Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate.

(S)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline ((S)-1-(4-methoxybenzyl)-OHIQ) is the key intermediate of the nonopioid antitussive dextromethorphan. In this study, (S)-IR61-V69Y/P123A/W179G/F182I/L212V (M4) was identified with a 766-fold improvement in catalytic efficiency compared with wide-type IR61 through enzyme engineering. M4 could completely convert 200 mM of 1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline into (S)-1-(4-methoxybenzyl)-OHIQ in 77% isolated yield, with >99% enantiomeric excess and a high space-time yield of 542 g L-1 day-1, demonstrating a great potential for the synthesis of dextromethorphan intermediate in industrial applications.

Assessment of the implementation of accelerated drug marketing registration procedures for antineoplastic and immunomodulating agents in China: based on 2016-2022 review data.

Objective: Since 2016, China has successively implemented Accelerated Drug Marketing Registration Procedures (ADMRPs) for drugs, including Breakthrough Therapy Drug (BTD), Conditional Approval (CA), and Priority Review and Approval (PRA), which have played an important role in promoting the development and review of clinically urgently needed drugs. In this study, we focused on the antineoplastic and immunomodulating agents approved for marketing through ADMRPs, to provide a reference for promoting the formation of a stable and mature regulatory system for the review and approval of antineoplastic drugs and immunomodulating agents in China. Methods: Reviewed the National Medical Products Administration (NMPA) drug review reports for the years 2016-2022 and screened the antineoplastic and immunomodulating agents approved through ADMRPs. Then, with the help of the NMPA website and the Yaozhi Database, two researchers independently queried and entered the detailed information of the selected drugs, and checked with each other. The attribute classification and main characteristics of the drugs were then analyzed with descriptive statistics to obtain the trend of drug types, drug review and approval status, and timeliness. Results: A total of 206 antineoplastic and immunomodulating agents were approved for marketing through five accelerated marketing registration procedures (or procedure combinations), with the average review time shortened by about 81 days. Among them, imported drugs accounted for a larger proportion, the most drugs for treating non-small cell lung cancer and lymphoma, and the largest number of PD-1/PDL-1 inhibitors, but pediatric drugs and rare disease drugs accounted for a smaller proportion. Conclusion: ADMRPs can promote the accessibility of antineoplastic and immunomodulating agents in China and safeguard the life and health rights of more patients. Nevertheless, it is necessary to pay attention to the expansion of the types of indications for medicines and to increase the development of drugs that are urgently needed by a small number of patients.

Alkali injury-induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation.

Inflammatory lymphangiogenesis is intimately linked to immune regulation and tissue homeostasis. However, current evidence has suggested that classic lymphatic vessels are physiologically absent in intraocular structures. Here, we show that neolymphatic vessels were induced in the iris after corneal alkali injury (CAI) in a VEGFR3-dependent manner. Cre-loxP-based lineage tracing revealed that these lymphatic endothelial cells (LECs) originate from existing Prox1+ lymphatic vessels. Notably, the ablation of iridial lymphangiogenesis via conditional deletion of VEGFR3 alleviated the ocular inflammatory response and pathological T cell infiltration. Our findings demonstrate that iridial neolymphatics actively participate in pathological immune responses following injury and suggest intraocular lymphangiogenesis as a valuable therapeutic target for the treatment of ocular inflammation.

Robust, Ultrafast and Reversible Photoswitching in Bulk Polymers Enabled by Octupolar Molecule Design.

