development of more intelligent fecal incontinence collection devices and the development of management and training strategies by health managers based on the specific context of medical nursing assistants to emphasize the role of medical nursing assistants and improve the quality of clinical care.

Association of Monocyte-to-HDL Cholesterol Ratio with Endothelial Dysfunction in Patients with Type 2 Diabetes.

Aims: To explore the relationship between monocyte-to-HDL cholesterol ratio (MHR) and endothelial function in patients with type 2 diabetes (T2DM). Methods: 243 patients diagnosed with T2DM were enrolled in this cross-sectional study. Patients were divided into two groups by flow-mediated dilation (FMD) quintile as nonendothelial dysfunction (FMD ≥ 6.4%) and endothelial dysfunction (FMD < 6.4%). The relationship between MHR and FMD was analyzed using Spearman's correlation, partial correlation, and multiple logistic regression analysis. ROC curve was fitted to evaluate the ability of MHR to predict endothelial dysfunction. Results: Endothelial dysfunction was present in 193 (79%) patients. Patients with endothelial dysfunction had higher MHR (p < 0.05) than those without endothelial dysfunction. Furthermore, MHR had a significantly positive correlation with endothelial dysfunction (r = 0.17, p < 0.05), and the positive association persisted even after controlling for confounding factors (r = 0.14, p < 0.05). Logistic regression showed that MHR was an independent contributor for endothelial dysfunction (OR: 1.35 (1.08, 1.70), p < 0.05) and the risk of endothelial dysfunction increases by 61% with each standard deviation increase in MHR (OR: 1.61 (1.12, 2.30), p < 0.05) (model 1). After adjusting for sex, age, BMI, disease course, hypertension, smoking, and drinking (model 2) as well as HbA1c, HOMA-IR, C-reactive protein, and TG (model 3), similar results were obtained. In ROC analysis, the area of under the ROC curve (AUC) for MHR was 0.60 (95% CI 0.52-0.69, p < 0.05). Conclusion: MHR was independently associated with endothelial dysfunction in T2DM patients. It could be a new biomarker for vascular endothelial function assessment.

Enhancement of multilayer lithium storage in a ß12-borophene/graphene heterostructure with built-in dipoles.

The combination of borophene with a supporting metallic layer is beneficial in stabilizing its structure and promoting its application in energy storage. Here, through first-principles calculations, we screen a ß12-borophene/graphene (ß12-B/G) heterostructure with superior structural integrity, strong interlayer binding, and high thermodynamic stability among different B/G heterostructures. Besides, it is noteworthy that ß12-B/G has been recently synthesized, further opening the possibility of expanding its use in energy storage. Then the selected target is systematically investigated as an anode material for lithium-ion batteries (LIBs). Compared with each monolayer component, multiple lithium-ion adsorption is achieved in the ß12-B/G heterostructure, resulting in an ultra-high theoretical specific capacity of 2267 mA h g-1. In addition, a lower diffusion energy barrier indicates faster electron transport and lithium-ion diffusion in the ß12-B/G heterostructure. Notably, the multilayer lithium adsorption avoids the formation of dendritic deposits, as evidenced by complete ionization of the cationic layers. Moreover, the disparity in the work functions of the individual layers gives rise to a built-in dipole in ß12-B/G, further enhancing the multilayer lithium storage and ion migration. All these results suggest that the construction of borophene-based heterostructures with built-in dipoles is a feasible way to design high-performance LIB anode materials.

Selective Manipulation of the Mitochondria Oxidative Stress in Different Cells Using Intelligent Mesoporous Silica Nanoparticles to Activate On-Demand Immunotherapy for Cancer Treatment.

