Result of a Pilot External Quality Assessment Scheme for Clinical Diagnosis of Inherited Metabolic Disorders in China.

BACKGROUND: We aimed to evaluate the diagnostic capabilities of Chinese laboratories for inherited metabolic disorders (IMDs) using gas chromatography-mass spectrometry (GC-MS) on urine samples. Meanwhile, based on the result of the pilot external quality assessment (EQA) scheme, we hope to establish a standardized and reliable procedure for future EQA practice. METHODS: We recruited laboratories that participated in the EQA of quantitative analysis of urinary organic acids with GC-MS before joining the surveys. In each survey, a set of five real urine samples was distributed to each participant. The participants should analyze the sample by GC-MS and report the "analytical result", "the most likely diagnosis", and "recommendation for further tests" to the NCCL before the deadline. RESULTS: A total of 21 laboratories participated in the scheme. The pass rates were 94.4% in 2020 and 89.5% in 2021. For all eight IMDs tested, the analytical proficiency rates ranged from 84.7% - 100%, and the interpretational performance rate ranged from 88.2% - 97.0%. The performance on hyperphenylalaninemia (HPA), 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), and ethylmalonic encephalopathy (EE) samples were not satisfactory. CONCLUSIONS: In general, the participants of this pilot EQA scheme are equipped with the basic capability for qualitative organic acid analysis and interpretation of the results. Limited by the small size of laboratories and samples involved, this activity could not fully reflect the state of clinical practice of Chinese laboratories. NCCL will improve the EQA scheme and implement more EQA activities in the future.

Solution-Processable Large-Area Black Phosphorus/Reduced Graphene Oxide Schottky Junction for High-Temperature Broadband Photodetectors.

2D materials-based broadband photodetectors have extensive applications in security monitoring and remote sensing fields, especially in supersonic aircraft that require reliable performance under extreme high-temperature conditions. However, the integration of large-area heterostructures with 2D materials often involves high-temperature deposition methods, and also limited options and size of substrates. Herein, a liquid-phase spin-coating method is presented based on the interface engineering to prepare larger-area Van der Waals heterojunctions of black phosphorus (BP)/reduced graphene oxide (RGO) films at room temperature on arbitrary substrates of any required size. Importantly, this method avoids the common requirement of high-temperature, and prevents the curling or stacking in 2D materials during the liquid-phase film formation. The BP/RGO films-based devices exhibit a wide spectral photo-response, ranging from the visible of 532 nm to infrared range of 2200 nm. Additionally, due to Van der Waals interface of Schottky junction, the array devices provide infrared detection at temperatures up to 400 K, with an outstanding photoresponsivity (R) of 12 A W-1 and a specific detectivity (D*) of ≈2.4 × 109 Jones. This work offers an efficient approach to fabricate large-area 2D Schottky junction films by solution-coating for high-temperature infrared photodetectors.

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.

Synergistic oxidation of toluene through bimetal/cordierite monolithic catalysts with ozone.

Toluene treatment has received extensive attention, and ozone synergistic catalytic oxidation was thought to be a potential method to degrade VOCs (violate organic compounds) due to its low reaction temperature and high catalytic efficiency. A series of bimetal/Cord monolithic catalysts were prepared by impregnation with cordierite, including MnxCu5-x/Cord, MnxCo5-x/Cord and CuxCo5-x/Cord (x = 1, 2, 3, 4). Analysis of textural properties, structures and morphology characteristics on the prepared catalysts were conducted to evaluate their performance on toluene conversion. Effects of active component ratio, ozone addition and space velocity on the catalytic oxidation of toluene were investigated. Results showed that MnxCo5-x/Cord was the best among the three bimetal catalysts, and toluene conversion and mineralization rates reached 100 and 96% under the condition of Mn2Co3/Cord with 3.0 g/m3 O3 at the space velocity of 12,000 h-1. Ozone addition in the catalytic oxidation of toluene by MnxCo5-x/Cord could efficiently avoid the 40% reduction of the specific surface area of catalysts, because it could lower the optimal temperature from 300 to 100 °C. (Co/Mn)(Co/Mn)2O4 diffraction peaks in XRD spectra indicated all the four MnxCo1-x/Cord catalysts had a spinel structure, and diffraction peak intensity of spinel reached the largest at the ratio of Mn:Co = 2:3. Toluene conversion rate increased with rising ozone concentration because intermediate products generated by toluene degradation might react with excess ozone to generate free radicals like ·OH, which would improve the toluene mineralization rate of Mn2Co3/Cord catalyst. This study would provide a theoretical support for its industrial application.

IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis.

Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.

Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis.

Immunotherapy targeting PD-L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine-threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD-L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN-γ-mediated PD-L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti-PD-1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD-L1/PD-1 signaling and is a promising target for combined immunotherapy.

