Cardiac MR Feature Tracking Derived Strain Analysis can Predict Return to Training following Exertional Heatstroke.

BACKGROUND: Exertional heatstroke (EHS) is increasingly common in young trained soldiers. However, the prognosis marker in EHS patients remains unclear. To evaluate cardiac MRI feature tracking (CMR-FT) derived left ventricle (LV) strain as a biomarker for return to training (RTT) in trained soldiers with EHS in a prospective CMR cohort. METHODS: Trained soldiers (participants) with EHS underwent cardiac MR cine sequences between June 2020 and August 2023. Two-dimensional (2D) LV strain parameters were derived. At 3 months after index CMR, the participants with persistent cardiac symptoms including chest pain, dyspnea, palpitations, syncope, and recurrent heat-related illness were defined as non-RTT. Multivariable logistic regression analysis is used to develop a predictive RTT model. The performance of different models was compared using the area under curve (AUC). RESULTS: A total of 80 participants (median age, 21 years; interquartile range (IQR), 20-23 years) and 27 health controls (median age, 21 years; IQR, 20-22 years) were prospectively included. Of the 77 participants, 32 (41.6%) had persistent cardiac symptoms and were not able to RTT at 3 months follow-up after experiencing EHS. The 2D global longitudinal strain (GLS) was significantly impaired in EHS participants compared to the healthy control group (-15.81 ± 1.67% vs -16.93 ± 1.22%, P =.001), which also showed significantly statistical differences between participants with RTT and non-RTT (-14.99 ± 3.54% vs -16.53 ± 1.43%, P <.001). 2D-GLS (≤ -15.00%) (odds ratio, 1.53; 95% confidence interval (CI): 1.08, 2.17; P =.016) was an independent predictor for RTT even after adjusting known risk factors. 2D-GLS provided incremental prognostic value over the clinical model and conventional CMR parameters model (AUCs: 0.72 vs 0.88, P =.013; 0.79 vs 0.88, P =.023; respectively). CONCLUSIONS: Two-dimensional global longitudinal strain (≤ -15.00%) is an incremental prognostic CMR biomarker to predict return to training in exertional heatstroke soldiers.

Exploring Uncharted Territory: Spectroscopic Evidence on a Novel Tetrel Bond with -C≡C- Triple Bond.

This study presents an investigation of the 2-butynyl alcohol···CO2 adduct, combining pulsed jet Fourier transform microwave spectroscopy with quantum chemical calculations. Two distinct isomers have been observed in the pulsed jet with a relative population ratio of 3/2. It marks the first instance of microwave spectroscopic evidence, to the best of our knowledge, suggesting the existence of a CCO2···π-C≡C- tetrel bond (π-C≡C-···π*CO2 interaction) in both observed isomers. This study highlights the importance of noncovalent interactions involving CO2 in reactant complexes, paving the way for more efficient applications of CO2 by understanding the physical basis of these noncovalent bonds.

Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption.

BACKGROUND: Diesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. METHODS AND RESULTS: Utilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, , and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 µg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/ß-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and ß-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. CONCLUSIONS: Our study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ ß-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability. METHODS AND RESULTS: Employing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we investigated the adverse effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an increase in the release of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, loss of intercellular junctional organization, and diminished tight junction (TJ) protein expression. Microarray analysis disclosed that 23 miRNAs were upregulated and 11 were downregulated in bEND.3 cells treated with 50 µg/mL DEPs compared to the controls. In particular, miR-466d-3p was identified as a significantly differentially expressed miRNA. Wnt3 was predicted to be a target of miR-466d-3p, and the Wnt signaling pathway was identified as one of the most significantly enriched pathways. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/ß-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and ß-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. CONCLUSIONS: Our study further confirmed that DEPs can induce the disruption of BBB integrity by inflammation. We identified changes in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a regulator of tight junction (TJ) proteins, which are critical for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ ß-catenin and Wnt/PCP signaling pathway can be activated by DEPs and is regulated by miR-466d-3p, and under the combined effects of Wnt/PCP and inflammation ultimately led to hyperpermeability BBB.

Monitoring nonlinear large gradient subsidence in mining areas through SBAS-InSAR with PUNet and Weibull model fusion.