Herein, the vitamin K2 (VK2)/maleimide (MA) coloaded mesoporous silica nanoparticles (MSNs), functional molecules including folic acid (FA)/triphenylphosphine (TPP)/tetrapotassium hexacyanoferrate trihydrate (THT), as well as CaCO3 are explored to fabricate a core-shell-corona nanoparticle (VMMFTTC) for on-demand anti-tumor immunotherapy. After application, the tumor-specific acidic environment first decomposed CaCO3 corona, which significantly levitates the pH value of tumor tissue to convert M2 type macrophage to the antitumor M1 type. The resulting VMMFTT would then internalize in both tumor cells and macrophages via FA-assisted endocytosis and free endocytosis, respectively. These distinct processes generate different amount of VMMFTT in above two cells followed by 1) TPP-induced accumulation in the mitochondria, 2) THT-mediated effective capture of various signal ions to cut off signal transmission and further inhibit glutathione (GSH) generation, 3) ions catalyzed reactive oxygen species (ROS) production through Fenton reaction, 4) sustained release of VK2 and MA to further enhance the ROS production and GSH depletion, which caused significant apoptosis of tumor cells and additional M2-to-M1 macrophage polarization via different processes of oxidative stress. Moreover, the primary tumor apoptosis further matures surrounding immature dendritic cells and activates T cells to continuously promote the antitumor immunotherapy.

Mechanism of PWAR6 regulating cisplatin drug sensitivity in non-small cell lung cancer through miR-577/PHACTR1.

lncRNA Prader Willi/Angelman Region RNA 6 (PWAR6) is considered to play a protective lncRNA in glioma, but, the role of PWAR6 in the occurrence and cisplatin resistance of non-small cell lung cancer (NSCLC) is elusive. In the study, we aimed to assess the role of PWAR6 in the cisplatin resistance of NSCLC. Based on the oebiotech and TargetScanHuman database, we predicted the interaction between PWAR6, miR-577 and PHACTR1. We then used small interfering RNA (siRNA), miRNA mimics and dual-luciferase reporter assay to explore the regulatory role of PWAR6/miR-577PHACTR1. Based on the online database, miR-577 can interact with PWAR6 and PHACTR1. Soon afterwards, we observed that the expression of PWAR6 and PHACTR1 was increased, while miR-577 expression was decreased in A549/DDP cells. And the cell viability was decreased, while cell apoptosis was increased in A549/DDP cells. What's more, PWAR6 knockdown can promote the expression of miR-577 and inhibit the expression of PHACTR1. PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells. Interestingly, we found that miR-577 can interact with PHACTR1 to regulate the proliferation and apoptosis of A549/DDP cells. To conclude, we speculated that PWAR6 knockdown elevated cell proliferation and reduced cell apoptosis of A549/DDP cells via miR-577/PHACTR1, providing the theoretical basis for the clinical treatment of NSCLC patients.

Prevalence and predictors of help-seeking behavior among post-partum women with urinary incontinence in China and Indonesia: A cross-sectional survey based on Andersen Help-Seeking Model.

INTRODUCTION: Urinary incontinence (UI) is a prevalent condition among post-partum women, and it can significantly affect their physical and psychosocial well-being. Therefore, it's crucial for post-partum women to discuss any UI symptoms they may be experiencing with their healthcare provider and seek appropriate treatment. PURPOSE: To investigate what leads post-partum women with UI to seek help in China and Indonesia based on the Andersen Help-Seeking Model. METHODS: A cross-sectional digital survey among post-partum women (6 weeks to 1 year) was conducted from May to November 2021 in China and Indonesia. The survey contents included: (1) demographic characteristics, (2) social support, (3) health care needs, (4) capacity and resources. For analysis, descriptive statistics, independent sample t-tests and chi-square tests were used to determine the differences between help-seeking and non-help-seeking women with UI, and logistic regression analysis and the receiver operating characteristic curve (ROC) was used to determine the predictors of heal-seeking behavior in post-partum women with UI. RESULTS: The prevalence of UI was 25 % (215/868) and 31 % (187/605) among post-partum women in China and Indonesia. Among post-partum women with UI, the help-seeking rate was 46 % (98/215) and 52 % (98/187) in China and Indonesia. Incontinence quality of Life, support from women of the family (Yes), knowing the available department for UI (Yes), current knowledge of UI and the current status of UI were independent risk factors for China (P<0.05). Support from husband (Yes), being asked about UI by a doctor (Yes) and the current status of UI were independent risk factors for Indonesia. The obtained area under ROC curve (AUC) for the model were 0.884 and 0.935 in China and Indonesia. CONCLUSIONS: The prevalence of UI and the rate of seeking help for UI in Indonesia were higher than those in China. Social support, needs and the availability of resources and organizational support to assist patients in their help-seeking efforts, were the main predictors affecting help-seeking behavior among post-partum women with UI.

