IL-1ß-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance.

Interleukin-1ß (IL-1ß) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1ß in cancer is ambiguous or even contradictory. Here, we found that upon IL-1ß stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1ß-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1ß expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1ß-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1ß and tumor cells by inhibiting NNT acetylation.

Metalation of metal-organic frameworks: fundamentals and applications.

Metalation of metal-organic frameworks (MOFs) has been developed as a prominent strategy for materials functionalization for pore chemistry modulation and property optimization. By introducing exotic metal ions/complexes/nanoparticles onto/into the parent framework, many metallized MOFs have exhibited significantly improved performance in a wide range of applications. In this review, we focus on the research progress in the metalation of metal-organic frameworks during the last five years, spanning the design principles, synthetic strategies, and potential applications. Based on the crystal engineering principles, a minor change in the MOF composition through metalation would lead to leveraged variation of properties. This review starts from the general strategies established for the incorporation of metal species within MOFs, followed by the design principles to graft the desired functionality while maintaining the porosity of frameworks. Facile metalation has contributed a great number of bespoke materials with excellent performance, and we summarize their applications in gas adsorption and separation, heterogeneous catalysis, detection and sensing, and energy storage and conversion. The underlying mechanisms are also investigated by state-of-the-art techniques and analyzed for gaining insight into the structure-property relationships, which would in turn facilitate the further development of design principles. Finally, the current challenges and opportunities in MOF metalation have been discussed, and the promising future directions for customizing the next-generation advanced materials have been outlined as well.

Cross-Modal Retrieval Between 13C NMR Spectra and Structures Based on Focused Libraries.

Library matching by comparing carbon-13 nuclear magnetic resonance (13C NMR) spectra with spectral data in the library is a crucial method for compound identification. In our previous paper, we introduced a deep contrastive learning system called CReSS, which used a library that contained more structures. However, CReSS has two limitations: there were no unknown structures in the library, and a redundant library reduces the structure-elucidation accuracy. Herein, we replaced the oversize traditional libraries with focused libraries containing a small number of molecules. A previously generative model, CMGNet, was used to generate focused libraries for CReSS. The combined model achieved a Top-10 accuracy of 54.03% when tested on 6,471 13C NMR spectra. In comparison, CReSS with a random reference structure library achieved an accuracy of only 9.17%. Furthermore, to expand the advantages of the focused libraries, we proposed SAmpRNN, which is a recurrent neural network (RNN). With the large focused library amplified by SAmpRNN, the structure-identification accuracy of the model increased in 70.0% of the 30 random example cases. In general, cross-modal retrieval between 13C NMR spectra and structures based on focused libraries (CFLS) achieved high accuracy and provided more accurate candidate structures than traditional libraries for compound identification.

Quality Evaluation of Guidelines for the Diagnosis and Treatment of Liver Failure.

OBJECTIVES: This study aimed to systematically assess the methodological quality and key recommendations of the guidelines for the diagnosis and treatment of liver failure (LF), furnishing constructive insights for guideline developers and equipping clinicians with evidence-based information to facilitate informed decision-making. DATA SOURCES: Electronic databases and manual searches from January 2011 to August 2023. STUDY SELECTION: Two reviewers independently screened titles and abstracts, then full texts for eligibility. Fourteen guidelines were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data and checked by two others. Methodological quality of the guidelines was appraised using the Appraisal of Guidelines for Research and Evaluation II tool. Of the 14 guidelines, only the guidelines established by the Society of Critical Care Medicine and the American College of Gastroenterology (2023) achieved an aggregate quality score exceeding 60%, thereby meriting clinical recommendations. It emerged that there remains ample room for enhancement in the quality of the guidelines, particularly within the domains of stakeholder engagement, rigor, and applicability. Furthermore, an in-depth scrutiny of common recommendations and supporting evidence drawn from the 10 adult LF guidelines unveiled several key issues: controversy exists in the recommendation, the absence of supporting evidence and confusing use of evidence for recommendations, and a preference in evidence selection. CONCLUSIONS: There are high differences in methodological quality and recommendations among LF guidelines. Improving these existing problems and controversies will benefit existing clinical practice and will be an effective way for developers to upgrade the guidelines.

Continuous-wave and SESAM mode-locked operation of a Yb:YSr3(PO4)3 laser.

