Trait anxiety is related to an impaired attention model for controllable threat cues: Evidence from ERPs.

Attentional bias to threat cues is maladaptive for individuals with high trait anxiety (HTA), but may become adaptive when the dangers signaled by these cues can be controlled by timely actions. However, it remains unclear how HTA individuals allocate attention to controllable threat cues. The current study examined whether trait anxiety is associated with an impaired attention model for controllable threat cues and explored the related underlying neural mechanisms. A sample of 21 participants with low trait anxiety (LTA) and 21 with HTA completed a modified cued anticipation task which allowed participants to control the appearance of threatening pictures associated with controllable threat cues. Results revealed that HTA individuals had no difference in N1 amplitude among controllable threat cues, uncontrollable threat cues, and neutral cues, while LTA individuals showed the greatest N1 amplitude on controllable cues. HTA individuals also exhibited lower N2 amplitude than LTA individuals. The current study provides electrophysiological evidence showing that HTA individuals have impaired attention for processing controllable threat cues and weak inhibitory control. Deficient attention to controllable threat cues may be crucial in the mechanisms underlying trait anxiety.

Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens.

Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution1-11. However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial12, we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases13, we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena.

Focused ultrasound-mediated brain genome editing.

Gene editing in the mammalian brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.

Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the "gold standard" for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative 27 (S19-1035) exhibits an IC50 value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.

Rapid and sensitive quantification of cyclamate in beverages by miniature microplasma optical emission spectrometry.

Most of the available methods for the quantification of cyclamate depend on laboratory instruments and their application in the field was limited. Herein, a simple and sensitive method was developed for the determination of cyclamate in beverage samples based on chemical vapor generation and miniature point discharge optical emission spectrometry (µPD-OES). The combination of headspace sampling and µPD-OES not only simplifies the separation process of cyclamate, improves sensitivity, and alleviates matrix interference but also eliminates the use of a bulky and expensive instrument. Under the optimal conditions, this method provided a limit of detection of 0.1 mg L-1 comparable to or better than most reported methods. The method eventually was applied to 14 different beverages and cyclamate was found below the threshold set by Chinese Standards for Food Additives. The proposed method provides great potential for the field analysis of cyclamate in the supervision of food safety.

Application of deblur technology for improving the clarity of digital subtractive angiography.

BACKGROUND: Digital subtraction angiography (DSA) is most commonly used in vessel disease examinations and treatments. We aimed to develop a novel deep learning-based method to deblur the large focal spot DSA images, so as to obtain a clearer and sharper cerebrovascular DSA image. METHODS: The proposed network cascaded several residual dense blocks (RDBs), which contain dense connected layers and local residual learning. Several loss functions for image restoration were investigated. Our training set consisted of 52 paired images of angiography with more than 350,000 cropped patches. The testing set included 10 body phantoms and 80 clinical images of different types of diseases for subjective evaluation. All test images were acquired using a large focal spot, and phantom images were simultaneously acquired using a micro focal spot as ground-truth. Peak-to-noise ratio (PSNR) and structural similarity (SSIM) were determined for quantitative analysis. The deblurring results were compared with the original data, and the image quality was subjectively evaluated and graded by two clinicians. RESULTS: For quantitative analysis of phantom images, the average PSNR/SSIM based on the deep-learning approach (35.34/0.9566) was better than that of large focal spot images (30.64/0.9163). For subjective evaluation of 80 clinical patient images, image quality in all types of cerebrovascular diseases was also improved based on a deep-learning approach (p < 0.001). CONCLUSIONS: Deep learning-based focal spot deblur algorithm can efficiently improve DSA image quality for better visualization of blood vessels and lesions in the image.

Efficient Synthesis and Evaluation of Novel Sulfonated Dihydropyrimidinthione Derivatives for the Treatment of UV-B Induced Corneal Damage.

UV-B induced corneal damage remains a challenge in clinics, and it is needed to develop novel and effective medicines against UV-B induced photodamage. 3,4-Dihydropyrimidine-2(1H)-thione derivatives have shown many interesting biological activities, including antibacterial, anti-inflammatory, antioxidant, etc. In order to find a promising anti-corneal photodamage agent, we designed and synthesized two novel sulfonated dihydropyrimidinthione derivatives to evaluate cytoprotective effect against UV-B mediated photodamage. With simple structure, compound 6 possessed good water solubility, photostability and biocompatibility. We demonstrated that 6 exhibited significant cytoprotective effects against UV-B mediated photodamage and the cell viability was up to 93% at 0.2 mg/mL. The corneal cells were highly sensitive to UV-B radiation, resulting in the release of inflammatory mediators and DNA damage, which were significantly reversed by 6. Moreover, compound 6 reduced Bax and cleaved Caspase-3 expressions to suppress UV-B mediated the intrinsic apoptosis pathway. Our findings suggest that 6 is a promising UV-B resistant agent with potential to be a promising drug candidate for the treatment of corneal photodamage.

