Identification and characterization of a PL35 GAGs lyase with 4-O-sulfated N-acetylgalactosamine (A-type)-rich structures producing property.

Glycosaminoglycan (GAG) lyases are important tools for investigating the structure of GAGs and preparing low-molecular-weight GAGs. The PL35 family, a recently established polysaccharide lyase family, should be further investigated. In this study, we discovered a new GAG lyase, CHa1, which belongs to the PL35 family. When expressed heterologously in Escherichia coli (BL21), CHa1 exhibited high expression levels and solubility. The optimal activity was observed in Tris-HCl buffer (pH 7.0) or sodium phosphate buffer (pH 8.0) at 30 °C. The specific activities towards HA, CSA, CSC, CSD, CSE, and HS were 3.81, 13.03, 36.47, 18.46, 6.46, and 0.50 U/mg protein, respectively. CHa1 digests substrate chains randomly that acting as an endolytic lyase and shows a significant preference for GlcA-containing structures, prefers larger oligosaccharides (≥UDP8) and can generate a series of oligosaccharides composed mainly of the A unit when digesting CSA. These oligosaccharides include ΔC-A, ΔC-A-A, ΔC-A-A-A, ΔC-A-A-A-A, and ΔC-A-A-A-A-A. The residues Tyr257 and His421 play crucial roles in the catalytic process, and Ser211, Asn212, Asn213, Trp214, Gln216, Lys360, Arg460 and Gln462 may participate in the binding process of CHa1. This study on CHa1 contributes to our understanding of the PL35 family and provides valuable tools for investigating the structure of GAGs.

Successful ECMO treatment in patients with cerebral hemorrhage and PROC gene mutation associated with VTE: a case report.

In this report, we report a case of a middle-aged male, admitted to the ICU with cerebral hemorrhage resulting from a severe high-altitude fall. The patient encountered significant challenges in oxygenation index correction, attributed to extensive embolism in both the primary and branch pulmonary arteries. Consequently, the patient underwent an immediate initiation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy, persisting for 20 days. During this treatment period, a mutation in the protein C (PROC) gene was identified. The medical team meticulously navigated the delicate balance between anticoagulation and bleeding risks. Eventually, the patient was successfully weaned off VA-ECMO and subsequently discharged. This report aims to delve into the etiology and therapeutic approaches of this uncommon case, with the intention of offering insightful reference for managing similar clinical scenarios in the future.

Sustainable Supramolecular Polymers.

Polymer waste is a pressing issue that requires innovative solutions from the scientific community. As a beacon of hope in addressing this challenge, the concept of sustainable supramolecular polymers (SSPs) emerges. This article discusses challenges and efforts in fabricating SSPs. Addressing the trade-offs between mechanical performance and sustainability, the ultra-tough and multi-recyclable supramolecular polymers are fabricated via tailoring mismatched supramolecular interactions. Additionally, the healing of kinetically inert polymer materials is realized through transient regulation of the interfacial reactivity. Furthermore, a possible development trajectory for SSPs is proposed, and the transient materials can be regarded as the next generation in this field. The evolution of SSPs promises to be a pivotal stride towards a regenerative economy, sparking further exploration and innovation in the realm of sustainable materials.

MSRMNet: Multi-scale skip residual and multi-mixed features network for salient object detection.

The current models for the salient object detection (SOD) have made remarkable progress through multi-scale feature fusion strategies. However, the existing models have large deviations in the detection of different scales, and the target boundaries of the prediction images are still blurred. In this paper, we propose a new model addressing these issues using a transformer backbone to capture multiple feature layers. The model uses multi-scale skip residual connections during encoding to improve the accuracy of the model's predicted object position and edge pixel information. Furthermore, to extract richer multi-scale semantic information, we perform multiple mixed feature operations in the decoding stage. In addition, we add the structure similarity index measure (SSIM) function with coefficients in the loss function to enhance the accurate prediction performance of the boundaries. Experiments demonstrate that our algorithm achieves state-of-the-art results on five public datasets, and improves the performance metrics of the existing SOD tasks. Codes and results are available at: https://github.com/xxwudi508/MSRMNet.

Gastrointestinal manifestations of critical ill heatstroke patients and their associations with outcomes: A multicentre, retrospective, observational study.

