Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6.

PURPOSE: Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and have achieved inspiring curative effects. But some discoveries have indicated that CDK 4/6 are not the requisite factors in some cell types because CDK2 partly compensates for the inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 inhibitors for significantly enhancing their potency. This study aims to explore the mechanism of the binding of CDK2/4/6 kinases and their inhibitors to design novel CDK2/4/6 inhibitors for significantly enhancing their potency in different kinds of cancers. MATERIALS AND METHODS: A series of 72 disparately functionalized 4-substituted N-phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 and CDK6 were collected to apply to this research. The total set of these derivatives was divided into a training set (54 compounds) and a test set (18 compounds). The derivatives were constructed through the sketch molecule module in SYBYL 6.9 software. A Powell gradient algorithm and Tripos force field were used to calculate the minimal structural energy and the minimized structure was used as the initial conformation for molecular docking. By the means of 3D-QSAR models, partial least squares (PLS) analysis, molecular dynamics (MD) simulations and binding free energy calculations, we can find the relationship between structure and biological activity. RESULTS: In this study, we used molecular docking, 3D-QSAR and molecular dynamics simulation methods to comprehensively analyze the interaction and structure-activity relationships of 72 new CDK2/4/6 inhibitors. We used detailed statistical data to reasonably verify the constructed 3D-QSAR models for three receptors (q2 of CDK2 = 0.714, R2pred = 0.764, q2 = 0.815; R2pred of CDK4 = 0.681, q2 = 0.757; R2pred of CDK6 = 0.674). MD simulations and decomposition energy analysis validated the reasonability of the docking results and identified polar interactions as crucial factors that influence the different bioactivities of the studied inhibitors of CDK2/4/6 receptors, especially the electrostatic interactions of Lys33/35/43 and Asp145/158/163. The nonpolar interaction with Ile10/12/19 was also critical for the differing potencies of the CDK2/4/6 inhibitors. We concluded that the following probably enhanced the bioactivity against CDK2/4/6 kinases: (1) electronegative groups at the N1-position and electropositive and moderate-sized groups at ring E; (2) electrogroups featured at R2; (3) carbon atoms at the X-position or ring C replaced by a benzene ring; and (4) an electrogroup as R4. CONCLUSION: Previous studies, to our knowledge, only utilized a single approach of 3D-QSAR and did not integrate this method with other sophisticated techniques such as molecular dynamics simulations to discover new potential inhibitors of CDK2, CDK4, or CDK6. So we applied the intergenerational technology, such as 3D-QSAR technology, molecular docking simulation techniques, molecular dynamics simulations and MMPBSA19/MMGBSA20-binding free energy calculations to statistically explore the correlations between the structure with biological activities. The constructed 3D-QSAR models of the three receptors were reasonable and confirmed by the excellent statistical data. We hope the results obtained from this work will provide some useful references for the development of novel CDK2/4/6 inhibitors.

CABP4 mutation in mice shows alteration in protein expression level and neuron discharge frequency.

Background: The calcium-binding protein 4 (CABP4) gene is a newly identified epilepsy-related gene that might be associated with a rare type of genetic focal epilepsy; that is, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro, mutant CABP4 causes an increased inward flow voltage of calcium ions and a significant increase in the electrical signal discharge in hippocampus neurons; however, the role of CABP4 in epilepsy has not yet been specifically described, and there is not yet a CABP4 mutant animal model recapitulating the epilepsy phenotype. Methods: We introduced a human CABP4 missense mutation into the C57BL/6J mouse genome and generated a knock-in strain carrying a glycine-to-aspartic acid mutation in the gene. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to evaluate the CABP4 expression level. Slice patch-clamp recording was carried out on pyramidal cells of prefrontal cortex layers II and III. Results: The CABP4G155D/+ mutant mice were viable and born at an expected Mendelian ratio. Surprisingly, the heterozygous (HE) mice did not display either an abnormal appearance or an overt seizure phenotype, and there was no statistically significant difference between the HE and wild-type (WT) mice in terms of overall messenger RNA (mRNA) and protein expression. However, the HE mutant mice showed an imbalance in the amount of protein expressed in the brain regions. Additionally, the patch-clamp recordings from the HE mouse layer II/III cortical pyramidal cells revealed an increase in the frequency of micro-excitatory post-synaptic currents (mEPSCs) but no change in the amplitude was observed. Conclusions: The findings of this study suggest that the CABP4 p.G155D mutation might be one of the mechanisms underlying seizure onset.