The subsidence of the earth's surface in mining areas is characterized by fast speed and large gradients. Conventional small baseline subset interferometric synthetic aperture radar (SBAS-InSAR) monitoring can significantly underestimate results, making it challenging to capture the surface's temporal subsidence features. In this context, this paper proposes a method for monitoring subsidence in mining areas. It utilizes a phase unwrapping network (PUNet) and a fused Weibull model within the SBAS-InSAR framework to address nonlinear and large-gradient subsidence. The basic principle of this method is to first process the SAR images using the small baseline method to obtain the differential interferogram, utilizing the PUNet to obtain reliable large-gradient unwrapped phases. Next, the Weibull model parameters of each pixel are calculated based on the unwrapped phase, and the temporal subsidence of each point on the surface is determined using the calculated parameters. This method introduces a nonlinear model into the SBAS-InSAR solution, which is more consistent with the subsidence characteristics of mining areas. Through experimentation in a backfilled mining working face, the proposed method in this paper yields superior monitoring results compared to conventional approaches.

Cadmium exposure elicited dynamic RNA m6A modification and epi-transcriptomic regulation in the Pacific whiteleg shrimp Litopenaeus vannamei.

N6-methyladenosine (m6A) methylation is the most prevalent post-transcriptional RNA modification in eukaryotic organisms, but its roles in the regulation of physiological resistance of marine crustaceans to heavy metal pollutants are poorly understood. In this study, the transcriptome-wide m6A RNA methylation profiles and dynamic m6A changes induced by acute Cd2+ exposure in the the pacific whiteleg shrimp Litopenaeus vannamei were comprehensively analyzed. Cd2+ toxicity caused a significant reduction in global RNA m6A methylation level, with major m6A regulators including the m6A methyltransferase METTL3 and the m6A binding protein YTHDF2 showing declined expression. Totally, 11,467 m6A methylation peaks from 6415 genes and 17,291 peaks within 7855 genes were identified from the Cd2+ exposure group and the control group, respectively. These m6A peaks were predominantly enriched in the 3' untranslated region (UTR) and around the start codon region of the transcripts. 7132 differentially expressed genes (DEGs) and 7382 differentially m6A-methylated genes (DMGs) were identified. 3186 genes showed significant changes in both gene expression and m6A methylation levels upon cadmium exposure, and they were related to a variety of biological processes and gene pathways. Notably, an array of genes associated with antioxidation homeostasis, transmembrane transporter activity and intracellular detoxification processes were significantly enriched, demonstrating that m6A modification may mediate the physiological responses of shrimp to cadmium toxicity via regulating ROS balance, Cd2+ transport and toxicity mitigation. The study would contribute to a deeper understanding of the evolutionary and functional significance of m6A methylation to the physiological resilience of decapod crustaceans to heavy metal toxicants.

Injectable agents for the induction of Peyronie's disease in model rats: a comparative study.

Peyronie's disease (PD) is a disorder characterized by fibrous plaque formation in the penile tissue that leads to curvature and complications in advanced stages. In this study, we aimed to compare four injectable induction agents for the establishment of a robust rat model of PD: transforming growth factor-ß1 (TGF-ß1), fibrin, sodium tetradecyl sulfate (STS) combined with TGF-ß1, and polidocanol (POL) combined with TGF-ß1. The results showed that injection of TGF-ß1 or fibrin into the tunica albuginea induced pathological endpoints without causing penile curvature. The STS + TGF-ß1 combination resulted in both histological and morphological alterations, but with a high incidence of localized necrosis that led to animal death. The POL + TGF-ß1 combination produced pathological changes and curvature comparable to STS + TGF-ß1 and led to fewer complications. In conclusion, fibrin, STS + TGF-ß1, and POL + TGF-ß1 all induced PD with a certain degree of penile curvature and histological fibrosis in rats. The POL + TGF-ß1 combination offered comparatively greater safety and clinical relevance and may have the greatest potential for PD research using model rats.

Quantile regression in the field of liver transplantation: A case study-based tutorial.

We present a tutorial on quantile regression, an underutilized yet valuable class of multivariable linear regression models that allow researchers to understand more fully the conditional distribution of response as compared to models based on conditional means. Quantile regression models are flexible, have attractive interpretations, and are implemented in most statistical software packages. Our focus is on intuitive understanding of quantile regression models, particularly as compared with more familiar regression methods such as conditional mean models as estimated using ordinary least squares (OLS). We frame our tutorial through two clinical case studies in the field of liver transplantation: one in the context of estimating recipient financial burden after transplantation and another in estimating intraoperative blood transfusion needs. Our real-world cases demonstrate how quantile regression models give researchers a richer understanding of relationships in the data and provide more nuanced clinical understanding compared to more commonly used linear regression models. We encourage researchers to explore quantile regression as a tool to answer relevant clinical research questions and support their more widespread adoption.

Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Complement factor I knockdown inhibits colon cancer development by affecting Wnt/ß-catenin/c-Myc signaling pathway and glycolysis.

BACKGROUND: Colon cancer (CC) occurrence and progression are considerably influenced by the tumor microenvironment. However, the exact underlying regulatory mechanisms remain unclear. AIM: To investigate immune infiltration-related differentially expressed genes (DEGs) in CC and specifically explored the role and potential molecular mechanisms of complement factor I (CFI). METHODS: Immune infiltration-associated DEGs were screened for CC using bioinformatics. Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines. Stable CFI-knockdown HT29 and HCT116 cell lines were constructed, and the diverse roles of CFI in vitro were assessed using CCK-8, 5-ethynyl-2'-deoxyuridine, wound healing, and transwell assays. Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice. Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting. RESULTS: Six key immune infiltration-related DEGs were screened, among which the expression of CFI, complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 was upregulated, whereas that of fatty acid-binding protein 1, and bone morphogenic protein-2 was downregulated. Furthermore, CFI could be used as a diagnostic biomarker for CC. Functionally, CFI silencing inhibited CC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CFI knockdown downregulated the expression of key glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and the Wnt pathway-related proteins (ß-catenin and c-Myc). Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/ß-catenin/c-Myc pathway. CONCLUSION: The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/ß-catenin/c-Myc pathway, indicating that it could serve as a promising target for therapeutic intervention in CC.

Distribution and spread of tigecycline resistance gene tet(X4) in Escherichia coli from different sources.

Tigecycline serves as a last-resort antimicrobial agent against severe infections caused by multidrug-resistant bacteria. Tet(X) and its numerous variants encoding flavin-dependent monooxygenase can confer resistance to tigecycline, with tet(X4) being the most prevalent variant. This study aims to investigate the prevalence and characterize tigecycline resistance gene tet(X) in E. coli isolates from various origins in Yangzhou, China, to provide insights into tet(X) dissemination in this region. In 2022, we tested the presence of tet(X) in 618 E. coli isolates collected from diverse sources, including patients, pig-related samples, chicken-related samples, and vegetables in Yangzhou, China. The antimicrobial susceptibility of tet(X)-positive E. coli isolates was conducted using the agar dilution method or the broth microdilution method. Whole genome sequencing was performed on tet(X)-positive strains using Illumina and Oxford Nanopore platforms. Four isolates from pig or pork samples carried tet(X4) and exhibited resistance to multiple antimicrobial agents, including tigecycline. They were classified as ST542, ST10, ST761, and ST48, respectively. The tet(X4) gene was located on IncFIA8-IncHI1/ST17 (n=2), IncFIA18-IncFIB(K)-IncX1 (n=1), and IncX1 (n=1) plasmids, respectively. These tet(X4)-carrying plasmids exhibited high similarity to other tet(X4)-bearing plasmids with the same incompatible types found in diverse sources in China. They shared related genetic environments of tet(X4) associated with ISCR2, as observed in the first identified tet(X4)-bearing plasmid p47EC. In conclusion, although a low prevalence (0.65%) of tet(X) in E. coli strains was observed in this study, the horizontal transfer of tet(X4) among E. coli isolates mediated by pandemic plasmids and the mobile element ISCR2 raises great concerns. Thus, heightened surveillance and immediate action are imperative to curb this clinically significant resistance gene and preserve the efficacy of tigecycline.

Identification of PgRg1-3 Gene for Ginsenoside Rg1 Biosynthesis as Revealed by Combining Genome-Wide Association Study and Gene Co-Expression Network Analysis of Jilin Ginseng Core Collection.