BACKGROUND: Extreme heat exposure is a growing health problem, and the effects of heat on the gastrointestinal (GI) tract is unknown. This study aimed to assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. AIM: To assess the incidence of GI symptoms associated with heatstroke and its impact on outcomes. METHODS: Patients admitted to the intensive care unit (ICU) due to heatstroke were included from 83 centres. Patient history, laboratory results, and clinically relevant outcomes were recorded at ICU admission and daily until up to day 15, ICU discharge, or death. GI symptoms, including nausea/vomiting, diarrhoea, flatulence, and bloody stools, were recorded. The characteristics of patients with heatstroke concomitant with GI symptoms were described. Multivariable regression analyses were performed to determine significant predictors of GI symptoms. RESULTS: A total of 713 patients were included in the final analysis, of whom 132 (18.5%) patients had at least one GI symptom during their ICU stay, while 26 (3.6%) suffered from more than one symptom. Patients with GI symptoms had a significantly higher ICU stay compared with those without. The mortality of patients who had two or more GI symptoms simultaneously was significantly higher than that in those with one GI symptom. Multivariable logistic regression analysis revealed that older patients with a lower GCS score on admission were more likely to experience GI symptoms. CONCLUSION: The GI manifestations of heatstroke are common and appear to impact clinically relevant hospitalization outcomes.

Metabolite-sensing GPCRs in rheumatoid arthritis.

Persistent inflammation in damaged joints results in metabolic dysregulation of the synovial microenvironment, causing pathogenic alteration of cell activity in rheumatoid arthritis (RA). Recently, the role of metabolite and metabolite-sensing G protein-coupled receptors (GPCRs) in the RA-related inflammatory immune response (IIR) has become a focus of research attention. These GPCRs participate in the progression of RA by modulating immune cell activation, migration, and inflammatory responses. Here, we discuss recent evidence implicating metabolic dysregulation in RA pathogenesis, focusing on the connection between RA-related IIR and GPCR signals originating from the synovial joint and gut. Furthermore, we discuss future directions for targeting metabolite-sensing GPCRs for therapeutic benefit, emphasizing the importance of identifying endogenous ligands and investigating the various transduction mechanisms involved.

GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with a complex etiology. Monocyte-derived macrophages (MDMs) infiltration are associated with RA severity. We have reported the deletion of G-protein-coupled receptor kinase 2 (GRK2) reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling. However, as more GRK2-interacting proteins were discovered, the GRK2 interactome mechanisms in RA have been understudied. Thus, in the collagen-induced arthritis mouse model, we performed genetic GRK2 deletion using GRK2f/fLyz2-Cre+/- mice. Synovial inflammation and M1 polarization were improved in GRK2f/fLyz2-Cre+/- mice. Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptor γ (PPARγ) as a new GRK2-interacting protein. We further confirmed that fms-related tyrosine kinase 1 (Flt-1), which promoted macrophage migration to induce angiogenesis, was inhibited by GRK2-PPARγ signaling. Mechanistically, excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγ ligand-binding domain and enhanced Flt-1 transcription. Furthermore, the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology, Flt-1+ macrophages induced-synovial inflammation, and angiogenesis. Altogether, we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling. Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration, affording a distinct way to control joint inflammation and angiogenesis of RA.

GTAMP-DTA: Graph transformer combined with attention mechanism for drug-target binding affinity prediction.

Drug target affinity prediction (DTA) is critical to the success of drug development. While numerous machine learning methods have been developed for this task, there remains a necessity to further enhance the accuracy and reliability of predictions. Considerable bias in drug target binding prediction may result due to missing structural information or missing information. In addition, current methods focus only on simulating individual non-covalent interactions between drugs and proteins, thereby neglecting the intricate interplay among different drugs and their interactions with proteins. GTAMP-DTA combines special Attention mechanisms, assigning each atom or amino acid an attention vector. Interactions between drug forms and protein forms were considered to capture information about their interactions. And fusion transformer was used to learn protein characterization from raw amino acid sequences, which were then merged with molecular map features extracted from SMILES. A self-supervised pre-trained embedding that uses pre-trained transformers to encode drug and protein attributes is introduced in order to address the lack of labeled data. Experimental results demonstrate that our model outperforms state-of-the-art methods on both the Davis and KIBA datasets. Additionally, the model's performance undergoes evaluation using three distinct pooling layers (max-pooling, mean-pooling, sum-pooling) along with variations of the attention mechanism. GTAMP-DTA shows significant performance improvements compared to other methods.