Investigation of multiple nosocomial infections using a semi-Markov multi-state model.

BACKGROUND: The prevalence of multiple nosocomial infections (MNIs) is on the rise, however, there remains a limited comprehension regarding the associated risk factors, cumulative risk, probability of occurrence, and impact on length of stay (LOS). METHOD: This multicenter study includes all hospitalized patients from 2020 to July 2023 in two sub-hospitals of a tertiary hospital in Guangming District, Shenzhen. The semi-Markov multi-state model (MSM) was utilized to analyze risk factors and cumulative risk of MNI, predict its occurrence probability, and calculate the extra LOS of nosocomial infection (NI). RESULTS: The risk factors for MNI include age, community infection at admission, surgery, and combined use of antibiotics. However, the cumulative risk of MNI is lower than that of single nosocomial infection (SNI). MNI is most likely to occur within 14 days after admission. Additionally, SNI prolongs LOS by an average of 7.48 days (95% Confidence Interval, CI: 6.06-8.68 days), while MNI prolongs LOS by an average of 15.94 days (95% CI: 14.03-18.17 days). Furthermore, the more sites of infection there are, the longer the extra LOS will be. CONCLUSION: The longer LOS and increased treatment difficulty of MNI result in a heavier disease burden for patients, necessitating targeted prevention and control measures.

Unveiling the role of RAC3 in the growth and invasion of cisplatin-resistant bladder cancer cells.

Bladder cancer is one of the most prevalent cancers worldwide, and its morbidity and mortality rates have been increasing over the years. However, how RAC family small GTPase 3 (RAC3) affects the proliferation, migration and invasion of cisplatin-resistant bladder cancer cells remains unclear. Bioinformatics techniques were used to investigate the expression of RAC3 in bladder cancer tissues. Influences of RAC3 in the grade, stage, distant metastasis, and survival rate of bladder cancer were also examined. Analysis of the relationship between RAC3 expression and the immune microenvironment (TIME), genomic mutations, and stemness index. In normal bladder cancer cells (T24, 5637, and BIU-87) and cisplatin-resistant bladder cancer cells (BIU-87-DDP), the expression of RAC3 was detected separately with Western blotting. Plasmid transfection was used to overexpress or silence the expression of RAC3 in bladder cancer cells resistant to cisplatin (BIU-87-DDP). By adding activators and inhibitors, the activities of the JNK/MAPK signalling pathway were altered. Cell viability, invasion, and its level of apoptosis were measured in vitro using CCK-8, transwell, and flow cytometry. The bioinformatics analyses found RAC3 levels were elevated in bladder cancer tissues and were associated with a poor prognosis in bladder cancer. RAC3 in BIU-87-DDP cells expressed a higher level than normal bladder cancer cells. RAC3 overexpression promoted BIU-87-DDP proliferation. The growth of BIU-87-DDP cells slowed after the knockdown of RAC3, and RAC3 may have had an impact on the activation of the JNK/MAPK pathway.

Ultrahigh precision laser nanoprinting based on defect-compensated digital holography for fast-fabricating optical metalenses.

