Stroke risk of COPD patients and death risk of COPD patients following a stroke: A systematic review and meta-analysis.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is closely related to the development and progression of cardiovascular disease. The purpose of this study is to clarify the answers to the following questions through systematic evaluation: the risk of stroke in COPD patients; the risk of stroke in acute exacerbations of COPD (AECOPD) patients; and the risk of death after stroke in COPD patients. METHODS: Two reviewers independently searched EMbase, PubMed, and the Cochrane Library for relevant literature from the date of creation to February 17, 2023, for studies relating COPD to stroke patients. Of the 8039 publications retrieved, we identified 27 articles that met our selection criteria. Fixed-effects or random-effects models were used to calculate ORs and 95% confidence intervals for the combined risk. RESULTS: combining studies on stroke risk in COPD patients by random-effects model suggested that COPD was an independent risk factor for stroke-associated pneumonia (OR 1.40, 95% CI: 1.24-1.59, I2 = 98.4%, P = .000), with significant heterogeneity in the results, and subgroup analysis did not find a source of heterogeneity. In the combined 7 AECOPD studies, a significantly higher risk of stroke was found (OR 1.53, 95% CI: 1.44-1.63, I2 = 49.2%, P = .066). In the combined 6 short- term prognostic studies, the relationship between COPD and risk of death was not highly significant (OR 1.12, 95% CI: 1.08-1.16, I2 = 37.4%, P = .131). In 10 long-term observational prognosis studies, COPD was suggested to be associated with death after stroke by combining data using a random-effects model (OR 1.20, 95% CI: 1.13-1.27, I2 = 56.8%, P = .014), and there was moderate heterogeneity in the combination, with subgroup analysis showing that stroke type may be a source of heterogeneity and the risk of death from ischemic stroke: OR 1.23, 95% CI: 1.17-1.29, I2 = 45.0%, P = .191 and the risk of death from both types of stroke: OR 1.12, 95% CI: 1.07-1.18, I2 =18.9%, P = .291. CONCLUSION: COPD is an independent risk factor for stroke. The risk of stroke is significantly increased, especially during AECOPD. In addition, the association between COPD and short-term death in stroke patients is insignificant, while it is more associated with fatal events in the long-term prognosis.

Association between diabetes and venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: Diabetes mellitus (DM) plays a vital role in the development of cardiovascular disease. However, its association with venous thromboembolism (VTE) remains unclear, for the published study results are conflicting. We performed a meta-analysis of published cohort studies and case-control studies to assess the role of DM in the formation and prognosis of VTE. METHODS: PubMed and EMBASE databases were searched for articles from the database's establishment until September 15, 2022. Of the 15,754 publications retrieved, 50 studies were identified that met the selection criteria. The New castle-Ottawa Scale was used to evaluate the quality of the literature. Pooled odds ratios (ORs) and 95% confidence intervals were calculated using fixed- or random-effect models. RESULTS: We combined OR using a random-effects or fixed-effects model: patients with DM had an increased risk of VTE (OR 1.27, 95% confidence interval [CI]: 1.15-1.41), which still showed a partial association in studies adjusted by confounding factors (OR 1.20, 95% CI: 1.07-1.35). DM was not significantly associated with VTE when analyzed in studies adjusted by body mass index (OR 1.04, 95% CI: 0.94-1.15). VTE patients with DM had a higher risk of short-term and long-term mortality than those without DM (OR 1.58 [95% CI: 1.26-1.99] for long-term mortality and OR 1.20 [95% CI: 1.19-1.21] for short-term mortality). CONCLUSION: There was no significant association between DM and VTE risk, and body mass index may be a significant confounding factor between DM and VTE risk. However, DM can still lead to an increased risk of long-term and short-term mortality in patients with VTE.

Potential Therapeutic Options for Premature Ovarian Insufficiency: Experimental and Clinical Evidence.