Coarctation of aorta combined with multiple aneurysms.

We reported a case of a 53-year-old patient with coarctation of the aorta and multiple aneurysmatic changes on the aortic arch. Enhanced computed tomography and reconstruction revealed significant coarctation and multiple aneurysmatic dilatations. The patient underwent stent implantation and was discharged with symptoms relieved. Follow-up examination progression of aneurysms, however, without symptoms.

Analysis of Size-Dependent Linear Static Bending, Buckling, and Free Vibration Based on a Modified Couple Stress Theory.

The purposes of this paper are to study bending, buckling, and vibration by considering micro-scale effects using the Kirchhoff thin-plate theory and to consider small deflections, neglecting higher-order nonlinear terms. The governing equations for the bending, buckling, and vibration of the system are obtained using the equilibrium method coupled with the Kirchhoff thin-plate theory and a modified couple stress theory (MCST). The concept of the equivalent bending stiffness (EBS) of micro-thin plates is proposed to describe the scale effect. The Navier method is used to obtain analytical solutions for the bending, buckling, and free vibration of thin plates under simply supported boundary conditions with scale effects. The numerical results are presented to investigate the influence of scale effects on deflection, critical buckling load, buckling topography, and thin-plate natural frequency. The results show that the scale effect increases the equivalent stiffness of the thin plate, which leads to a decrease in deflection, a larger critical buckling load, and an increase in natural frequency, but does not affect the buckling topography. The MSCT is invalid when the thickness is greater than 10 times the scale effect parameter, thus defining the scope of application of the scale effect. This research study may contribute to the design of micro-scale devices such as MEMSs/NEMSs.

LncRNA FENDRR with m6A RNA methylation regulates hypoxia-induced pulmonary artery endothelial cell pyroptosis by mediating DRP1 DNA methylation.

BACKGROUND: Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. METHODS: The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. RESULTS: We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA-DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. CONCLUSION: In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.

Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C125 -DEEA20 ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Short dual antiplatelet therapy in patients with high bleeding risk undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of an abbreviated duration of dual antiplatelet therapy (DAPT) in patients with high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) (PCI-HBR patients) remain controversial. METHODS: The Cochrane Library, PubMed, EMBASE, and Ovid MEDLINE databases were searched. Studies that enrolled PCI-HBR patients as research subjects, compared different DAPT durations, and reported incidences of major adverse cardiac events (MACE) and net adverse clinical events (NACE) in PCI-HBR patients were obtained. The studies were stratified according to the DAPT duration (1, 3, and 6 months), and meta-analysis was subsequently performed. RESULTS: Nine studies (10 cohorts) were included in the meta-analysis. Compared with those who received DAPT for >1 month, PCI-HBR patients who received the 1-month DAPT regimen had comparable risks of NACE and MACE. Compared to those who received DAPT for >3 months, the risk of developing MACE in PCI-HBR patients who received the 3-month DAPT was not increased; however, the risk of ischemic stroke and stent thrombosis increased. Compared to those who received DAPT for >6 months, patients who received the 6-month DAPT had a reduction in the risk of major bleeding without an increase in NACE and MACE. CONCLUSIONS: Shortening the DAPT regimen to 1 or 6 months did not increase the risk of MACE, and the 6-month DAPT regimen reduced the risk of major bleeding. However, the 3-month DAPT regimen increased the risk of ischemic stroke. Thus, shortened DAPT reduced the risk of MACE and bleeding, with a small absolute increase in ischemic strokes.

Antioxidant Biodegradable Covalent Cyclodextrin Frameworks as Particulate Carriers for Inhalation Therapy against Acute Lung Injury.