The 3D structured light field manipulated by a digital-micromirror-device (DMD)-based digital hologram has demonstrated its superiority in fast-fabricating stereo nanostructures. However, this technique intrinsically suffers from defects of light intensity in generating modulated focal spots, which prevents from achieving high-precision micro/nanodevices. In this Letter, we have demonstrated a compensation approach based on adapting spatial voxel density for fabricating optical metalenses with ultrahigh precision. The modulated focal spot experiences intensity fluctuations of up to 3% by changing the spatial position, leading to a 20% variation of the structural dimension in fabrication. By altering the voxel density to improve the uniformity of the laser cumulative exposure dosage over the fabrication region, we achieved an increased dimensional uniformity from 94.4% to 97.6% in fabricated pillars. This approach enables fast fabrication of metalenses capable of sub-diffraction focusing of 0.44λ/NA with the increased mainlobe-sidelobe ratio from 1:0.34 to 1:0.14. A 6 × 5 supercritical lens array is fabricated within 2 min, paving a way for the fast fabrication of large-scale photonic devices.

Radiating diversification and niche conservatism jointly shape the inverse latitudinal diversity gradient of Potentilla L. (Rosaceae).

BACKGROUND: The latitudinal diversity gradient (LDG), characterized by an increase in species richness from the poles to the equator, is one of the most pervasive biological patterns. However, inverse LDGs, in which species richness peaks in extratropical regions, are also found in some lineages and their causes remain unclear. Here, we test the roles of evolutionary time, diversification rates, and niche conservatism in explaining the inverse LDG of Potentilla (ca. 500 species). We compiled the global distributions of ~ 90% of Potentilla species, and reconstructed a robust phylogenetic framework based on whole-plastome sequences. Next, we analyzed the divergence time, ancestral area, diversification rate, and ancestral niche to investigate the macroevolutionary history of Potentilla. RESULTS: The genus originated in the Qinghai-Tibet Plateau during the late Eocene and gradually spread to other regions of the Northern Hemisphere posterior to the late Miocene. Rapid cooling after the late Pliocene promoted the radiating diversification of Potentilla. The polyploidization, as well as some cold-adaptive morphological innovations, enhanced the adaptation of Potentilla species to the cold environment. Ancestral niche reconstruction suggests that Potentilla likely originated in a relatively cool environment. The species richness peaks at approximately 45 °N, a region characterized by high diversification rates, and the environmental conditions are similar to the ancestral climate niche. Evolutionary time was not significantly correlated with species richness in the latitudinal gradient. CONCLUSIONS: Our results suggest that the elevated diversification rates in middle latitude regions and the conservatism in thermal niches jointly determined the inverse LDG in Potentilla. This study highlights the importance of integrating evolutionary and ecological approaches to explain the diversity pattern of biological groups on a global scale.

OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.

Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.

Analysis of cancer-associated fibroblasts related genes identifies COL11A1 associated with lung adenocarcinoma prognosis.

BACKGROUND: The treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma. METHODS: The Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated. RESULTS: Using the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma. CONCLUSION: COL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.

Evaluation and clinical significance of contrast-enhanced ultrasound on changes in liver blood flow perfusion after TIPS surgery.