Premature ovarian insufficiency (POI) is a condition in which a woman experiences premature decline in ovarian function before the age of 40 years, manifested by menstrual disorders, decreased fertility, and possibly postmenopausal symptoms such as insomnia, hot flashes, and osteoporosis, and is one of the predominant clinical syndromes leading to female infertility. Genetic, immunologic, iatrogenic and other factors, alone or in combination, have been reported to trigger POI, yet the etiology remains unknown in most cases. The main methods currently used clinically to ameliorate menopausal symptoms due to hypoestrogenemia in POI patients are hormone replacement therapy, while the primary methods available to address infertility in POI patients are oocyte donation and cryopreservation techniques, both of which have limitations to some degree. In recent years, researchers have continued to explore more efficient and safe therapies, and have achieved impressive results in preclinical trials. In this article, we will mainly review the three most popular therapies and their related signaling pathways published in the past ten years, with the aim of providing ideas for clinical applications.

DNA double-strand break genetic variants in patients with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a clinically heterogeneous disease that may seriously affect the physical and mental health of women of reproductive age. POI primarily manifests as ovarian function decline and endocrine disorders in women prior to age 40 and is an established cause of female infertility. It is crucial to elucidate the causative factors of POI, not only to expand the understanding of ovarian physiology, but also to provide genetic counselling and fertility guidance to affected patients. Factors leading to POI are multifaceted with genetic factors accounting for 7% to 30%. In recent years, an increasing number of DNA damage-repair-related genes have been linked with the occurrence of POI. Among them, DNA double-strand breaks (DSBs), one of the most damaging to DNA, and its main repair methods including homologous recombination (HR) and non-homologous end joining (NHEJ) are of particular interest. Numerous genes are known to be involved in the regulation of programmed DSB formation and damage repair. The abnormal expression of several genes have been shown to trigger defects in the overall repair pathway and induce POI and other diseases. This review summarises the DSB-related genes that may contribute to the development of POI and their potential regulatory mechanisms, which will help to further establish role of DSB in the pathogenesis of POI and provide theoretical guidance for the study of the pathogenesis and clinical treatment of this disease.

Prevalence, Risk Factor and Clinical Characteristics of Venous Thrombus Embolism in Patients with Acute Exacerbation of COPD: A Prospective Multicenter Study.

Background and Objective: The prevalence of venous thrombus embolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) is higher than in patients without COPD. Owing to the similarity of clinical symptoms between PE and acute exacerbation COPD (AECOPD), PE is likely to be overlooked or underdiagnosed in patients with AECOPD. The aim of the study was to investigate the prevalence, risk factor, clinical characteristics, and prognostic impact of VTE in patients with AECOPD. Methods: This multicenter, prospective, cohort study was conducted in 11 research centers of China. Data on the baseline characteristics, VTE-related risk factors, clinical symptoms, laboratory examination results, computed tomography pulmonary angiography (CTPA) and lower limb venous ultrasound of AECOPD patients were collected. Patients were followed up for 1 year. Results: A total of 1580 AECOPD patients were included in the study. The mean (SD) age was 70.4 (9.9) years and 195 (26%) patients were women. The prevalence of VTE was 24.5% (387/1580) and PE was 16.8% (266/1580). VTE patients were older; had higher BMI; and longer course of COPD than non-VTE patients. The history of VTE, cor pulmonale, less purulent sputum, increased respiratory rate, higher D-dimer, and higher NT-proBNP/BNP were independently associated with VTE in hospitalized patients with AECOPD. The mortality at 1-year was higher in patients with VTE than patients without VTE (12.9% vs 4.5%, p<0.01). There was no significant difference in the prognosis of patients with PE in segmental or subsegmental arteries and in main pulmonary arteries or lobar arteries (P>0.05). Conclusion: VTE is common in COPD patients and is associated with poor prognosis. Patients with PE at different locations had poorer prognosis than patients without PE. It is necessary to perform active screening strategy for VTE in AECOPD patients with risk factors.

EptA of Riemerella anatipestifer mediates phenotypes involved in colistin resistance and virulence.