Improving the photoswitching rate and robustness of photochromic molecules in bulk solids is paramount for practical applications but remains an on-going challenge. Here, we introduce an octupolar design paradigm to develop a new family of visible light organic photoswitches, namely multi-branched octupolar Stenhouse Adducts (MOPSAs) featuring a C3-symmetrical A3-(D-core) architecture with a dipolar donor-acceptor (D-A) photochrome in each branch. Our design couples multi-dimensional geometric and electronic effects of MOPSAs to enable robust ultrafast reversible photoswitching in bulk polymers. Specifically, the optimal MOPSA (4 wt %) in commercial polyurethane films accomplishes nearly 100 % discoloration in 6 s under visible light with ∼ 100 % thermal-recovery in 17.4 s at 60 °C, while the acquired kinetics constants are 3∼7 times that of dipolar DASA counterpart and 1∼2 orders of magnitude higher than those of reported DASAs in polymers. Importantly, the MOPSA-doped polymer films sustain 500 discoloration/recovery cycles with slow degradation, superior to the existing DASAs in polymers (≤30 cycles). We discover that multi-dipolar coupling in MOPSA enables enhanced polarization and electron delocalization, promoting the rate-determining thermal cyclization, while the branched and non-planar geometry of MOPSA induces large free volume to facilitate the isomerization. This design can be extended to develop spiropyran or azobenzene-based ultrafast photochromic films. The superior photoswitching performance of MOPSAs together with their high-yield and scalable synthesis and facile film processing inspires us to explore their versatile uses as smart inks or labels for time-temperature indicators, optical logic encryption and multi-levelled data encryption.

Development and validation of a deep learning signature for predicting lymphovascular invasion and survival outcomes in clinical stage IA lung adenocarcinoma: A multicenter retrospective cohort study.

PURPOSE: The presence of lymphovascular invasion (LVI) influences the management and outcomes of patients with clinical stage IA lung adenocarcinoma. The objective was the development of a deep learning (DL) signature for the prediction of LVI and stratification of prognosis. METHODS: A total of 2077 patients from three centers were retrospectively enrolled and divided into a training set (n = 1515), an internal validation set (n = 381), and an external set (n = 181). A -three-dimensional residual neural network was used to extract the DL signature and three models, namely, the clinical, DL, and combined models, were developed. Diagnostic efficiency was assessed by ROC curves and AUC values. Kaplan-Meier curves and Cox proportional hazards regression analyses were conducted to evaluate links between various factors and disease-free survival. RESULTS: The DL model could effectively predict LVI, shown by AUC values of 0.72 (95 %CI: 0.68-0.76) and 0.63 (0.54-0.73) in the internal and external validation sets, respectively. The incorporation of DL signature and clinical-radiological factors increased the AUC to 0.74 (0.71-0.78) and 0.77 (0.70-0.84) in comparison with the DL and clinical models (AUC of 0.71 [0.68-0.75], 0.71 [0.61-0.81]) in the internal and external validation sets, respectively. Pathologic LVI, LVI predicted by both DL and combined models were associated with unfavorable prognosis (all p < 0.05). CONCLUSION: The effectiveness of the DL signature in the diagnosis of LVI and prognosis prediction in patients with clinical stage IA lung adenocarcinoma was demonstrated. These findings suggest the potential of the model in clinical decision-making.

Structural and mechanistic insights into ribosomal ITS2 RNA processing by nuclease-kinase machinery.

Precursor ribosomal RNA (pre-rRNA) processing is a key step in ribosome biosynthesis and involves numerous RNases. A HEPN (higher eukaryote and prokaryote nucleotide binding) nuclease Las1 and a polynucleotide kinase Grc3 assemble into a tetramerase responsible for rRNA maturation. Here, we report the structures of full-length Saccharomyces cerevisiae and Cyberlindnera jadinii Las1-Grc3 complexes, and C. jadinii Las1. The Las1-Grc3 structures show that the central coiled-coil domain of Las1 facilitates pre-rRNA binding and cleavage, while the Grc3 C-terminal loop motif directly binds to the HEPN active center of Las1 and regulates pre-rRNA cleavage. Structural comparison between Las1 and Las1-Grc3 complex exhibits that Grc3 binding induces conformational rearrangements of catalytic residues associated with HEPN nuclease activation. Biochemical assays identify that Las1 processes pre-rRNA at the two specific sites (C2 and C2'), which greatly facilitates rRNA maturation. Our structures and specific pre-rRNA cleavage findings provide crucial insights into the mechanism and pathway of pre-rRNA processing in ribosome biosynthesis.