Research progress on the mechanism of astragaloside IV in the treatment of asthma.

Asthma is a common chronic respiratory disease, and its treatment is a core problem and challenge in clinical practice. Glucocorticoids (GCs) are the first-line therapy for the treatment of asthma. Local and systemic adverse reactions caused by GCs create obstacles to the treatment of asthma. Therefore, the research target is to find a new, safe, and effective therapeutic medicine at present. Natural products are an important source for treating asthma with low cost and low toxicity. Astragaloside IV (AS-IV) is an active ingredient of traditional Chinese medicine Astragalus mongholicus Bunge. Previous studies have indicated that AS-IV plays a therapeutic role in the treatment of asthma by inhibiting airway inflammation and remodeling the airway, and by regulating immunity and neuroendocrine function (Fig. 1) . It has a variety of biological characteristics such as multi-target intervention, high safety, and good curative effect. This article reviews the specific mechanism of AS-IV for the treatment of asthma to provide references for subsequent research.

Dienediamine: A safe surrogate for the herbicide paraquat.

Paraquat (PQ) has been used as an herbicide worldwide because of its potent activity against weeds. However, it is highly toxic to humans. The very high fatality of PQ poisoning is due to its inherent toxicity and the lack of any effective treatment. Consequently, developing a non-toxic herbicide with comparable efficacy to PQ will contribute to global food security and help prevent PQ-related fatalities. Herein, we report a new herbicide called dienediamine, which was discovered from how to intervene the redox cycle of PQ, an inherent toxicity nature. Dienediamine, the "reduced" form of PQ with no function as an electron transfer agent, was shown to be non-toxic through comprehensive in vivo and in vitro experiments at molar concentrations equivalent to PQ's absolute lethal dose. Remarkably, dienediamine can undergo conversion to PQ under natural sunlight and ambient air conditions, exhibiting herbicidal activities that are comparable to those of PQ. The conversion of dienediamine to PQ, which is toxic to chloroplasts, is the key mechanism underlying its potent herbicidal activity. Our study discovers that dienediamine is a safe and superior alternative to PQ, possessing significant potential for application in sustainable agriculture globally.

Enantioselective C-H Arylation for Axially Chiral Heterobiaryls.

An enantioselective palladium-catalyzed C-H arylation of functionalized pyrazoles/triazoles/imidazoles is developed, affording a variety of axially chiral ortho-nitro/formyl-substituted heterobiaryls with excellent enantioselectivities and good yields. The method features a deuterated P-chiral phosphorus ligand CD3-AntPhos, a broad substrate scope of functionalized heterobiaryls, mild reaction conditions, and low palladium loadings.

Development and validation of a Decision-Making Ability Scale for postpartum urinary incontinence women engaging in pelvic floor physical therapy.