Colistin (polymyxin E) is a group of cationic antimicrobial cyclic peptides and is recognized as a last-resort defense against lethal infections with carbapenem-resistant pathogens. In addition to the plasmid-borne mobilized phosphoethanolamine (PEA) transferases, the functional expression of lipid A-modifying enzymes encoded on chromosomes has been attributed to intrinsic bacterial colistin resistance. However, the mechanisms of colistin resistance in Riemerella anatipestifer remain unknown. Herein, the GE296_RS09715 gene-encoded Lipid A PEA transferases (RaEptA) was identified in R. anatipestifer. Genetic and structural analyses revealed that the amino acid sequence of RaEptA shared 26.6%-33.1% similarities with the family of Lipid A PEA transferases (EptA) and MCR-like proteins and have defined 12 residues that contribute to the formation of phosphatidylethanolamine (PE)-recognizable cavities. Comparative analyses of colistin resistance in RA-LZ01 and RA-LZ01ΔRaEptA showed the level of colistin has fallen from 96 µg mL-1 down to 24 ~ 32 µg mL-1 . Site-directed mutagenesis assay of the PE-binding cavity and expression of the mutants reveals that K309-rRaEptA can remodel the surface of Escherichia coli and rendering it resistant to colistin, suggesting this point-mutation of P309K is necessary for EptA-mediated lipid A modification. Moreover, the virulence of RA-LZ01ΔRaEptA was attenuated compared with RA-LZ01 both in vivo and vitro. Taken together, the results represent the RaEptA involved in the colistin resistance and pathogenicity, and the P309K mutation might alter bacterial adaptation and increase the spread of colistin resistance from R. anatipestifer to other gram-negative bacteria. The findings of this study suggest another scenario for the spread of colistin resistance genes and should be considered by a wide audience.

Multisite assessment of reproducibility in high-content cell migration imaging data.

High-content image-based cell phenotyping provides fundamental insights into a broad variety of life science disciplines. Striving for accurate conclusions and meaningful impact demands high reproducibility standards, with particular relevance for high-quality open-access data sharing and meta-analysis. However, the sources and degree of biological and technical variability, and thus the reproducibility and usefulness of meta-analysis of results from live-cell microscopy, have not been systematically investigated. Here, using high-content data describing features of cell migration and morphology, we determine the sources of variability across different scales, including between laboratories, persons, experiments, technical repeats, cells, and time points. Significant technical variability occurred between laboratories and, to lesser extent, between persons, providing low value to direct meta-analysis on the data from different laboratories. However, batch effect removal markedly improved the possibility to combine image-based datasets of perturbation experiments. Thus, reproducible quantitative high-content cell image analysis of perturbation effects and meta-analysis depend on standardized procedures combined with batch correction.

SMURF1 inhibits the Th17 and Th17.1 polarization and improves the Treg/Th17 imbalance in systemic lupus erythematosus through the ubiquitination of RORγt.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. This study aimed to investigate the role of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) in the Th17 and Th17.1 differentiation and Treg/Th17 imbalance, which are major factors contributing to the pathogenesis of SLE. SLE patients and healthy individuals were recruited to detect the SMURF1 levels in naïve CD4+ cells from peripheral blood. Purified and expanded naïve CD4+ T cells were employed to evaluate the effects of SMURF1 on Th17 and Th17.1 polarization in vitro. MRL/lpr lupus model was employed to explore the disease phenotype as well as Treg/Th17 balance in vivo. The results showed that SMURF1 was down-regulated in naïve CD4+ T cells in peripheral blood of patients with SLE and in spleen of MRL/lpr mice. SMURF1 overexpression suppressed the polarization of naïve CD4+ T cells toward Th17 and Th17.1 phenotype and down-regulated the expression of retinoid-related orphan receptor-gammat (RORγt). Subsequently, SMURF1 down-regulation aggravated the disease phenotype, inflammation, and the Treg/Th17 imbalance in MRL/lpr mice. Furthermore, we found that SMURF overexpression promoted the ubiquitination and decreases the stability of RORγt. In conclusion, SMURF1 inhibited the polarization of Th17 and Th17.1 cells and improved the Treg/Th17 imbalance in SLE, which was mediated as least partly by the ubiquitination of RORγt.