To investigate the clinical value of contrast-enhanced ultrasound in the prediction of hepatic encephalopathy (HE) in patients with hepatitis B cirrhosis after intrahepatic portal-systemic shunt via jugular vein. In this retrospective study, we collected data from 75 patients with hepatitis B, cirrhosis, and portal hypertension who underwent jugular intrahepatic portosystemic shunt from February 2019 to February 2022. The diagnostic instrument used was the TOSHIBA Aplio500 color Doppler ultrasound with contrast-enhanced ultrasound capabilities. The trial group comprised 20 patients with HE within 3 months postsurgery, while the control group (CG) included 55 patients without HE within the same postoperative period. All patients underwent various examinations before and within 48 hours after surgery, including observation of liver and spleen size and stent position, as well as assessment of blood flow direction in portal and hepatic veins. Subsequently, contrast-enhanced ultrasound was employed to examine and observe perfusion changes of contrast agents in hepatic veins, hepatic arteries, and portal veins (PV). Changes in PV pressure gradient, intrahepatic, and stent blood flow perfusion (BFP) were explored in both postoperative trials and CGs. The trial group exhibited higher BFP volume, PV pressure gradient difference, and percentage decrease compared to the CG. A weak positive correlation was observed between blood flow within the liver stent and PV pressure gradient difference, as well as the percentage decrease in PV pressure gradient. The correlation coefficient between blood flowing perfusion volume within the stent and the difference in PV pressure gradient was R = 0.415 (P = .000). The correlating coefficient between BFP amount within the stent and the percentage decrease in PV pressure gradient was R = 0.261 (P = .027). The area under the receiver operating characteristic curve for stent perfusion volume, difference in PV pressure gradient, and percentage decrease in PV pressure gradient was 0.691, 0.759, and 0.742, respectively. An increase in PV pressure gradient accelerates blood flow within the stent, predisposing to HE. Changes in hepatic BFP following transjugular intrahepatic portosystemic shunt can effectively predict the occurrence of HE, demonstrating significant clinical relevance.

Physically based simulation of focusing schlieren imaging for a hypersonic boundary layer flow.

Focusing schlieren systems are more advantageous than conventional schlieren systems in providing a schlieren image with certain spatial discrimination along the light path. The present work employed a hybrid of the optical-transfer matrix and ray-tracing method to faithfully replicate complete physical imaging processes throughout a focusing schlieren optic system. A direct numerical simulation of a hypersonic boundary layer flow was employed to synthesize focusing schlieren images. The influence of various configuration parameters on the properties of focusing schlieren image such as local schlieren structure, brightness, sensitivity, and depth of field were systematically explored. In addition, an approximation method was proposed as a simplified means to facilitate the simulation of a focusing schlieren image.

Using Machine Learning and Finite Element Analysis to Extract Traction-Separation Relations at Bonding Wire Interfaces of Insulated Gate Bipolar Transistor Modules.

For insulated gate bipolar transistor (IGBT) modules using wire bonding as the interconnection method, the main failure mechanism is cracking of the bonded interface. Studying the mechanical properties of the bonded interface is crucial for assessing the reliability of IGBT modules. In this paper, first, shear tests are conducted on the bonded interface to test the bonded interface's strength. Then, finite element-cohesive zone modeling (FE-CZM) is established to describe the mechanical behavior of the bonded interface. A novel machine learning (ML) architecture integrating a convolutional neural network (CNN) and a long short-term memory (LSTM) network is used to identify the shape and parameters of the traction separation law (TSL) of the FE-CZM model accurately and efficiently. The CNN-LSTM architecture not only has excellent feature extraction and sequence-data-processing abilities but can also effectively address the long-term dependency problem. A total of 1800 sets of datasets are obtained based on numerical computations, and the CNN-LSTM architecture is trained with load-displacement (F-δ) curves as input parameters and TSL shapes and parameters as output parameters. The results show that the error rate of the model for TSL shape prediction is only 0.186%. The performance metric's mean absolute percentage error (MAPE) is less than 3.5044% for all the predictions of the TSL parameters. Compared with separate CNN and LSTM architectures, the proposed CNN-LSTM-architecture approach exhibits obvious advantages in recognizing TSL shapes and parameters. A combination of the FE-CZM and ML methods in this paper provides a promising and effective solution for identifying the mechanical parameters of the bonded interfaces of IGBT modules.

Multifocal meta-fiber based on the fractional Talbot effect.