OBJECTIVE: This study aimed to develop and validate a Decision-Making Ability Scale (DMA-S) for postpartum urinary incontinence (PPUI) women engaging in pelvic floor physical therapy (PFPT). METHODS: Items were created in line with a review of the literature and exploratory qualitative study with 22 women. The items were submitted for expert opinion and a pilot implementation was made with 58 women with PPUI. Furthermore, the construct validity of the scale was tested with exploratory factor analysis (EFA) (n = 220) and confirmatory factor analysis (CFA) (n = 240). Internal consistency for the Chronbach's α and test-retest reliability for the intraclass correlation coefficient (ICC) were also investigated for the DMA-S in the study. RESULTS: The results of the EFA indicated a Kaiser-Meyer-Olkin value of 0.85 and Bartlett's test of sphericity showed a χ2 value of 8352.101, p < 0.001. After removing one item with factor loading values below 0.50, the resulting factor structure accounted for 83.38% of the total variance. The fit indices of the scale model tested in the CFA were determined as χ2 /df = 1.08 < 3, root mean square error of approximation = 0.018 < 0.08, comparative fit index = 0.996 > 0.90, Tucker-Lewis index = 0.995 > 0.90, goodness-of-fit index (GFI) = 0.933 > 0.90, adjusted GFI = 0.916 > 0.90, and incremental fit index = 0.996 > 0.90. The Cronbach's α values were 0.95-0.97 for the subdimensions of the scale and 0.93 for the total scale. Data also showed a good test-retest stability (ICC = 0.984). CONCLUSION: The DMA-S is a reliable and valid tool for assessing the decision-making ability for PPUI women engaging in PFPT.

Comprehensive analysis of the lncRNAs-related immune gene signatures and their correlation with immunotherapy in lung adenocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs)-related immune genes (lrRIGs) play a crucial role in the development and progression of lung adenocarcinoma (LUAD). However, reliable prognostic signatures based on lrRIGs have not yet been identified. METHODS: We screened lrRIGs associated with the prognosis of LUAD using The Cancer Genome Atlas (TCGA) database and then established a novel prognostic nine-gene signature composed of CD79A, INHA, SHC3, LIFR, TNFRSF11A, GPI, F2RL1, SEMA7A and WFDC2 through bioinformatic approaches. A risk score derived from this gene signature was used to divide LUAD patients into the low- and high-risk groups. The latter was confirmed to have markedly worse overall survival (O.S.). A nomogram was developed using the risk score and other independent prognostic elements, demonstrating excellent performance in predicting the O.S. rate of LUAD patients. RESULTS: We observed that the infiltration of diverse immune cell subtypes and response to immunotherapy and chemotherapy significantly differed between the low- and high-risk groups. CONCLUSIONS: Overall, stratification based on this gene signature could be used to guide better therapeutic management and improve outcomes for LUAD patients.

Structural mechanism for specific binding of chemical compounds to amyloid fibrils.

Amyloid fibril is an important pharmaceutical target for diagnostic and therapeutic treatment of neurodegenerative diseases. However, rational design of chemical compounds that interact with amyloid fibrils is unachievable due to the lack of mechanistic understanding of the ligand-fibril interaction. Here we used cryoelectron microscopy to survey the amyloid fibril-binding mechanism of a series of compounds including classic dyes, (pre)clinical imaging tracers and newly identified binders from high-throughput screening. We obtained clear densities of several compounds in complex with an α-synuclein fibril. These structures unveil the basic mechanism of the ligand-fibril interaction, which exhibits remarkable difference from the canonical ligand-protein interaction. In addition, we discovered a druggable pocket that is also conserved in the ex vivo α-synuclein fibrils from multiple system atrophy. Collectively, these findings expand our knowledge of protein-ligand interaction in the amyloid fibril state, which will enable rational design of amyloid binders in a medicinally beneficial way.

Enantioselective Transformations in the Synthesis of Therapeutic Agents.

The proportion of approved chiral drugs and drug candidates under medical studies has surged dramatically over the past two decades. As a consequence, the efficient synthesis of enantiopure pharmaceuticals or their synthetic intermediates poses a profound challenge to medicinal and process chemists. The significant advancement in asymmetric catalysis has provided an effective and reliable solution to this challenge. The successful application of transition metal catalysis, organocatalysis, and biocatalysis to the medicinal and pharmaceutical industries has promoted drug discovery by efficient and precise preparation of enantio-enriched therapeutic agents, and facilitated the industrial production of active pharmaceutical ingredient in an economic and environmentally friendly fashion. The present review summarizes the most recent applications (2008-2022) of asymmetric catalysis in the pharmaceutical industry ranging from process scales to pilot and industrial levels. It also showcases the latest achievements and trends in the asymmetric synthesis of therapeutic agents with state of the art technologies of asymmetric catalysis.