Prediction of 19F NMR chemical shifts for organic compounds with ORCA.

Accurate assignment of 19F NMR has long been a challenge, and quantum chemical methods are possible solutions. Herein we reported a scaling method for the prediction of 19F NMR chemical shift with freely available ORCA program package. Performance of 31 DFT functionals coupled with 11 basis sets were evaluated and influence of geometry optimization was also studied with five functionals coupled with three basis sets. The significance of geometry was further examined through the execution of relaxed surface scans of seven flexible compounds, and averaged shieldings of obtained conformers yielded notable improvement of the correlation between calculated isotropic shielidings and experimental chemical shifts. Utilization of the best scaling factor obtained successfully assigned of fluorine atoms in multifluorinated molecules with different conformations. The method reported here was computationally inexpensive, easily available with acceptable accuracy.

Biocompatibility and osteogenic potential of choline phosphate chitosan-coated biodegradable Zn1Mg.

Zinc alloys have demonstrated considerable potentials as implant materials for biodegradable vascular and orthopedic applications. However, the high initial release of Zn2+ can trigger intense immune responses that impede tissue healing. To address this challenge and enhance the osteogenic capacity of zinc alloys, the surface of Zn1Mg was subjected to CO2 plasma modification (Zn1Mg-PP) followed by grafting with choline phosphate chitosan (Zn1Mg-PP-PCCs). This study aims to investigate the in vitro and in vivo biocompatibility of the surface-modified Zn1Mg. The effect of the surface modification on the inflammatory response and osteogenic repair process was investigated. Compared with unmodified Zn1Mg, the degradation rate of Zn1Mg-PP-PCCs was significantly decreased, avoiding the cytotoxicity triggered by the release of large amounts of Zn2+. Moreover, PCCs significantly enhanced the cell-material adhesion, promoted the proliferation of osteoblasts (MC3T3-E1) and upregulated the expression of key osteogenic factors in vitro. Notably, the in vivo experiments revealed that the surface modification of Zn1Mg suppressed inhibited the expression of inflammatory cytokines, promoting the secretion of anti-inflammatory factors, thereby reducing inflammation and promoting bone tissue repair. Furthermore, histological analysis of tissue sections exhibited strong integration between the material and the bone, along with well-defined new bone formation and reduced osteoclast aggregation on the surface. This was attributed to the improved immune microenvironment by PCCs, which promoted osteogenic differentiation of osteoblasts. These findings highlight that the preparation of PCCs coatings on zinc alloy surfaces effectively inhibited ion release and modulated the immune environment to promote bone tissue repair. STATEMENT OF SIGNIFICANCE: Surface modification of biodegradable Zn alloys facilitates the suppression of intense immune responses caused by excessive ion release concentrations from implants. We modified the surface of Zn1Mg with choline phosphate chitosan (PCCs) and investigated the effects of surface modification on the inflammatory response and osteogenic repair process. In vitro results showed that the PCCs coating effectively reduced the degradation rate of Zn1Mg to avoid cytotoxicity caused by high Zn2+ concentration, favoring the proliferation of osteoblasts. In addition, in vivo results indicated that Zn1Mg-PP-PCCs attenuated inflammation to promote bone repair by modulating the release of inflammation-related factors. The surface-modified Zn1Mg implants demonstrated strong osseointegration, indicating that the PCCs coating effectively modulated the immune microenvironment and promoted bone healing.

Classification and treatment strategy for Moyamoya disease-related aneurysms.

BACKGROUND: Moyamoya disease (MMD) is a cerebrovascular disorder characterized by progressive unilateral or bilateral stenosis of the distal internal carotid artery. As hemodynamic features in MMD patients alter, the comorbidity of intracranial aneurysm (IA) is sometimes observed clinically. We aim to investigate clinical characteristics and therapeutic strategies for the comorbidity of Moyamoya disease with intracranial aneurysms (MMD-IA). METHODS: A total of 13 MMD-IA patients were recruited in this study and were manifested to be intracranial hemorrhage. We reviewed the surgical technique notes for all patients. RESULTS: According to the locations of an aneurysm, MMD-IA could be divided into several categories: (1) MMD-IA at a circle of Willis-aneurysms usually located at the trunk of Willis circle; (2) MMD-IA at collateral anastomosis-aneurysms located at the distal end of collateral anastomosis; and (3) MMA-IA at basal ganglia region. In this report, aneurysms in 10 patients located at Willis circle, 2 at the pericallosal artery, and 1 at the basal ganglia region. Among them, endovascular embolism was performed among 5 patients. Aneurysm clipping was conducted among 7 patients. A patient with an aneurysm at the basal ganglia region just accepted revascularization treatment. All the treatments were successful. Follow-up studies, ranging from 6 to 24 months, demonstrated all patients received satisfactory curative effects. CONCLUSION: Diverse clinical presentations could be observed among MMD-IA patients. Individualized neurosurgical treatments should be chosen according to the locations of the aneurysm.