Ginseng, an important medicinal plant, is characterized by its main active component, ginsenosides. Among more than 40 ginsenosides, Rg1 is one of the ginsenosides used for measuring the quality of ginseng. Therefore, the identification and characterization of genes for Rg1 biosynthesis are important to elucidate the molecular basis of Rg1 biosynthesis. In this study, we utilized 39,327 SNPs and the corresponding Rg1 content from 344 core ginseng cultivars from Jilin Province. We conducted a genome-wide association study (GWAS) combining weighted gene co-expression network analysis (WGCNA), SNP-Rg1 content association analysis, and gene co-expression network analysis; three candidate Rg1 genes (PgRg1-1, PgRg1-2, and PgRg1-3) and one crucial candidate gene (PgRg1-3) were identified. Functional validation of PgRg1-3 was performed using methyl jasmonate (MeJA) regulation and RNAi, confirming that this gene regulates Rg1 biosynthesis. The spatial-temporal expression patterns of the PgRg1-3 gene and known key enzyme genes involved in ginsenoside biosynthesis differ. Furthermore, variations in their networks have a significant impact on Rg1 biosynthesis. This study established an accurate and efficient method for identifying candidate genes, cloned a novel gene controlling Rg1 biosynthesis, and identified 73 SNPs significantly associated with Rg1 content. This provides genetic resources and effective tools for further exploring the molecular mechanisms of Rg1 biosynthesis and molecular breeding.

Maternal Hypertensive Disorder in Pregnancy and Childhood Strabismus in Offspring.

Importance: Maternal hypertensive disorder in pregnancy (HDP) might affect ocular health in offspring; however, its association with strabismus remains unclear. Objective: To examine the association of maternal HDP with overall and type-specific strabismus in offspring. Design, Setting, and Participants: In the Jiangsu Birth Cohort study, a population-based study in China, pregnant women were recruited from April 24, 2014, to November 30, 2018. A total of 6195 offspring had maternal HDP diagnosis information, of whom 3078 were excluded due to having no information on ocular alignment or due to having ocular diseases other than strabismus or refractive error. Offspring underwent ocular examinations at 3 years of age, completed May 21, 2022. Data were analyzed from May 28, 2022, through December 15, 2023. Exposure: Maternal HDP, categorized into hypertension and preeclampsia or with blood pressure (BP) well controlled (systolic BP, <130; diastolic BP, <80 mm Hg) and poorly controlled (systolic BP, ≥130; diastolic BP, ≥80 mm Hg). Main Outcomes and Measures: The primary outcome was the incidence of strabismus in offspring. Poisson generalized linear mixed models were used to estimate the association between maternal HDP and strabismus. Results: Among the included 3117 children (mean [SD] age, 36.30 [0.74] months; 1629 boys [52.3%]), 143 (4.6%) were exposed to maternal HDP and 368 (11.8%) had strabismus. Offspring exposed to maternal HDP had an 82% increased risk of overall strabismus (relative risk [RR], 1.82 [95% CI, 1.21-2.74]), an 82% increased risk of exophoria (RR, 1.82 [95% CI, 1.11-3.00]), and a 136% increased risk of intermittent exotropia (RR, 2.36 [95% CI, 1.13-4.93]) compared with unexposed offspring. When considering the type of maternal HDP, the risk for all strabismus was high for offspring exposed to preeclampsia (RR, 2.38 [95% CI, 1.39-4.09]) compared with unexposed offspring. When considering the BP control level of maternal HDP, the risk for all strabismus was high for offspring born to mothers with HDP and poorly controlled BP (RR, 2.07 [95% CI, 1.32-3.24]) compared with unexposed offspring. Conclusions and Relevance: These findings suggest that maternal HDP is associated with an increased risk of offspring strabismus. Early screening of strabismus might be recommended for offspring with maternal HDP. Further exploration of the underlying mechanism of the association between HDP and strabismus is warranted.

Synergistic barium titanate/MXene composite as a high-performance piezo-photocatalyst for efficient dye degradation.