The risk of dementia or cognitive impairment in patients with cataracts: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to investigate whether cataract disease is associated with the risk of developing dementia or cognitive impairment. METHODS: A systematic search of the literature in PubMed, the Extracts Database (Embase), the Cochrane Library and the Web of Science databases was performed from the inception data of each database until 1 September 2022. Sensitivity analyses were performed to assess the robustness and reliability of the overall findings. All extracted data were statistically analyzed using Stata software v.16.0. Publication bias was assessed using funnel plots and the Egger test. RESULTS: There were 11 publications included in this study, which consisted of 489,211participants, spanning 10 countries from 2012 to 2022. Aggregation suggested that cataracts were associated with cognitive impairment (odds ratio [OR] = 1.32; 95% CI: 1.21-1.43; I 2 = 45.4.%; p = 0.000). The presence of cataracts is significantly associated with an increased risk of developing all-cause dementia (relative risk [RR] = 1.17; 95% CI: 1.08-1.26; I2 = 0.0%; p = 0.000). In subgroup analyses, having cataracts may increase the risk of Alzheimer's disease (hazard ratio [HR] = 1.28; 95% CI: 1.13-1.45; I2 = 0.0%; p = 0.000) and vascular dementia (HR = 1.35; 95% CI = 1.06-1.73; I2 = 0.0%, p = 0.015). The data from the Egger's test showed no significant evidence of publication bias. CONCLUSIONS: Cataracts are associated with the risk of cognitive impairment and dementia, including Alzheimer's disease, and vascular dementia.

Prediction of prokinetic agents in critically ill patients with feeding intolerance: a prospective observational clinical study.

Background: Prokinetic agents are currently considered the first-line therapy to improve gastric emptying when feeding intolerance occurred in critically ill adults. In this study, we developed a technique to assess the feasibility of predicting prokinetic agent efficacy in critically ill patients. Methods: The first images of each patient were obtained after EFI had occurred but before the first dose of prokinetic agents was administered and additional images were obtained every morning until the seventh day. The gastric antrum echodensity was recorded based on grayscale values (50th percentile, ED50; 85th percentile, ED85; mean, EDmean) and daily energy and protein intake was collected as the judgment for effective and ineffective group. A receiver operating characteristic curve was analyzed to distinguish the thresholds between the two groups and thus determine the ability of the gastric antrum echodensity to predict the efficacy of prokinetic agents. Results: In total, 83 patients were analyzed. Patients in the ineffective group had a higher ED50 (58.13 ± 14.48 vs. 49.88 ± 13.78, p < 0.001, difference 95% CI: 5.68, 10.82), ED85 (74.81 ± 16.41 vs. 65.70 ± 16.05, p < 0.001, difference 95% CI:6.16, 12.05), and EDmean (60.18 ± 14.31 vs. 51.76 ± 14.08, p < 0.001, difference 95% CI: 5.85, 11.00) than those in the effective group. Patients in the effective group more easily reached the target energy 16.21 ± 7.98 kcal/kg vs. 9.17 ± 6.43 kcal/kg (p < 0.001), 0.72 ± 0.38 g/kg vs. 0.42 ± 0.31 g/kg (p < 0.001) than in the ineffective group intake by day. Conclusion: The gastric antrum echodensity might serve as a tool for judging the efficacy of prokinetic agents, helping clinicians to decide whether to use prokinetic agents or place a post-pyloric tube when feeding intolerance occurs in critically ill patients.Clinical trial registration:http://www.chictr.org.cn/addproject2.aspx, ChiCTR2200058373. Registered 7 April 2022.

Imaging cellular forces with photonic crystals.

Current techniques for visualizing and quantifying cellular forces have limitations in live cell imaging, throughput, and multi-scale analysis, which impede progress in cell force research and its practical applications. We developed a photonic crystal cellular force microscopy (PCCFM) to image vertical cell forces over a wide field of view (1.3 mm ⨯ 1.0 mm, a 10 ⨯ objective image) at high speed (about 20 frames per second) without references. The photonic crystal hydrogel substrate (PCS) converts micro-nano deformations into perceivable color changes, enabling in situ visualization and quantification of tiny vertical cell forces with high throughput. It enabled long-term, cross-scale monitoring from subcellular focal adhesions to tissue-level cell sheets and aggregates.