Effects of Zr Addition on the Microstructural Evolution, Mechanical Properties, and Corrosion Behavior of Novel Biomedical Ti-Zr-Mo-Mn Alloys.

ß-Type Ti alloys have been widely investigated as implant materials owing to their excellent mechanical properties, corrosion resistance, and biocompatibility. In the present work, the effects of Zr on the microstructure, mechanical properties, and corrosion behaviors of Ti-Zr-Mo-Mn alloys were systematically studied. With the increase of Zr content, the phase composition gradually changed from intragranular-α + ß of (TZ)5:1MM alloy to grain-boundary-α + ß of (TZ)2:1MM alloy and finally transferred to a single ß phase structure of (TZ)1:1MM alloy. The (TZ)1:1MM alloy exhibited a good mechanical combination with a yield strength of 750.8 MPa, an elastic modulus of 61.3 GPa, and a tensile ductility of 14.6%. Moreover, the addition of Zr can effectively stabilize the passivation film and reduce the sensitivity of microgalvanic corrosion in simulated body fluid, leading to enhanced corrosion resistance in the TZMM alloys. X-ray photoelectron spectroscopy analysis together with the ion-sputtering technique revealed that the passivation films formed on TZMM alloys possessed a bilayered structure (outer Ti+Zr mixed-oxide layer and inner Zr-oxide-rich layer), in which the inner Zr oxide layer plays an important role in the corrosion resistance of the TZMM alloys. In vitro biocompatibility evaluations demonstrated that the TZMM alloys can support cell adhesion and proliferation with high biocompatibility comparable to that of CP-Ti, while in vivo biocompatibility evaluations validated the bone osteointegration ability of TZMM alloys after long-term implantation. The above results indicate that novel TZMM alloys are promising candidates for implant material.

Interception Proximity Labeling for Interrogating Cell Efflux Microenvironment.

The difficulty in elucidating the microenvironment of extracellular H2O2 efflux has led to the lack of a critical extracellular link in studies of the mechanisms of redox signaling pathways. Herein, we mounted horseradish peroxidase (HRP) to glycans expressed globally on the living cell surface and constructed an interception proximity labeling (IPL) platform for H2O2 efflux. The release of endogenous H2O2 is used as a "physiological switch" for HRP to enable proximity labeling. Using this platform, we visualize the oxidative stress state of tumor cells under the condition of nutrient withdrawal, as well as that of macrophages exposed to nonparticulate stimuli. Furthermore, in combination with a proteomics technique, we identify candidate proteins at the invasion interface between fungal mimics (zymosan) and macrophages by interception labeling of locally accumulated H2O2 and confirm that Toll-like receptor 2 binds zymosan in a glycan-dependent manner. The IPL platform has great potential to elucidate the mechanisms underlying biological processes involving redox pathways.

Accurate assessment of electrocatalytic carbon dioxide reduction products at industrial-level current density.

During the electrocatalytic CO2 reduction reaction, the faradaic efficiency of products seriously deviates from 100% due to the misjudgment of outlet flow, especially at industrial-level large current density. In this work, several modified equations and internal standard methods are recommended to calibrate the thermal mass flowmeter and establish benchmarks for CO2 reduction performance assessment.

Site-selected in situ polymerization for living cell surface engineering.

The construction of polymer-based mimicry on cell surface to manipulate cell behaviors and functions offers promising prospects in the field of biotechnology and cell therapy. However, precise control of polymer grafting sites is essential to successful implementation of biomimicry and functional modulation, which has been overlooked by most current research. Herein, we report a biological site-selected, in situ controlled radical polymerization platform for living cell surface engineering. The method utilizes metabolic labeling techniques to confine the growth sites of polymers and designs a Fenton-RAFT polymerization technique with cytocompatibility. Polymers grown at different sites (glycans, proteins, lipids) have different membrane retention time and exhibit differential effects on the recognition behaviors of cellular glycans. Of particular importance is the achievement of in situ copolymerization of glycomonomers on the outermost natural glycan sites of cell membrane, building a biomimetic glycocalyx with distinct recognition properties.

Impact of recombinant human brain natriuretic peptide on emergency dialysis and prognosis in end-stage renal disease patients with type 4 cardiorenal syndrome.