Functional Characterization of a Novel SMR-Type Efflux Pump RanQ, Mediating Quaternary Ammonium Compound Resistance in Riemerella anatipestifer.

Riemerella anatipestifer (R. anatipestifer) is a multidrug-resistant bacterium and an important pathogen responsible for major economic losses in the duck industry. Our previous study revealed that the efflux pump is an important resistance mechanism of R. anatipestifer. Bioinformatics analysis indicated that the GE296_RS02355 gene (denoted here as RanQ), a putative small multidrug resistance (SMR)-type efflux pump, is highly conserved in R. anatipestifer strains and important for the multidrug resistance. In the present study, we characterized the GE296_RS02355 gene in R. anatipestifer strain LZ-01. First, the deletion strain RA-LZ01ΔGE296_RS02355 and complemented strain RA-LZ01cΔGE296_RS02355 were constructed. When compared with that of the wild-type (WT) strain RA-LZ01, the mutant strain ΔRanQ showed no significant influence on bacterial growth, virulence, invasion and adhesion, morphology biofilm formation ability, and glucose metabolism. In addition, the ΔRanQ mutant strain did not alter the drug resistance phenotype of the WT strain RA-LZ01 and displayed enhanced sensitivity toward structurally related quaternary ammonium compounds, such as benzalkonium chloride and methyl viologen, which show high efflux specificity and selectivity. This study may help elucidate the unprecedented biological functions of the SMR-type efflux pump in R. anatipestifer. Thus, if this determinant is horizontally transferred, it could cause the spread of quaternary ammonium compound resistance among bacterial species.

OmpA is involved in the invasion of duck brain microvascular endothelial cells by Riemerella anatipestifer.

Bacterial meningitis is a major cause of morbidity and mortality. Despite advances in antimicrobial chemotherapy, the disease remains detrimental to humans, livestock, and poultry. Riemerella anatipestifer is a gram-negative bacterium causing duckling serositis and meningitis. However, the virulence factors contributing to its binding and invasion of duck brain microvascular endothelial cells (DBMECs) and penetration of the blood-brain barrier (BBB) have never been reported. In this study, immortalized DBMECs were successfully generated and used as an in vitro-model of duck BBB. Furthermore, ompA gene deletion mutant of the pathogen and multiple complemented strains carrying the complete ompA gene and its truncated forms were constructed. Bacterial growth, invasion, and adhesion assays and animal experiments were performed. The results show that the OmpA protein of R. anatipestifer had no effect on bacterial growth and adhesion ability to DBMECs. The role of OmpA in the invasion of R. anatipestifer into DBMECs and duckling BBB was confirmed. The amino acids 230-242 of OmpA represents a key domain involved in R. anatipestifer invasion. In addition, another OmpA1164 protein constituted by the amino acids 102-488 within OmpA could function as a complete OmpA. The signal peptide sequence from amino acids 1-21 had no significant effect on OmpA functions. In conclusion, this study illustrated that OmpA is an important virulence factor mediating R. anatipestifer invasion of DBMECs and penetration of the duckling BBB.

Remarkably enhanced thermal properties of tobacco granules with high-thermal-conductivity nanoparticles.

Heated tobacco products (HTPs) are a novel type of cigarette that have received extensive attention. The tobacco plug could be made from tobacco granules (TGs), which are heated but not burned during the inhalation process. Thermal conductivity is an important property to evaluate the speed of heating TGs to meet the critical temperature for generating aerosol. Nevertheless, thermal physics properties of TGs is rarely reported. In this study, the thermophysical performance for the tobacco granules is systematically studied. An effective strategy of raising the thermal conductivity of TGs by introducing a small amount of nanoparticles of high-thermal-conductivity-materials (HTCMs, copper, silver, and graphene) is proposed, which not only results in a 35% improvement in the thermal conductivity but also reduces the maximum temperature for generating aerosol. In addition, introducing Cu and Ag particles in the TGs are favorable for improving the antibacterial effect. This method is worth promoting for enhancing the thermal conductivity of other plant-derived heated products.

Antimicrobial Resistance Surveillance of Tigecycline-Resistant Strains Isolated from Herbivores in Northwest China.