We report on the continuous-wave (CW) and, for what we believe to be the first time, passively mode-locked (ML) laser operation of an Yb3+-doped YSr3(PO4)3 crystal. Utilizing a 976-nm spatially single-mode, fiber-coupled laser diode as pump source, the Yb:YSr3(PO4)3 laser delivers a maximum CW output power of 333 mW at 1045.8 nm with an optical efficiency of 55.7% and a slope efficiency of 60.9%. Employing a quartz-based Lyot filter, an impressive wavelength tuning range of 97 nm at the zero level was achieved in the CW regime, spanning from 1007 nm to 1104 nm. In the ML regime, incorporating a commercially available semiconductor saturable absorber mirror (SESAM) to initiate and maintain soliton-like pulse shaping, the Yb:YSr3(PO4)3 laser generated pulses as short as 61 fs at 1062.7 nm, with an average output power of 38 mW at a repetition rate of ∼66.7 MHz.

Growth, spectroscopy and SESAM mode-locking of a "mixed" Yb:Ca(Gd,Y)AlO4 disordered crystal.

We present the growth, spectroscopy, continuous-wave (CW) and passively mode-locked (ML) operation of a novel "mixed" tetragonal calcium rare-earth aluminate crystal, Yb3+:Ca(Gd,Y)AlO4. The absorption, stimulated-emission, and gain cross-sections are derived for π and σ polarizations. The laser performance of a c-cut Yb:Ca(Gd,Y)AlO4 crystal is studied using a spatially single-mode, 976-nm fiber-coupled laser diode as a pump source. A maximum output power of 347 mW is obtained in the CW regime with a slope efficiency of 48.9%. The emission wavelength is continuously tunable across 90 nm (1010 - 1100 nm) using a quartz-based Lyot filter. With a commercial SEmiconductor Saturable Absorber Mirror to initiate and maintain ML operation, soliton pulses as short as 35 fs are generated at 1059.8 nm with an average output power of 51 mW at ∼65.95 MHz. The average output power can be scaled to 105 mW for slightly longer pulses of 42 fs at 1063.5 nm.

Chiral Brønsted Acid-Catalyzed Asymmetric Reaction via Vinylidene ortho-Quinone Methides.

Vinylidene ortho-quinone methides (VQMs) have been proven to be versatile and crucial intermediates in the catalytic asymmetric reaction in last decade, and thus have drawn considerable concentrations on account of the practical application in the construction of enantiomerically pure functional organic molecules. However, in comparison to the well established chiral Brønsted base-catalyzed asymmetric reaction via VQMs, chiral Brønsted acid-catalyzed reaction is rarely studied and there is no systematic summary to date. In this review, we summarize the recent advances in the chiral Brønsted acid-catalyzed asymmetric reaction via VQMs according to three types of reactions: a) intermolecular asymmetric nucleophilic addition to VQMs; b) intermolecular asymmetric cycloaddition of VQMs; c) intramolecular asymmetric cyclization of VQMs. Finally, we put forward the remained challenges and opportunities for potential breakthroughs in this area.

Klf4 methylated by Prmt1 restrains the commitment of primitive endoderm.

The second cell fate decision in the early stage of mammalian embryonic development is pivotal; however, the underlying molecular mechanism is largely unexplored. Here, we report that Prmt1 acts as an important regulator in primitive endoderm (PrE) formation. First, Prmt1 depletion promotes PrE gene expression in mouse embryonic stem cells (ESCs). Single-cell RNA sequencing and flow cytometry assays demonstrated that Prmt1 depletion in mESCs contributes to an emerging cluster, where PrE genes are upregulated significantly. Furthermore, the efficiency of extraembryonic endoderm stem cell induction increased in Prmt1-depleted ESCs. Second, the pluripotency factor Klf4 methylated at Arg396 by Prmt1 is required for recruitment of the repressive mSin3a/HDAC complex to silence PrE genes. Most importantly, an embryonic chimeric assay showed that Prmt1 inhibition and mutated Klf4 at Arg 396 induce the integration of mouse ESCs into the PrE lineage. Therefore, we reveal a regulatory mechanism for cell fate decisions centered on Prmt1-mediated Klf4 methylation.

Breaking down barriers: rationalisations and motivation to stop among Chinese male smokers under cigarette dependence.