Generating a Sustained Oxygen-Stable Atomic Concentration in a High-Temperature Gas Effect Investigation.

Modulated laser absorption spectroscopy is an ideal technique for evaluating flow-field parameters and determining flow-field quality by measuring the atoms dissociated in high-temperature environments. However, to obtain the absolute number density of atoms in the flow field, it is necessary to compare the measured modulated absorption spectroscopy signal with a known atomic concentration and establish a quantitative relationship through concentration calibration. Nevertheless, it remains a challenging task to prepare transient atomic samples with known concentrations that meet the calibration requirements. This study utilized the alternating-current glow discharge technique to dissociate oxygen in the air flow, resulting in the continuous generation of oxygen atoms. The absolute number densities of the generated oxygen atoms were determined by measuring the direct absorption spectra of centered on 777 nm for oxygen atoms. The number densities of the generated atoms were finely tuned by adjusting the discharge parameters. Throughout the 120-min continuous operation of the discharge system, the concentration of excited-state oxygen atoms remained stable within the range of (2.51 ± 0.02) × 108 cm-3, demonstrating the remarkable stability of the transient atomic concentration generated by the glow discharge plasma. This observation suggests that the generated atoms can be utilized as a standardized atomic sample of known concentration for absolute concentration calibration purposes.

Identification and characterization of a novel heparinase PCHepII from marine bacterium Puteibacter caeruleilacunae.

Heparin (HP) and heparan sulfate (HS) are multifunctional polysaccharides widely used in clinical therapy. Heparinases (Hepases) are enzymes that specifically catalyse HP and HS degradation, and they are valuable tools for studying the structure and function of these polysaccharides and for preparing low molecular weight heparins. In this study, by searching the NCBI database, a novel enzyme named PCHepII was discovered in the genome of the marine bacterium Puteibacter caeruleilacuae. Heterologously expressed PCHepII in Escherichia coli (BL21) has high expression levels and good solubility, active in sodium phosphate buffer (pH 7.0) at 20°C. PCHepII exhibits an enzyme activity of 254 mU/mg towards HP and shows weak degradation capacity for HS. More importantly, PCHepII prefers to catalyse the high-sulfated regions of HP and HS rather than the low-sulfated regions. Although PCHepII functions primarily as an endolytic Hepase, it mainly generates disaccharide products during the degradation of HP substrates over time. Investigations reveal that PCHepII exhibits a preference for catalysing the degradation of small substrates, especially HP tetrasaccharides. The catalytic sites of PCHepII include the residues His199, Tyr254, and His403, which play crucial roles in the catalytic process. The study and characterization of PCHepII can potentially benefit research and applications involving HP/HS, making it a promising enzyme.

Leverage of nuclease-deficient CasX for preventing pathological angiogenesis.

Gene editing with a CRISPR/Cas system is a novel potential strategy for treating human diseases. Pharmacological inhibition of phosphoinositide 3-kinase (PI3K) δ suppresses retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Here we show that an innovative system of adeno-associated virus (AAV)-mediated CRISPR/nuclease-deficient (d)CasX fused with the Krueppel-associated box (KRAB) domain is leveraged to block (81.2% ± 6.5%) in vitro expression of p110δ, the catalytic subunit of PI3Kδ, encoded by Pik3cd. This CRISPR/dCasX-KRAB (4, 269 bp) system is small enough to be fit into a single AAV vector. We then document that recombinant AAV serotype (rAAV)1 efficiently transduces vascular endothelial cells from pathologic retinal vessels, which show high expression of p110δ; furthermore, we demonstrate that blockade of retinal p110δ expression by intravitreally injected rAAV1-CRISPR/dCasX-KRAB targeting the Pik3cd promoter prevents (32.1% ± 5.3%) retinal p110δ expression as well as pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. These data establish a strong foundation for treating pathological angiogenesis by AAV-mediated CRISPR interference with p110δ expression.

Effects and potential mechanisms of IGF1/IGF1R in the liver fibrosis: A review.