Piezo-photocatalysis combines photocatalysis and piezoelectric effects to enhance catalytic efficiency by creating an internal electric field in the photocatalyst, improving carrier separation and overall performance. This study presents a high-performance piezo-photocatalyst for efficient dye degradation using a synergistic barium titanate (BTO)-MXene composite. The composite was synthesized via a facile method, combining the unique properties of BTO nanoparticles with the high conductivity of MXene. The structural and morphological analysis confirmed the successful formation of the composite, with well-dispersed BTO nanoparticles on the MXene surface. The piezo-photocatalytic activity of the composite was evaluated using a typical dye solution (Rhodamine B: RhB) under ultraviolet irradiation and mechanical agitation. The results revealed a remarkable enhancement in dye degradation (90 % in 15 min for piezo-photocatalysis) compared to individual stimuli (58.2 % for photocatalysis and 95.8 % in 90 min for piezocatalysis), highlighting the synergistic effects between BTO and MXene. The enhanced catalytic performance was attributed to the efficient charge separation and transfer facilitated by the composite's structure, leading to increased reactive species generation and dye molecule degradation. Furthermore, the composite exhibited excellent stability and reusability, showcasing its potential for practical applications in wastewater treatment. Overall, this work represents a promising strategy for designing high-performance synergistic catalysts, addressing the pressing need for sustainable solutions in environmental remediation.

Unleashing the potential: type I CRISPR-Cas systems in actinomycetes for genome editing.

Covering: up to the end of 2023Type I CRISPR-Cas systems are widely distributed, found in over 40% of bacteria and 80% of archaea. Among genome-sequenced actinomycetes (particularly Streptomyces spp.), 45.54% possess type I CRISPR-Cas systems. In comparison to widely used CRISPR systems like Cas9 or Cas12a, these endogenous CRISPR-Cas systems have significant advantages, including better compatibility, wide distribution, and ease of operation (since no exogenous Cas gene delivery is needed). Furthermore, type I CRISPR-Cas systems can simultaneously edit and regulate genes by adjusting the crRNA spacer length. Meanwhile, most actinomycetes are recalcitrant to genetic manipulation, hindering the discovery and engineering of natural products (NPs). The endogenous type I CRISPR-Cas systems in actinomycetes may offer a promising alternative to overcome these barriers. This review summarizes the challenges and recent advances in CRISPR-based genome engineering technologies for actinomycetes. It also presents and discusses how to establish and develop genome editing tools based on type I CRISPR-Cas systems in actinomycetes, with the aim of their future application in gene editing and the discovery of NPs in actinomycetes.

Adaptive differential steering strategy for distributed driving unmanned ground vehicle with variable configurations based on modified localized modelling sliding mode control.

When performing complex tasks such as position transfer and material transportation, the distributed driving unmanned platform with variable configurations needs to address the challenge of multi-wheel cooperative torque distribution control to achieve high-performance differential steering and enhance vehicle dynamics. The configuration change will impact the dynamic performance of the unmanned platform, posing a challenge to the performance of the existing control strategy based on mathematical model development. In order to address the aforementioned issues, this paper analyzes the impact of changes in vehicle configuration on steering gain and proposes a hierarchical adaptive differential steering strategy based on variable vehicle configurations. Firstly, the response characteristics of the yaw angle relative to the active yaw moment under the influence of changes in wheelbase and tread are analyzed. Based on this analysis, two structural modes, maneuverable and balanced, are selected. Secondly, a localized-modelling sliding mode control method with an extended state observer is proposed to estimate the desired yaw moment in the upper controller, considering the motor's execution delay. Then, the lower controller optimizes the torque of each wheel in real-time using the whale optimization algorithm. It aims to optimize tire energy dissipation and tire load rate while ensuring driving stability and achieving differential steering. Finally, through co-simulation and experiments on a scaled prototype, the reliability of the dynamics theory and the superiority of the control algorithm are validated. This optimization has led to significant improvements in the tire dissipation energy index and tire load rate index.

Comparative genomic sequencing to characterize Mycoplasma pneumoniae genome, typing, and drug resistance.

To analyze the characteristics of Mycoplasma pneumoniae as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. Thirteen clinical strains isolated from 2003 to 2019 were selected, 10 of which were resistant to erythromycin (MIC >64 µg/mL), including 8 P1-type I and 2 P1-type II. Three were sensitive (<1 µg/mL) and P1-type II. One resistant strain had an A→G point mutation at position 2064 in region V of the 23S rRNA, the others had it at position 2063, while the three sensitive strains had no mutation here. Genome assembly and comparative genome analysis revealed a high level of genome consistency within the P1 type, and the primary differences in genome sequences concentrated in the region encoding the P1 protein. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. Clinical information showed seven cases were diagnosed with severe pneumonia, all of which were infected with drug-resistant strains. Notably, BS610A4 and CYM219A1 exhibited a gene multi-copy phenomenon and shared a conserved functional domain with the DUF31 protein family. Clinically, the patients had severe refractory pneumonia, with pleural effusion, necessitating treatment with glucocorticoids and bronchoalveolar lavage. The primary variations between strains occur among different P1-types, while there is a high level of genomic consistency within P1-types. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.IMPORTANCEMycoplasma pneumoniae is an important pathogen of community-acquired pneumonia, and macrolide resistance brings difficulties to clinical treatment. We analyzed the characteristics of M. pneumoniae as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. The work addressed primary variations between strains that occur among different P1-types, while there is a high level of genomic consistency within P1-types. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. All the strains isolated from severe pneumonia cases were drug-resistant, two of which exhibited a gene multi-copy phenomenon, sharing a conserved functional domain with the DUF31 protein family. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.