BACKGROUND: Smoking rationalisation beliefs are a huge barrier to quitting smoking. What types of rationalisations should be emphasised in smoking cessation interventions? Although past literature has confirmed the negative relationship between those beliefs and motivation to stop smoking, little is known regarding the importance and performance of those beliefs on motivation with varying cigarette dependence. The study aimed to ascertain rationalisations that are highly important for motivation yet perform poorly in different cigarette dependence groups. METHODS: The cross-sectional study was conducted from November 19 to December 9, 2023 in Guiyang City, China. Adult male current smokers were enrolled. Partial least squares structural equation modelling was used to test the hypothesis. The multi-group analysis was used to determine the moderating effect of cigarette dependence, and the importance-performance map analysis was utilised to assess the importance and performance of rationalisations. RESULTS: A total of 616 adult male current smokers were analysed, and they were divided into the low cigarette dependence group (n = 297) and the high cigarette dependence group (n = 319). Except for risk generalisation beliefs, smoking functional beliefs (H1: -ß = 0.131, P < 0.01), social acceptability beliefs (H3: ß = -0.258, P < 0.001), safe smoking beliefs (H4: ß = -0.078, P < 0.05), self-exempting beliefs (H5: ß = -0.244, P < 0.001), and quitting is harmful beliefs (H6: ß = -0.148, P < 0.01) all had a significant positive influence on motivation. Cigarette dependence moderated the correlation between rationalisations and motivation. In the high-dependence group, the social acceptability beliefs and smoking functional beliefs were located in the "Concentrate Here" area. In the low-dependence group, the social acceptability beliefs were also situated in there. CONCLUSIONS: Social acceptability beliefs and smoking functional beliefs showed great potential and value for improvement among high-dependence smokers, while only social acceptability beliefs had great potential and value for improvement among low-dependence smokers. Addressing these beliefs will be helpful for smoking cessation. The multi-group analysis and the importance-performance map analysis technique have practical implications and can be expanded to other domains of health education and intervention practice.

[Synthesis and tissue distribution of bufadienolides in Bufo bufo gargarizans].

This study explored the biosynthesis of bufadienolides(BDs) in Bufo bufo gargarizans to solve the dilemma of the decreasing resources of B. bufo gargarizans and provide a theoretical basis for the sustainable utilization of the resources. Ultra-high performance liquid chromatography-Orbitrap-mass spectrometry(UHPLC-Orbitrap-MS) was employed to detect the synthesis sites of BDs in B. bufo gargarizans, and the results were verified by desorption electrospray ionization-mass spectrometry imaging(DESI-MSI) and homogenate incubation experiments. BDs in B. bufo gargarizans had the highest content in the liver and the highest concentration in the gallbladder, in addition to the parotid gland and skin, which suggested that the liver could synthesize BDs. The results of DESI-MSI also showed that BDs were mainly enriched in the liver rather than the immature parotid gland. The incubation experiment of liver homogenates demonstrated the liver of B. bufo gargarizans had the ability to synthesize BDs. This study showed that the liver was a major organ for the synthesis of BDs in B. bufo gargarizans during metamorphosis, development, and growth, which provided strong theoretical support for the biosynthesis of BDs and the sustainable utilization of B. bufo gargarizans resources.

DOTA-Based Plectin-1 Targeted Contrast Agent Enables Detection of Pancreatic Cancer in Human Tissue.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy with extremely poor patient survival rates. A key reason for the poor prognosis is the lack of effective diagnostic tools to detect the disease at curable, premetastatic stages. Tumor surgical resection is PDAC's first-line treatment, however distinguishing between cancerous and healthy tissue with current imaging tools remains a challenge. In this work, we report a DOTA-based fluorescent probe targeting plectin-1 for imaging PDAC with high specificity. To enable heterogeneous functionalization of the DOTA-core with multiple targeting peptide units and the fluorophore, a novel, fully clickable synthetic route that proceeds in one pot was developed. Extensive validation of the probe set the stage for PDAC detection in mice and human tissue. Altogether, these findings may pave the way for improved clinical understanding and early detection of PDAC progression as well as more accurate resection criteria.

Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.

OBJECTIVE: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined. DESIGN: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated. RESULTS: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients. CONCLUSIONS: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

Advances in the Application of Artificial Intelligence-Based Spectral Data Interpretation: A Perspective.

The interpretation of spectral data, including mass, nuclear magnetic resonance, infrared, and ultraviolet-visible spectra, is critical for obtaining molecular structural information. The development of advanced sensing technology has multiplied the amount of available spectral data. Chemical experts must use basic principles corresponding to the spectral information generated by molecular fragments and functional groups. This is a time-consuming process that requires a solid professional knowledge base. In recent years, the rapid development of computer science and its applications in cheminformatics and the emergence of computer-aided expert systems have greatly reduced the difficulty in analyzing large quantities of data. For expert systems, however, the problem-solving strategy must be known in advance or extracted by human experts and translated into algorithms. Gratifyingly, the development of artificial intelligence (AI) methods has shown great promise for solving such problems. Traditional algorithms, including the latest neural network algorithms, have shown great potential for both extracting useful information and processing massive quantities of data. This Perspective highlights recent innovations covering all of the emerging AI-based spectral interpretation techniques. In addition, the main limitations and current obstacles are presented, and the corresponding directions for further research are proposed. Moreover, this Perspective gives the authors' personal outlook on the development and future applications of spectral interpretation.