Multi-focusing of light is a crucial capability for photonic devices that can be effectively achieved by precisely modulating the phase delay on the incident wavefront. However, integrating functional structures into optical fibers for remote light focusing remains challenging due to the complex device design and limited fabrication approaches. Here, we present the design and fabrication of metalens array on the end-face of a tailored single-mode step-index fiber for focusing light field into closely packed focal spot array. The metalenses are configured based on the fractional Talbot effect and benefit a modular design capability. Light passing through the optical fiber can be focused into different focal planes. With a synergistic 3D laser nanoprinting technique based on two-photon polymerization, high-quality meta-fibers are demonstrated for focusing light parallelly with a uniform numerical aperture (NA) as high as approximately 0.77. This may facilitate various applications such as optical trapping, generation of sophisticated beam profiles, and boosting light coupling efficiencies.

A statistical learning method for simultaneous copy number estimation and subclone clustering with single-cell sequencing data.

The availability of single-cell sequencing (SCS) enables us to assess intra-tumor heterogeneity and identify cellular subclones without the confounding effect of mixed cells. Copy number aberrations (CNAs) have been commonly used to identify subclones in SCS data using various clustering methods, as cells comprising a subpopulation are found to share a genetic profile. However, currently available methods may generate spurious results (e.g., falsely identified variants) in the procedure of CNA detection, thereby diminishing the accuracy of subclone identification within a large, complex cell population. In this study, we developed a subclone clustering method based on a fused lasso model, referred to as FLCNA, which can simultaneously detect CNAs in single-cell DNA sequencing (scDNA-seq) data. Spike-in simulations were conducted to evaluate the clustering and CNA detection performance of FLCNA, benchmarking it against existing copy number estimation methods (SCOPE, HMMcopy) in combination with commonly used clustering methods. Application of FLCNA to a scDNA-seq data set of breast cancer revealed different genomic variation patterns in neoadjuvant chemotherapy-treated samples and pretreated samples. We show that FLCNA is a practical and powerful method for subclone identification and CNA detection with scDNA-seq data.

Engineering High-Tortuosity 3D Gradient Structure and CFD-Assisted Multifield Analysis for Solar Interfacial Evaporation.

Solar interfacial evaporation is a promising method for solving the global shortage of fresh water. While 2D evaporators can efficiently localize solar-converted heat at the thin layer of the water-air interface, 3D solar evaporators can maximize energy reutilization while maintaining effective mass transport ability, few studies are conducted to explore the effect of gradient porosity on evaporation performance. In this study, a multifield assisted strategy based on a gradient 3D structure with high tortuosity is proposed, which creates a thermal field environment for efficient evaporation through high absorption of sunlight and excellent photothermal conversion and uses the gradient structure to optimize the internal pressure field to enhance water evaporation and transport. This hierarchically nanostructured solar absorber, with porosity inhomogeneity-induced pressure gradient and optimized temperature management, is a valuable design idea for manufacturing a more efficient 3D solar evaporator in the field of seawater desalination. Owing to the understanding of optimizing the dimension by various simulation parameters, the evaporation efficiencies of such structures are found to be 165.7%, suppressing the most evaporator. Moreover, it can provide new ideas and references for the fields of mass transfer and thermal management.

Telemedicine network latency management system in 5G telesurgery: a feasibility and effectiveness study.

BACKGROUND: Network latency is the most important factor affecting the performance of telemedicine. The aim of the study is to assess the feasibility and efficacy of a novel network latency management system in 5G telesurgery. METHODS: We conducted 20 telesurgery simulation trials (hitching rings to columns) and 15 remote adrenalectomy procedures in the 5G network environment. Telemedicine Network Latency Management System and the traditional "Ping command" method (gold standard) were used to monitor network latency during preoperative simulated telesurgery and formal telesurgery. We observed the working status of the Telemedicine Network Latency Management System and calculated the difference between the network latency data and packet loss rate detected by the two methods. In addition, due to the lower latency of the 5G network, we tested the alert function of the system using the 4G network with relatively high network latency. RESULTS: The Telemedicine Network Latency Management System showed no instability during telesurgery simulation trials and formal telesurgery. After 20 telesurgery simulation trials and 15 remote adrenalectomy procedures, the p-value for the difference between the network latency data monitored by the Telemedicine Network Latency Management System and the "Ping command" method was greater than 0.05 in each case. Meanwhile, the surgeons reported that the Telemedicine Network Latency Management System had a friendly interface and was easy to operate. Besides, when the network latency exceeded a set threshold, a rapid alarm sounded in the system. CONCLUSION: The Telemedicine Network Latency Management System was simple and easy to operate, and it was feasible and effective to use it to monitor network latency in telesurgery. The system had an intuitive and concise interface, and its alarm function increased the safety of telesurgery. The system's own multidimensional working ability and information storage capacity will be more suitable for telemedicine work.