A CT-based deep learning model: visceral pleural invasion and survival prediction in clinical stage IA lung adenocarcinoma.

Pathologic visceral pleural invasion (VPI) in patients with early-stage lung cancer can result in the upstaging of T1 to T2, in addition to having implications for surgical resection and prognostic outcomes. This study was designed with the goal of establishing and validating a CT-based deep learning (DL) model capable of predicting VPI status and stratifying patients based on their prognostic outcomes. In total, 2077 patients from three centers with pathologically confirmed clinical stage IA lung adenocarcinoma were enrolled. DL signatures were extracted with a 3D residual neural network. DL model was able to effectively predict VPI status. VPI predicted by the DL models, as well as pathologic VPI, was associated with shorter disease-free survival. The established deep learning signature provides a tool capable of aiding the accurate prediction of VPI in patients with clinical stage IA lung adenocarcinoma, thus enabling prognostic stratification.

Different Microeukaryotic Trophic Groups Show Different Latitudinal Spatial Scale Dependences in Assembly Processes across the Continental Shelves of China.

The relative role of stochasticity versus determinism is critically dependent on the spatial scale over which communities are studied. However, only a few studies have attempted to reveal how spatial scales influence the balance of different assembly processes. In this study, we investigated the latitudinal spatial scale dependences in assembly processes of microeukaryotic communities in surface water and sediment along the continental shelves of China. It was hypothesized that different microeukaryotic trophic groups (i.e., autotroph, heterotroph, mixotroph, and parasite) showed different latitudinal scale dependences in their assembly processes. Our results disclosed that the relative importance of different assembly processes depended on a latitudinal space scale for planktonic microeukaryotes. In surface water, as latitudinal difference increased, the relative contributions of homogenous selection and homogenizing dispersal decreased for the entire community, while those of heterogeneous selection and drift increased. The planktonic autotrophic and heterotrophic groups shifted from stochasticity-dominated processes to heterogeneous selection as latitudinal differences surpassed thresholds of 8° and 16°, respectively. For mixotrophic and parasitic groups, however, the assembly processes were always dominated by drift across different spatial scales. The balance of different assembly processes for the autotrophic group was mainly driven by temperature, whereas that of the heterotrophic group was driven by salinity and geographical distance. In sediment, neither the entire microeukaryotic community nor the four trophic groups showed remarkable spatial scale dependences in assembly processes; they were always overwhelmingly dominated by the drift. This work provides a deeper understanding of the distribution mechanisms of microeukaryotes along the continental shelves of China from the perspective of trophic groups.

How antibiotic exposure affect predator-prey interactions by population dynamics in ciliates?

Biodiversity loss resulting from environmental pollution is a global concern. While interspecific interactions are central to ecology, the impact of environmental pollution on predator-prey interactions and its ecological consequences, such as extinction and biodiversity loss, remain unclear. To investigate the effects of antibiotic exposure on predation strength and the resulting ecological consequence, the Didinium-Paramecium was utilized as a predator-prey model and exposed to nitrofurazone or erythromycin, two common pollutants, respectively. Initially, we determined prey population growth dynamics, body size, and predator numerical-functional responses. Subsequently, these above parameters were integrated into a mathematical model of predator-prey predation. Then both the long time-series data and phase portraits obtained through model simulation were used to estimate interaction strength and to predict the outcome of predator-prey coexistence. Our results revealed that exposure to either antibiotic significantly reduced prey population growth parameters (e.g., µmax and K) while increasing individual body size. The combined effects of antibiotic exposure and predation pressure on population growth inhibition or body size promotion were variable, mostly additive, with a few cases of synergy and extremely rare antagonism, depending on antibiotic exposure concentration. As antibiotic exposure concentration increased, the predator rmax generally declined, while functional responses varied depending on specific parameters, implying a decrease in predator-prey interaction strength. Analyses of phase portrait features showed that the population oscillation amplitude decreased with increasing antibiotic exposure concentrations, the cycle length of adjacent peaks increased, and prey extinction occurred earlier. In conclusion, antibiotic exposure reduced both predator and prey fitness, underlying the reason antibiotics reduces the strength of predator-prey interaction. Despite the indirect benefits of prey gain from this, the presence of predators can expedite the process of prey extinction caused by antibiotic exposure.