Analyte-Triggered Excited-State Intramolecular Proton Transfer- Delayed Fluorescence: A General Approach for Time-Resolved Turn-On Fluorescence Imaging.

The research of delayed fluorescence (DF) has been a hot topic in biological imaging. However, the development of analyte-triggered small molecule DF probes remains a considerable challenge. Herein a novel excited-state intramolecular proton transfer-delayed fluorescence (ESIPT-DF) approach to construct analyte-stimulated DF probes was reported. These new classes of ESIPT-DF luminophores were strategically designed and synthesized by incorporating 2-(2'-hydroxyphenyl)benzothiazole (HBT), a known ESIPT-based fluorophore, as acceptor with a series of classic donor moieties, which formed a correspondingly twisted donor-acceptor pair within each molecule. Thereinto, HBT-PXZ and HBT-PTZ exhibited significant ESIPT and DF characters with lifetimes of 5.37 and 3.65 µs in the solid state, respectively. Furthermore, a caged probe HBT-PXZ-Ga was developed by introducing a hydrophilic d-galactose group as the recognition unit specific for ß-galactosidase (ß-gal) and ESIPT-DF blocking agent and applied to investigate the influence of metal ions on ß-gal activity on the surface of Streptococcus pneumoniae as a convenient tool. This ESIPT-DF "turn-on" approach is easily adaptable for the measurement of many different analytes using only a predictable modification on the caged group without modification of the core structure.

Dual-mode tunable absorber based on quasi-bound states in the continuum.

In this Letter, we propose a novel, to the best of our knowledge, dual-mode tunable absorber that utilizes quasi-bound states in the continuum (q-BIC) based on the periodically arranged silicon cylinders tetramer. By introducing asymmetry perturbation through manipulating the diameters of diagonal cylinders in the all-dielectric structure, the symmetry-protected BIC (SP-BIC) transforms into q-BIC, leading to the emergence of one transmission and one reflection Fano-like resonant mode. The relationship between the quality factor of each mode and the asymmetry parameter α is analyzed, revealing an exponential dependence with an exponent of -1.75, i.e., Q ∝ α-1.75. To explain the underlying physics, multipole decomposition analysis and Aleksandra's theory are applied. Subsequently, a monolayer graphene is introduced to the all-dielectric structure to demonstrate the application of the dual-mode tunable absorber. When the critical coupling condition is satisfied, each mode can achieve the theoretical maximum absorption, demonstrating the distinctive capability of our proposed absorber for tuning and efficient light absorption. This research provides valuable insights into light-matter interactions and opens up possibilities for optical modulation and the development of graphene-based devices.

Base-Promoted Formal (3 + 2) Cycloaddition of α-Halohydroxamates with Electron-Deficient Alkenyl-iminoindolines To Synthesize Spiro-indolinepyrrolidinones.

Construction of pyrrolidinyl-spiroindoles with easily available starting materials has attracted considerable attention from the synthesis community and is in great demand. Here, we describe a base-promoted formal (3 + 2) cycloaddition of α-halohydroxamates with alkenyl-iminoindolines. The present methodology features mild reaction conditions and a broad substrate scope with up to 99% yield and excellent diastereoselectivity. The versatility of this approach is demonstrated through valuable synthetic transformations. Preliminary mechanistic studies shed light on the mechanism of this cycloaddition process.

Porous MOF Featuring 2D Intersecting Channels Based on a Pentanuclear Mn5(COO)10CO3 Cluster with Upgrading of Pipeline Natural Gas.

Natural gas plays a crucial role in daily and industrial production, but the impurities contained in natural gas limit its further use. It is very important to develop adsorbents that can separate CH4 from multicomponent mixtures, but there are still many challenges and problems. Herein, a novel porous MOF {[Mn5(pbdia)2(CO3)(H2O)2] ↔ 5H2O ↔ 2DMF}n (pbdia = 2,2'-(5-carboxy-1,3-phenylene)bis(oxy) diterephthalic acid) was successfully synthesized based on a flexible pentacarboxylic acid ligand and a unique pentanuclear Mn5(COO)10CO3 cluster. The MOF reveals a 3D porous structure with 2D intersecting channels, which shows high C3H8, C2H6, and CO2 adsorption capacities and affinities over CH4. Moreover, the ideal adsorption solution theory selectivities of C3H8/CH4, C2H6/CH4, and CO2/CH4 can reach 263.0, 27.0, and 7.7, respectively, suggesting a potential for removing the low content of C3H8, C2H6, and CO2 from pipeline natural gas, which was further confirmed by breakthrough curves and GCMC simulations.