Treatment of manganese and lead poisoning with sodium para-aminosalicylic acid: A contemporary update.

Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa2-EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application.

Psychiatric disorders in patients with hepatocellular carcinoma: A large US cohort of commercially insured individuals.

BACKGROUND/AIMS: Patients with hepatocellular cancer (HCC) are vulnerable to psychological distress given a new cancer diagnosis superimposed on pre-existing chronic liver disease. We aimed to characterise the psychiatric burden in HCC, risk factors for incident diagnosis and treatment patterns over time. METHODS: Using IQVIA PharMetrics® Plus for Academics-a nationally representative claims database of the commercially insured US population-we identified psychiatric diagnoses and treatment among patients with newly diagnosed HCC. Multivariable logistic regression modelling identified factors associated with psychiatric diagnosis and treatment. RESULTS: Of 11,609 patients with HCC, 2166 (18.6%) had a psychiatric diagnosis after cancer diagnosis with depression (58.3%) and anxiety (53.0%) being most common. Women (aOR 1.33, 95% CI [1.19-1.49]), pre-existing psychiatric diagnoses (aOR 9.12 [8.08-10.3]) and HCC treatment type (transplant: aOR 2.15 [1.66-2.77]; locoregional therapies: aOR 1.74 [1.52-1.99]; hospice: aOR 2.43 [1.79-3.29]) were significantly associated with psychiatric diagnosis. Female sex, ascites, higher comorbidity and treatment type were associated with incident psychiatric diagnosis. Pharmacotherapy was used in 1392 (64.3%) patients with a psychiatric diagnosis, with antidepressants (46.2%) and anxiolytics (32.8%) being most common. Psychiatric diagnoses increased from 14.8% in 2006-2009 to 21.1% in 2018-2021 (p < 0.001). In almost 20% of patients with pre-existing psychiatric conditions, therapy was discontinued after HCC diagnosis. CONCLUSIONS: Nearly 2 of 10 patients with HCC were diagnosed with a psychiatric condition after cancer diagnosis with unique sociodemographic and clinical risk factors identified. This highlights a risk for increased psychological burden in need of early evaluation and treatment among patients with newly diagnosed HCC.

Exploring the Molecular Therapeutic Mechanisms of Gemcitabine through Quantitative Proteomics.

Gemcitabine (GEM) is widely employed in the treatment of various cancers, including pancreatic cancer. Despite their clinical success, challenges related to GEM resistance and toxicity persist. Therefore, a deeper understanding of its intracellular mechanisms and potential targets is urgently needed. In this study, through mass spectrometry analysis in data-dependent acquisition mode, we carried out quantitative proteomics (three independent replications) and thermal proteome profiling (TPP, two independent replications) on MIA PaCa-2 cells to explore the effects of GEM. Our proteomic analysis revealed that GEM led to the upregulation of the cell cycle and DNA replication proteins. Notably, we observed the upregulation of S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator. Combining SKP2 inhibition with GEM showed synergistic effects, suggesting SKP2 as a potential target for enhancing the GEM sensitivity. Through TPP, we pinpointed four potential GEM binding targets implicated in tumor development, including in breast and liver cancers, underscoring GEM's broad-spectrum antitumor capabilities. These findings provide valuable insights into GEM's molecular mechanisms and offer potential targets for improving treatment efficacy.

Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism.

Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine's regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine's impact on HLP. Moreover, matrine's potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, thermal proteome profiling analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine's capacity to upregulate LDLR expression and highlights its potential in treating HLP. These findings offer insights into matrine's mechanism of action and open new avenues for drug research and lipid metabolism regulation.