Hanging Photothermal Fabric Based on Polyaniline/Carbon Nanotubes for Efficient Solar Water Evaporation.

Solar-driven water evaporation is essential to provide sustainable and ecofriendly sources of fresh water. However, there are still great challenges in preparing materials with broadband light absorption for high photothermal efficiency as well as in designing devices with large evaporation areas and small heat dissipation areas to boost the water evaporation rate. We designed a hanging-mode solar evaporator based on the polyaniline/carbon nanotube (PANI/CNT) fabric, in which the photothermal fabric acts as the solar evaporator and the micropores on the cotton fabric act as the water transfer channels. The hanging mode provides efficient evaporation at both interfaces by greatly reducing the heat dissipation area. The hanging mode PANI/CNT fabric solar evaporator can achieve an evaporation rate of 2.81 kg·m-2·h-1 and a photothermal efficiency of 91.74% under a solar illumination of 1 kW·m-2. This high-performance evaporator is designed by regulating the photothermal material and evaporation device, which provides a novel strategy for sustainable desalination.

The antipsychotic drug penfluridol inhibits N-linked glycoprotein processing and enhances T-cell-mediated tumor immunity.

Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface Wheat germ agglutinin (WGA) staining. In the presence of penfluridol, cell membrane glycoproteins PD-L1 shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man5-7GlcNAc2 glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between PD-1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the anti-tumor effect of the anti-PD-L1 antibody in vivo. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in anti-tumor therapy through activation of T-cell immunity.

Silibinin Prevents TGFß-Induced EMT of RPE in Proliferative Vitreoretinopathy by Inhibiting Stat3 and Smad3 Phosphorylation.

Purpose: The purpose of this study was to investigate the effects of silibinin on epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) and proliferative vitreoretinopathy (PVR) formation, as well as its underlying molecular mechanism. Methods: Cellular morphological change and EMT molecular markers were evaluated by using phase contrast imaging, qPCR, and Western blot (WB) to investigate the impact of silibinin on the EMT of ARPE-19 cells. Scratch assay and transwell assay were used to study the effect of silibinin on cell migration. An intravitreally injected RPE-induced rat PVR model was used to assess the effect of silibinin on PVR in vivo. RNA-seq was applied to study the molecular mechanism of silibinin-mediated PVR prevention. Results: Silibinin inhibited TGFß1-induced EMT and migration of RPE in a dose-dependent manner in vitro. Moreover, silibinin prevented proliferative membrane formation in an intravitreal injected RPE-induced rat PVR model. In line with these findings, RNA-seq revealed a global suppression of TGFß1-induced EMT and migration-related genes by silibinin in RPEs. Mechanistically, silibinin reduced TGFß1-induced phosphorylation levels of Smad3 and Stat3, and Smad3 nuclear translocation in RPE. Conclusions: Silibinin inhibits the EMT of RPE cells in vitro and prevents the formation of PVR membranes in vivo. Mechanistically, silibinin inhibits Smad3 phosphorylation and suppresses Smad3 nuclear translocation through the inhibition of Stat3 phosphorylation. These findings suggest that silibinin may serve as a potential treatment for PVR.

Metal-organic frameworks/metal nanoparticles as smart nanosensing interfaces for electrochemical sensors applications: a mini-review.