Drug therapies for acute lung injury (ALI) are far from satisfactory, primarily because drugs cannot specifically target the lungs. Direct delivery of drugs to the deep alveolar regions by inhalation administration is crucial for the treatment of ALI. However, conventional inhalable carriers such as lactose and mannitol are generally inactive. Therefore, the use of a novel pharmacologically active carrier for pulmonary delivery may produce synergetic effects in treating ALI. Considering the pathophysiological environment of ALI, which typically featured excessive reactive oxygen species (ROS) and acute inflammation, we synthesized a novel kind of biodegradable and ROS-sensitive cross-linked covalent cyclodextrin frameworks (OC-COF) with uniform inhalable particle size to treat ALI. OC-COF was devised to incorporate H2O2-scavenging peroxalate ester linkages, which could hydrolyze and eliminate ROS generated in inflammatory sites. Ligustrazine (LIG), an antioxidant and anti-inflammatory natural compound, was loaded into OC-COF and evaluated as a dry powder inhaler (LIG@OC-COF) in vitro and in vivo, showing favorable aerodynamic properties and prominent antioxidant and anti-inflammatory capacities for the synergistic effects of OC-COF and LIG. In ALI rats, inhalation of LIG@OC-COF with a one-fifth LIG dose significantly alleviated the inflammation, oxidant stress, and lung damage. Western blot analysis demonstrated that LIG@OC-COF protected the lungs by regulating the Nrf2/NF-κB signaling pathway. In summary, this study provides a novel ROS-responsive material as an inhalable particulate carrier for the improved treatment of ALI and other medical conditions.

Discovery of Novel Aldo-Keto Reductase 1C3 Inhibitors as Chemotherapeutic Potentiators for Cancer Drug Resistance.

As a crucial target which is overexpressed in a variety of cancers, aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance to many clinical agents. However, a limited number of AKR1C3-selective inhibitors are applied clinically, which indicates the importance of identifying active compounds. Herein, we report the discovery, synthesis, and evaluation of novel and potent AKR1C3 inhibitors with structural diversity. Molecular dynamics simulations of these active compounds provide reasonable clarification of the interpreted biological data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential to be superior therapeutic agents for re-sensitizing drug-resistant cell lines to chemotherapy, especially the pan-AKR1C inhibitor S07-2010. Our study identifies new structural classes of AKR1C3 inhibitors and enriches the structural diversity, which facilitates the future rational design of inhibitors and structural optimization. Moreover, these compounds may serve as promising therapeutic adjuvants toward new therapeutics for countering drug resistance.

Fecal gene detection based on next generation sequencing for colorectal cancer diagnosis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Given its insidious onset, the condition often already progresses to advanced stage when symptoms occur. Thus, early diagnosis is of great significance for timely clinical intervention, efficacy enhancement, and prognostic improvement. Featuring high throughput, fastness, and rich information, next generation sequencing (NGS) can greatly shorten the detection time, which is a widely used detection technique at present. AIM: To screen specific genes or gene combinations in fecal DNA that are suitable for diagnosis and prognostic prediction of CRC, and to establish a technological platform for CRC screening, diagnosis, and efficacy monitoring through fecal DNA detection. METHODS: NGS was used to sequence the stool DNA of patients with CRC, which were then compared with the genetic testing results of the stool samples of normal controls and patients with benign intestinal disease, as well as the tumor tissues of CRC patients. Specific genes or gene combinations in fecal DNA suitable for diagnosis and prognostic prediction of CRC were screened, and their significances in diagnosing CRC and predicting patients' prognosis were comprehensively evaluated. RESULTS: High mutation frequencies of TP53, APC, and KRAS were detected in the stools and tumor tissues of CRC patients prior to surgery. Contrastively, no pathogenic mutations of the above three genes were noted in the postoperative stools, the normal controls, or the benign intestinal disease group. This indicates that tumor-specific DNA was detectable in the preoperative stools of CRC patients. The preoperative fecal expression of tumor-associated genes can reflect the gene mutations in tumor tissues to some extent. Compared to the postoperative stools and the stools in the two control groups, the pathogenic mutation frequencies of TP53 and KRAS were significantly higher for the preoperative stools (χ 2 = 7.328, P < 0.05; χ 2 = 4.219, P < 0.05), suggesting that fecal TP53 and KRAS genes can be used for CRC screening, diagnosis, and prognostic prediction. No significant difference in the pathogenic mutation frequency of the APC gene was found from the postoperative stools or the two control groups (χ 2 = 0.878, P > 0.05), so further analysis with larger sample size is required. Among CRC patients, the pathogenic mutation sites of TP53 occurred in 16 of 27 preoperative stools, with a true positive rate of 59.26%, while the pathogenic mutation sites of KRAS occurred in 10 stools, with a true positive rate of 37.04%. The sensitivity and negative predictive values of the combined genetic testing of TP53 and KRAS were 66.67% (18/27) and 68.97%, respectively, both of which were higher than those of TP53 or KRAS mutation detection alone, suggesting that the combined genetic testing can improve the CRC detection rate. The mutation sites TP53 exon 4 A84G and EGFR exon 20 I821T (mutation start and stop positions were both 7579436 for the former, while 55249164 for the latter) were found in the preoperative stools and tumor tissues. These "undetected" mutation sites may be new types of mutations occurring during the CRC carcinogenesis and progression, which needs to be confirmed through further research. Some mutations of "unknown clinical significance" were found in such genes as TP53, PTEN, KRAS, BRAF, AKT1, and PIK3CA, whose clinical values is worthy of further exploration. CONCLUSION: NGS-based fecal genetic testing can be used as a complementary technique for the CRC diagnosis. Fecal TP53 and KRAS can be used as specific genes for the screening, diagnosis, prognostic prediction, and recurrence monitoring of CRC. Moreover, the combined testing of TP53 and KRAS genes can improve the CRC detection rate.