LTN1 promotes RLR degradation to inhibit immune response to RNA virus through the ESCRT pathway.

The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiquitinated protein degradation, which timely terminates signaling pathway hyperactivation. However, whether the ESCRT system participates in regulating RIGI-like receptor (RLR)-mediated antiviral responses remains unknown. In this study, we show that LTN1/listerin, a major component of RQC, can recruit E3 ubiquitin ligase TRIM27 to trigger K63-linked polyubiquitination of RIGI and IFIH1/MDA5. This K63-linked polyubiquitination facilitates the sorting and degradation of RIGI and IFIH1 proteins through the ESCRT-dependent pathway. Concordantly, LTN1 deficiency enhances the innate antiviral response to infection with RNA viruses. Thus, our work uncovers a new mechanism for RIGI and IFIH1 degradation and identifies the role of LTN1 in negatively regulating RLR-mediated antiviral innate immunity, which may provide new targets for the intervention of viral infection.Abbreviation: 5'-pppRNA: 5' triphosphate double stranded RNA; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; ESCRT: endosomal sorting complexes required for transport; CHX: cycloheximide; IFIH1/MDA5: interferon induced with helicase C domain 1; IFN: interferon; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptors; RQC: ribosome-associated protein quality control; SeV: Sendai virus; TRIM27: tripartite motif-containing 27; VSV: vesicular stomatitis virus; VPS4: vacuolar protein sorting 4.

Dwell time and bloodstream infection incidence of umbilical venous catheterization in China.

Importance: Central line-associated bloodstream infection (CLABSI) is one of the most serious complications of central venous access devices. Reducing the risk of CLABSI is of utmost significance in efforts to improve neonatal mortality rates and enhance long-term prognosis. Objective: To determine the dwell time and incidence of CLABSI of umbilical venous catheterization (UVC) for preterm infants in China. Methods: Preterm infants with UVC admitted to 44 tertiary neonatal intensive care units in 24 provinces in China were enrolled. Study period was from November 2019 to August 2021. The end point of observations was 48 h after umbilical venous (UV) catheter removal. The primary outcomes were dwell time of UV catheter and UVC-associated CLABSI. Data between infants with UV catheter dwell time ≤7 days and >7 days, and with birth weight (BW) ≤1000 g and >1000 g were compared. Results: In total, 2172 neonates were enrolled (gestational age 30.0 ± 2.4 weeks, BW 1258.5 ± 392.8 g). The median UV catheter dwell time was 7 (6-10) days. The incidence of UVC-associated CLABSI was 3.03/1000 UV catheter days. For infants with UV catheter dwell time ≤7 days and >7 days, the UVC-associated CLABSI incidence was 3.71 and 2.65 per 1000 UV catheter days, respectively, P = 0.23. For infants with UVC dwell times of 3-6, 7-12, and 13-15 days, the UVC-associated CLABSI rates were 0.14%, 0.68%, and 2.48% (P < 0.01). The Kaplan-Meier plot of UV catheter dwell time to CLABSI showed no difference between infants with BW ≤1000 g and >1000 g (P = 0.60). Interpretation: The median dwell time of UV catheter was 7 days, and the incidence of UVC-associated CLABSI was 3.03/1000 catheter days in China. The daily risk of UVC-associated CLABSI and other complications increased with the dwell time.

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.