Metal-organic frameworks (MOFs) are porous materials with huge specific surface area and abundant active sites, which are composed of metal ions or clusters and organic ligands in the form of coordination bonds. In recent years, MOFs have been successfully applied in many fields due to their excellent physical, chemical, and biological properties. Electrochemical sensors have advantages such as economy, portability, and sensitivity, making them increasingly valued in the field of sensors. Many studies have shown that the electrode materials will affect the performance of electrochemical sensors. Therefore, the research on electrode materials is still one of the hotspots. MOFs are also commonly used to construct electrochemical sensors. However, electrochemical sensors prepared from single MOFs have shortcomings such as insufficient conductivity, low sensitivity, and poor electrochemical catalytic ability. In order to compensate for these defects, a new type of nanocomposite material with very ideal conductivity was formed by adding metal nanoparticles (MNPs) to MOFs. The combination of the two is expected to be widely applied in the field of sensors. This review summarizes the applications of various MNPs/MOFs composites in the field of electrochemical sensors and provides some references for the development of MNPs/MOFs composites-based electrochemical sensors in the future.

Construction and mechanism study of lignin-based polyurethane with high strength and high self-healing properties.

Lignin is a natural polymer with abundant functional groups with great application prospects in lignin-based polyurethane elastomers with self-healing abilities. In this study, a lignin self-healing polyurethane (PUDA-L) was specially designed using lignin as the raw material of polyurethane, combining lignin with Diels-Alder (DA) bond and hydrogen bonds. The experimental results showed that PUDA-L was prepared with good thermal stability, fatigue resistance, shape memory effect, excellent mechanical strength, and self-healing ability by partially replacing the crosslinking agents with bio-based lignin and hydroxylated modified lignin to increase the hydroxyl content. Polyurethane has a tensile strength of up to 29 MPa and an elongation at break of up to 500 %. The excellent self-healing ability of PUDA-L originates from the internal DA bonds and cross-linked hydrogen bonds. After the dumbbell sample was fused and heated at 130 °C for 4 h, the elastomer could be completely healed, the tensile strength was restored to 29 MPa, and the self-healing efficiency was up to 100 %. The developed PUDA-L elastomer has promising applications in sensors and smart skins.

Clinical Features, Antibiotic Susceptibilities, and Outcomes of Endophthalmitis Caused by Streptococcal Infection: Children vs. Adults.

Streptococcus spp. are common causative organisms of endophthalmitis. Analysis of the clinical features, antibiotic susceptibilities, and outcomes of streptococcal endophthalmitis in children and adults may guide future management. Sixty-seven patients (67 eyes) with streptococcal endophthalmitis who were admitted to the Zhongshan Ophthalmic Center between January 2013 and December 2022 were retrospectively reviewed. The mean age was 20.7 ± 21.6 years, and 59.7% were children. Streptococcal infection accounted for 13.9% of culture-proven bacterial endophthalmitis cases; the proportion was higher in children than in adults (32.3% vs. 7.6%, p < 0.01) and increased from 8.1% in 2013-2017 to 20.1% in 2018-2022 (p < 0.01). Eye trauma was the most common etiology in both children and adults (82.5% and 66.7%, respectively). Viridans group streptococci were the most common isolates, followed by S. pneumoniae. The susceptibility rates of the streptococci to vancomycin, cefuroxime, and levofloxacin were 100%, 95.5%, and 93.0%, respectively. The overall mean best-corrected visual acuity increased from 2.74 ± 0.19 logMAR initially to 2.32 ± 0.75 logMAR at the last follow-up (p < 0.05). In conclusion, streptococcal infections have increased in cases of bacterial endophthalmitis in recent years and are more common in children. The commonly used antibiotics, vancomycin, cefuroxime, and fluoroquinolone, showed higher antibiotic susceptibility. After prompt treatment, visual outcomes improved.

EE-Explorer: A Multimodal Artificial Intelligence System for Eye Emergency Triage and Primary Diagnosis.