Particle Design and Inhalation Delivery of Iodine for Upper Respiratory Tract Infection Therapy.

Diseases caused by upper respiratory tract (URT) and pulmonary infections have been a serious threat to human health for millennia and lack of targeted effective therapeutic techniques. In this study, two kinds of cyclodextrin particles with typical particle shapes of nanocubes and microbars were synthesized through a facile process. Subsequently, the particles were used as carriers for loading and stabilizing iodine and characterizations were performed to demonstrate the loading mechanism. Next-generation impactor (NGI) experiments showed that iodine-loaded microbars (I2@microbars) had a deposition rate of 79.75% in URT, while iodine-loaded nanocubes (I2@nanocubes) were delivered to the deep lungs with a fine particle fraction (FPF) of 46.30%. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) indicated that the iodine-loaded nanocubes and microbars had similar bactericidal effect to povidone iodine solution. Cell viability studies and extracellular pro-inflammatory factor (TNF-α, IL-1ß, IL-6) evaluations demonstrate noncytotoxic effects of the blank carriers and anti-inflammatory effects of iodine-loaded samples. The irritation of the rat pharynx by I2@microbars was evaluated for the behavioral observations, body weight changes, histopathological studies, and TNF-α, IL-1ß, and IL-6 levels in pharyngeal tissues. The results showed that I2@microbars had no irritation to rat pharyngeal tissues at therapeutic doses. In conclusion, the present study provides novel treatment of URT infections via supramolecular cyclodextrin carriers for URT local therapy with iodine loading by a solvent-free method, which enhances the stability and reduces the inherent irritation without inhibiting their antimicrobial effects. Two kinds of cyclodextrin particles with typical shapes of microbars and nanocubes were synthesized by a facile process. Subsequently, iodine was successfully loaded into the particles by gas-solid interaction. The iodine-loaded microbars showed air dynamics characteristics for inhalation delivery to the upper respiratory tract with little alveolar deposition in the lungs.

Molecular Triplet Sensitization of Monolayer Semiconductors in 2D Organic/Inorganic Hybrid Heterostructures.

Hybrid heterostructures (HSs) comprising organic and two-dimensional (2D) monolayer semiconductors hold great promise for optoelectronic applications. So far, research efforts on organic/2D HSs have exclusively focused on coupling directly photoexcited singlets to monolayer semiconductors. It remains unexplored whether and how the optically dark triplets in organic semiconductors with intriguing properties (e.g., long lifetime) can be implemented for modulating light-matter interactions of hybrid HSs. Herein, we investigate the triplet sensitization of monolayer semiconductors by time-resolved spectroscopic studies on Pd-octaethylporphyrin (PdOEP)/WSe2 and PdOEP/WS2 HSs with type I and type II band alignment, respectively. We show that PdOEP triplets formed in ∼5 ps from intersystem crossing can transfer energy or charge to WSe2 or WS2 monolayers, respectively, leading to a significant photoluminescence enhancement (180%) in WSe2 or long-lived charge separation (>2 ns) in WS2. The triplet transfer occurs in ∼100 ns, which is more than 3 orders of magnitude slower than singlet and can be attributed to its tightly localized nature. Further study of thickness dependence reveals the dictating role of triplet diffusion for triplet sensitization in organic/2D HSs. This study shows the great promise of much less explored molecular triplets on sensitizing 2D monolayer semiconductors and provides the guidance to achieve long-range light harvesting and energy migration in organic/2D HSs for enhanced optoelectronic applications.