Structural characteristics of a low molecular weight velvet antler protein and the anti-tumor activity on S180 tumor-bearing mice.

Velvet antler is a traditional Chinese medicine with various pharmacological values, which is an important raw material for traditional Chinese medicinal wine. Nevertheless, the chemical compositions and bioactivities of velvet antler residue used for making medicinal wine are rarely reported, leading to a waste of resources. In this study, a velvet antler protein (VA-pro) was extracted from velvet antler residue by simulating the gastrointestinal digestion, and its composition, structural characteristics and in vivo anti-tumor activities were determined and investigated. VA-pro possessed high purity with a relatively low molecular weight as 22.589 kDa under HPLC, one- and two-dimensional electrophoresis, and it contained high contents of Pro, Gly, Glu and Ala. Besides, the secondary structure of VA-pro was dominated by ß-turn and ß-sheet, and VA-pro possessed similar protein sequence, isoelectric point and amino acid compositions to hypothetical protein G4228_020061. The in vivo results substantiated that VA-pro could improve the body weights and immune organ indices, increase the expressions of sera cytokines and regulate the distributions of T and B lymphocytes subsets in peripheral blood of S180 tumor-bearing mice. Furthermore, VA-pro could effectively inhibit solid S180 tumors growth by inducing S phase cell cycle arrest mediated through mitochondria. To summarize, our study provided theoretical support that VA-pro had the potential to be used as an immunopotentiator in immunocompromised or cancer-bearing hosts.

Evaluation of guidelines for the diagnosis and treatment of achalasia.

Due to the unclear quality of the current guidelines, users may be confused about how to diagnose and treat achalasia. The objective of this work is to systematically evaluate the methodological quality of the current guidelines for diagnosing and treating achalasia and to determine the heterogeneity among recommendations. We systematically searched literature databases to retrieve relevant guidelines for the diagnosis and treatment of achalasia. The Appraisal of Guidelines for Research and Evaluation II tool was used to evaluate the quality of the included guidelines. Key recommendations in the guidelines were extracted, and the reasons for the heterogeneity of the key recommendations between different guidelines were further analyzed. Seven guidelines on the diagnosis and treatment of achalasia are included in this study. The overall score of three guidelines exceeded 60%. The average score in domain 5 was the lowest, at 41.8%. The average scores in domain 2, domain 3, and domain 6 were also low, at 45.4%, 57.1% and 56.9%, respectively. The main recommendations and quality of evidence for different guidelines vary greatly, mainly due to the different emphases among different guidelines, the lack of systematic retrieval, or the unfairness of evidence use in some guidelines. There are considerable differences in the methodological quality of diagnosis and treatment guidelines for achalasia. Additionally, the differences in the main recommendations and evidence support among guidelines are also obvious. Guideline developers should improve the above related factors to decrease the heterogeneity, and they should further formulate or update the guidelines for the diagnosis and treatment of achalasia.

Candidate genes for litter size in Xinjiang sheep identified by Specific Locus Amplified Fragment (SLAF) sequencing.

The aim of this study was to investigate the selection signatures at a genome-wide level in 'Pishan' sheep using Specific Locus Amplified Fragment (SLAF)-seq. Blood samples from 126 ewes were sequenced using SLAF tags, and the ovarian tissues from 8 ewes (Bashbay sheep, a single litter size group (SG group); 'Pishan' sheep, double litter size group (DG group)) were collected to detect expression levels by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Selection signature analysis was performed using global fixation index (Fst) and nucleotide diversity (π) ratio. A total of 1,192,168 high-quality SLAFs were identified. Notably, 2380 candidate regions under selection using two approaches were identified. A total of 2069 genes were identified, which were involved in dopaminergic synapses, thyroid hormone synthesis, ovarian steroidogenesis and thyroid hormone signalling pathways. Furthermore, Growth Differentiation Factor 9 (GDF9), Period Circadian Regulator 2 (PER2), Thyroid Stimulating Hormone Receptor (TSHR), and Nuclear Receptor Coactivator 1 (NCOA1) reside within these regions and pathways. The expression levels of GDF9 and PER2 genes in sheep tissue of the DG group were significantly higher than those in the SG group. These genes are interesting candidates for litter size and provide a starting point for further identification of conservation strategies for 'Pishan' sheep.