Recombinant human brain natriuretic peptide (rhBNP) effects on type 4 cardiorenal syndrome (CRS) and adverse events such as heart failure rehospitalization and all-cause mortality have not been assessed in large-scale research. This study evaluated the impact of rhBNP on emergency dialysis and prognosis in end-stage renal disease (ESRD) patients with type 4 CRS, and the risk factors of emergency dialysis. This retrospective cohort study included patients with type 4 CRS and ESRD admitted for decompensated heart failure between January 2016 and December 2021. Patients were divided into the rhBNP and non-rhBNP cohorts, according to whether they were prescribed rhBNP. The primary outcomes were emergency dialysis at first admission and cardiovascular events within a month after discharge. A total of 77 patients were included in the rhBNP cohort (49 males and 28 females, median age 67) and 79 in the non-rhBNP cohort (47 males and 32 females, median age 68). After adjusting for age, residual renal function, and primary diseases, Cox regression analysis showed that rhBNP was associated with emergency dialysis (HR = 0.633, 95% CI 0.420-0.953) and cardiovascular events (HR = 0.410, 95% CI 0.159-0.958). In addition, multivariate logistic regression analysis showed that estimated glomerular filtration rate (eGFR) (OR = 0.782, 95% CI 0.667-0.917, P = 0.002) and procalcitonin (PCT) levels (OR = 1.788, 95% CI 1.193-2.680, P = 0.005) at the first visit were independent risk factors for emergency dialysis while using rhBNP was a protective factor for emergency dialysis (OR = 0.195, 95% CI 0.084-0.451, P < 0.001). This study suggests that RhBNP can improve cardiac function and reduce the occurrence of emergency dialysis and cardiovascular events in ESRD patients with type 4 CRS.

SIGNET: transcriptome-wide causal inference for gene regulatory networks.

Gene regulation plays an important role in understanding the mechanisms of human biology and diseases. However, inferring causal relationships between all genes is challenging due to the large number of genes in the transcriptome. Here, we present SIGNET (Statistical Inference on Gene Regulatory Networks), a flexible software package that reveals networks of causal regulation between genes built upon large-scale transcriptomic and genotypic data at the population level. Like Mendelian randomization, SIGNET uses genotypic variants as natural instrumental variables to establish such causal relationships but constructs a transcriptome-wide gene regulatory network with high confidence. SIGNET makes such a computationally heavy task feasible by deploying a well-designed statistical algorithm over a parallel computing environment. It also provides a user-friendly interface allowing for parameter tuning, efficient parallel computing scheduling, interactive network visualization, and confirmatory results retrieval. The Open source SIGNET software is freely available ( https://www.zstats.org/signet/ ).

Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors.

As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors 11 and 39 were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the 11-GAC and 27-GAC complexes revealed a novel binding mode against GAC. The potency of 11 and 27 against GACK320A further highlighted the importance of the binding. Notably, compounds 11 and 39 regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound 11 also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that 11 is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future.

Intranasal Delivery of Endothelial Cell-Derived Extracellular Vesicles with Supramolecular Gel Attenuates Myocardial Ischemia-Reperfusion Injury.

Purpose: Myocardial ischemia-reperfusion injury after myocardial infarction has always been a difficult problem in clinical practice. Endothelial cells and their secreted extracellular vesicles are closely related to inflammation, thrombosis formation, and other processes after injury. Meanwhile, low-molecular-weight gelators have shown great potential for nasal administration. This study aims to explore the therapeutic effects and significance of endothelial cell-derived extracellular vesicles combined with a hydrogel for nasal administration on myocardial ischemia-reperfusion injury. Methods: We chose a gel system composed of a derivative of glutamine amide and benzaldehyde as the extracellular vesicle delivery vehicle. This hydrogel was combined with extracellular vesicles extracted from mouse aortic endothelial cells and administered multiple times intranasally in a mouse model of ischemia-reperfusion injury to the heart. The delivery efficiency of the extracellular vesicle-hydrogel combination was evaluated by flow cytometry and immunofluorescence. Echocardiography, TTC Evan's Blue and Masson's staining were used to assess mouse cardiac function, infarct area, and cardiac fibrosis level. Flow cytometry, ELISA, and immunofluorescence staining were used to investigate changes in mouse inflammatory cells, cytokines, and vascular neogenesis. Results: The vesicles combined with the hydrogel have good absorption in the nasal cavity. The hydrogel combined with vesicles reduces the levels of pro-inflammatory Ly6C (high) monocytes/macrophages and neutrophils. It can also reduce the formation of microcirculation thrombi in the infarcted area, improve endothelial barrier function, and increase microvascular density in the injured area. As a result, the heart function of mice is improved and the infarct area is reduced. Conclusion: We first demonstrated that the combination of extracellular vesicles and hydrogel has a better absorption efficiency in the nasal cavity, which can improve myocardial ischemia-reperfusion injury by inhibiting inflammatory reactions and protecting endothelial function. Nasal administration of vesicles combined with hydrogel is a potential therapeutic direction.