PURPOSE: To develop a multimodal artificial intelligence (AI) system, EE-Explorer, to triage eye emergencies and assist in primary diagnosis using metadata and ocular images. DESIGN: A diagnostic, cross-sectional, validity and reliability study. METHODS: EE-Explorer consists of 2 models. The triage model was developed from metadata (events, symptoms, and medical history) and ocular surface images via smartphones from 2038 patients presenting to Zhongshan Ophthalmic Center (ZOC) to output 3 classifications: urgent, semiurgent, and nonurgent. The primary diagnostic model was developed from the paired metadata and slitlamp images of 2405 patients from ZOC. Both models were externally tested on 103 participants from 4 other hospitals. A pilot test was conducted in Guangzhou to evaluate the hierarchical referral service pattern assisted by EE-Explorer for unspecialized health care facilities. RESULTS: A high overall accuracy, as indicated by an area under the receiver operating characteristic curve (AUC) of 0.982 (95% CI, 0.966-0.998), was obtained using the triage model, which outperformed the triage nurses (P < .001). In the primary diagnostic model, the diagnostic classification accuracy (CA) and Hamming loss (HL) in the internal testing were 0.808 (95% CI 0.776-0.840) and 0.016 (95% CI 0.006-0.026), respectively. In the external testing, model performance was robust for both triage (average AUC, 0.988, 95% CI 0.967-1.000) and primary diagnosis (CA, 0.718, 95% CI 0.644-0.792; and HL, 0.023, 95% CI 0.000-0.048). In the pilot test in the hierarchical referral settings, EE-explorer demonstrated consistently robust performance and broad participant acceptance. CONCLUSION: The EE-Explorer system showed robust performance in both triage and primary diagnosis for ophthalmic emergency patients. EE-Explorer can provide patients with acute ophthalmic symptoms access to remote self-triage and assist in primary diagnosis in unspecialized health care facilities to achieve rapid and effective treatment strategies.

Co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia predict prognosis and immunotherapy response in glioblastoma.

OBJECTIVES: Anesthetic drugs had been reported may impact the bio-behavior of the tumor. Propofol and sevoflurane are common anesthetics in the operation for glioblastoma (GBM). This study aims to establish a co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia to predict prognosis and immunotherapy response in GBM. METHOD: GPM tissues with different anesthetics gene expression profiles (GSE179004) were obtained from the Gene Expression Omnibus (GEO) database. Core modules and central genes associated with propofol and sevoflurane anesthesia were identified by weighted gene coexpression network analysis (WGCNA) and establish a risk score prognostic model. Immune cell signature analysis in TCGA datasets was predicted via CIBERSORT. At last, serum methylation level of O6-methylguanine-DNA methyltransferase (MGMT) promoter was detected in GPM patient in different time during perioperative period. RESULTS: The burlywood1 group screened was significantly associated with sevoflurane-treated GBM tissue. 22 independent prognostic differential genes were construct a prognostic-related genes risk score in GBM, and showed good predictive ability. The risk score was strongly correlated with the age of the patients, but not with the sex of the patients. In addition, the differential responses to immunotherapy in high and low risk groups were analyzed, indicating that sevoflurane signature genes were consistent in the classification of gliomas. High-risk patients have high T-cell damage score and are less sensitive to immunotherapy. At last, serum methylation level of MGMT promoter was decreased in GBM patients during propofol and sevoflurane anesthesia. CONCLUSIONS: Propofol and sevoflurane anesthesia associated impact on the gene expression of GBM, included the methylation level of MGMT promoter. Propofol and sevoflurane anesthesia-based risk score prognostic model, which has good prognostic power and is an independent prognostic factor in GBM patients. Therefore, this model can be used as a new biomarker for judging the prognosis of GBM patients.KEY MESSAGESPropofol and sevoflurane anesthesia-based risk score prognostic model has good prognostic power and is an independent prognostic factor in GBM patients.High Propofol and sevoflurane anesthesia-based risk score GBM patients have high T-cell damage scores and are less sensitive to immunotherapy.Serum methylation level of MGMT promoter decrease during propofol and sevoflurane anesthesia in GBM patients.