The Neutrophil-to-Lymphocyte Ratio is Associated with the Requirement and the Duration of Invasive Mechanical Ventilation in Acute Respiratory Distress Syndrome Patients: A Retrospective Study.

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality and most ARDS patients require ventilatory support. Applying appropriate ventilation strategies based on patients' individual situations has a direct impact upon patients' outcome. The neutrophil-to-lymphocyte ratio (NLR) has been shown to predict the early requirement of invasive mechanical ventilation (IMV) in patients with coronavirus disease 2019 (COVID-19). Our study aimed to investigate the relationship between baseline NLR and IMV in ARDS. Methods: A retrospective study was performed on patients who were diagnosed with ARDS using the Berlin definition and admitted to the First Affiliated Hospital of Soochow University from 2017 to 2022. Clinical data within 24 h after the ARDS diagnosis were collected from the medical record system. Based on the ventilation strategies during hospitalization, patients were divided into three groups and their clinical characteristics were compared. Furthermore, logistic regression analysis was used to screen the independent risk factors for IMV. STROBE checklist was used for this manuscript. Results: 520 ARDS patients were included and the median NLR value in IMV group was significantly higher than that of other groups (P < 0.001). NLR was significantly associated with the requirement of IMV in ARDS patients (OR, 1.042; 95% CI, 1.025-1.060; P < 0.001), other independent risk factors included PaO2/FiO2, Hb, lactate, and use of vasoactive drugs (all P < 0.05). Moreover, we found that the duration of IMV was longer in patients with high NLR (8[IQR, 3-13], 10[IQR, 6-16], respectively, P=0.025). Conclusions: Our results revealed that high baseline NLR level was significantly correlated with an increased risk of IMV in patients with ARDS. Furthermore, higher NLR was associated with prolonged duration of IMV in patients with ARDS.

Concordant and Heterogeneity of Single-Cell Transcriptome in Cardiac Development of Human and Mouse.

Normal heart development is vital for maintaining its function, and the development process is involved in complex interactions between different cell lineages. How mammalian hearts develop differently is still not fully understood. In this study, we identified several major types of cardiac cells, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), ECs/FBs, epicardial cells (EPs), and immune cells (macrophage/monocyte cluster, MACs/MONOs), based on single-cell transcriptome data from embryonic hearts of both human and mouse. Then, species-shared and species-specific marker genes were determined in the same cell type between the two species, and the genes with consistent and different expression patterns were also selected by constructing the developmental trajectories. Through a comparison of the development stage similarity of CMs, FBs, and ECs/FBs between humans and mice, it is revealed that CMs at e9.5 and e10.5 of mice are most similar to those of humans at 7 W and 9 W, respectively. Mouse FBs at e10.5, e13.5, and e14.5 are correspondingly more like the same human cells at 6, 7, and 9 W. Moreover, the e9.5-ECs/FBs of mice are most similar to that of humans at 10W. These results provide a resource for understudying cardiac cell types and the crucial markers able to trace developmental trajectories among the species, which is beneficial for finding suitable mouse models to detect human cardiac physiology and related diseases.

A highly effective and stable butyrylcholinesterase inhibitor with multi-faceted neuroprotection and cognition improvement.

Butyrylcholinesterase (BChE) has been more and more attractive for treating neurodegenerative diseases, especially Alzheimer's disease (AD). In this study, we conducted activity and druggability optimization based on the structures that were previously reported. Most compounds exhibited pronounced BChE inhibitory capacity with nanomolar IC50 values. Based on the results of inhibiting activity and cyto-safety evaluations, two compounds (7, eqBChE IC50 = 2.94 nM, hBChE IC50 = 34.6 nM, and 20, eqBChE IC50 = 0.15 nM, hBChE IC50 = 45.2 nM) have been selected as candidates. High stability of compound 20 contributed to significantly improved blood concentration and tissue exposure, resulting in a reduced administration and effective dose in pharmacodynamic experiments. Two candidates exhibited remarkable neuroprotective properties and cognition improving activity, by benefiting cholinergic system, reducing the total Aß amount and increasing the ghrelin content. Simultaneous modulation in the center and periphery greatly improves the efficiency of BChE inhibitors. Considering the regulation on ghrelin level, BChE inhibition could improve not only symptoms but also nutritional status of AD patients.