Liver fibrosis is a wound-healing response due to persistent liver damage and it may progress to cirrhosis and even liver cancer if no intervention is given. In the current cognition, liver fibrosis is reversible. So, it is of great significance to explore the related gene targets or biomarker for anti-fibrosis of liver. Insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) are mainly expressed in the liver tissues and play critical roles in the liver function. The present review summarized the role of IGF1/IGF1R and its signaling system in liver fibrosis and illustrated the potential mechanisms including DNA damage repair, cell senescence, lipid metabolism and oxidative stress that may be involved in this process according to the studies on the fibrosis of liver or other organs. In particular, the roles of IGF1 and IGF1R in DNA damage repair were elaborated, including membrane-localized and nucleus-localized IGF1R. In addition, for each of the potential mechanism in anti-fibrosis of liver, the signaling pathways of the IGF1/IGF1R mediated and the cell species in liver acted by IGF1 and IGF1R under different conditions were included. The data in this review will support for the study about the effect of IGF1/IGF1R on liver fibrosis induced by various factors, meanwhile, provide a basis for the study of liver fibrosis to focus on the communications between the different kinds of liver cells.

The effects of early mobilization in mechanically ventilated adult ICU patients: systematic review and meta-analysis.

Background: The effects of early mobilization (EM) on intensive care unit (ICU) patients remain unclear. A meta-analysis of randomized controlled trials was performed to evaluate its effect in mechanically ventilated adult ICU patients. Methods: We searched randomized controlled trials (RCTs) published in Medline, Embase, and CENTRAL databases (from inception to November 2022). According to the difference in timing and type, the intervention group was defined as a systematic EM group, and comparator groups were divided into the late mobilization group and the standard EM group. The primary outcome was mortality. The secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV), and adverse events. EM had no impact on 180-day mortality and hospital mortality between intervention groups and comparator groups (RR 1.09, 95% CI 0.89-1.33, p = 0.39). Systemic EM reduced the ICU length of stay (LOS) (MD -2.18, 95% CI -4.22--0.13, p = 0.04) and the duration of MV (MD -2.27, 95% CI -3.99--0.56, p = 0.009), but it may increase the incidence of adverse events in patients compared with the standard EM group (RR 1.99, 95% CI 1.25-3.16, p = 0.004). Conclusion: Systematic EM has no significant effect on short- or long-term mortality in mechanically ventilated adult ICU patients, but systematic EM could reduce the ICU LOS and duration of MV.

Transient regulation of gel properties by chemical reaction networks.

Transient regulation of gel properties by chemical reaction networks (CRNs) represents an emerging and effective strategy to program or temporally control the structures, properties, and functions of gel materials in a self-regulated manner. CRNs provide significant opportunities to construct complex or sustainable gels with excellent dynamic features, thus expanding the application scope of these materials. CRN-based methods for transiently regulating the gel properties are receiving increasing attention, and the related fields are worth further studying. This feature article focuses on the CRN-mediated transient regulation of six properties of gels, which are transient gelation, transient liquefaction of gels, transient assembly of macroscopic gels, temporary actuation of gels, transient healing ability of kinetically inert gels, and cascade reaction-based self-reporting of external stimuli. Recent advances that showcase the six properties of gels controlled by CRNs are featured, the characterization and structural elucidation of gels are detailed, and the significance, achievements, and expectations of this field are discussed. The strategy of transient regulation of gel properties via CRNs is potentially useful for building the next generation of adaptive functional materials.

Accurate Stride-Length Estimation Based on LT-StrideNet for Pedestrian Dead Reckoning Using a Shank-Mounted Sensor.

Pedestrian dead reckoning (PDR) is a self-contained positioning technology and has been a significant research topic in recent years. Pedestrian-stride-length estimation is the core part of the PDR system and directly affects the performance of the PDR. The current stride-length-estimation method is difficult to adapt to changes in pedestrian walking speed, which leads to a rapid increase in the error of the PDR. In this paper, a new deep-learning model based on long short-term memory (LSTM) and Transformer, LT-StrideNet, is proposed to estimate pedestrian-stride length. Next, a shank-mounted PDR framework is built based on the proposed stride-length-estimation method. In the PDR framework, the detection of pedestrian stride is achieved by peak detection with a dynamic threshold. An extended Kalman filter (EKF) model is adopted to fuse the gyroscope, accelerometer, and magnetometer. The experimental results show that the proposed stride-length-estimation method can effectively adapt to changes in pedestrian walking speed, and our PDR framework has excellent positioning performance.