There is no doubt that antimicrobial resistance (AMR) is a global threat to public health and safety, regardless of whether it's caused by people or natural transmission. This study aimed to investigate the genetic characteristics and variations of tigecycline-resistant Gram-negative isolates from herbivores in northwest China. In this study, a total of 300 samples were collected from various provinces in northwest China, and 11 strains (3.67%) of tigecycline-resistant bacteria were obtained. In addition, bacterial identification and antibiotic susceptibility testing against 14 antibiotics were performed. All isolates were multiple drug-resistant (MDR) and resistant to more than three kinds of antibiotics. Using an Illumina MiSeq platform, 11 tigecycline-resistant isolates were sequenced using whole genome sequencing (WGS). The assembled draft genomes were annotated, and then sequences were blasted against the AMR gene database and virulence factor database. Several resistance genes mediating drug resistance were detected by WGS, including fluoroquinolone resistance genes (gyrA_S83L, gyrA_D87N, S83L, parC_S80I, and gyrB_S463A), fosfomycin resistance genes (GlpT_E448K and UhpT_E350Q), beta-lactam resistance genes (FtsI_D350N and S357N), and the tigecycline resistance gene (tetR N/A). Furthermore, there were five kinds of chromosomally encoded genetic systems that confer MDR (MarR_Y137H, G103S, MarR_N/A, SoxR_N/A, SoxS_N/A, AcrR N/A, and MexZ_K127E). A comprehensive analysis of MDR strains derived from WGS was used to detect variable antimicrobial resistance genes and their precise mechanisms of resistance. In addition, we found a novel ST type of Escherichia coli (ST13667) and a newly discovered point mutation (K127E) in the MexZ gene of Pseudomonas aeruginosa. WGS plays a crucial role in AMR control, prevention strategies, as well as multifaceted intervention strategies.

Characteristics of NtCCD1-3 from tobacco, and protein engineering of the CCD1 to enhance ß -ionone production in yeast.

Biosynthesis of ß-ionone by microbial cell factories has become a promising way to obtain natural ß-ionone. The catalytic activity of carotenoid cleavage dioxygenase 1 (CCD1) in cleavage of ß-carotene to ß-ionone severely limits its biosynthesis. In this study, NtCCD1-3 from Nicotiana tabacum with high ability to cleave ß-carotene was screened. Multiple strategies for improving the ß-ionone yield in Saccharomyces cerevisiae were performed. The results showed that NtCCD1-3 could cleave a variety of caroteniods at the 9,10 (9',10') double bonds and lycopene at the 5,6 (5',6') positions. The insertion site delta for NtCCD1-3 gene was more suitable for enhancing the yield of ß-ionone, showing 19.1-fold increase compared with the rox1 site. More importantly, mutant K38A of NtCCD1-3 in membrane-bonding domains could greatly promote ß-ionone production by more than 3-fold. We also found that overexpression of the NADH kinase Pos5 could improve ß-ionone yield up to 1.5 times. These results may provide valuable references for biosynthesis of ß-ionone.

Construction of Prognostic Risk Model for Small Cell Lung Cancer Based on Immune-Related Genes.

Small cell lung cancer (SCLC) is a highly invasive and fatal malignancy. Research at the present stage implied that the expression of immune-related genes is associated with the prognosis in SCLC. Accordingly, it is essential to explore effective immune-related molecular markers to judge prognosis and treat SCLC. Our research obtained SCLC dataset from Gene Expression Omnibus (GEO) and subjected mRNAs in it to differential expression analysis. Differentially expressed mRNAs (DEmRNAs) were intersected with immune-related genes to yield immune-related differentially expressed genes (DEGs). The functions of these DEGs were revealed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Thereafter, we categorized 3 subtypes of immune-related DEGs via K-means clustering. Kaplan-Meier curves analyzed the effects of 3 subtypes on SCLC patients' survival. Single-sample gene set enrichment analysis (ssGSEA) and ESTIMATE validated that the activation of different immune gene subtypes differed significantly. Finally, an immune-related-7-gene assessment model was constructed by univariate-Lasso-multiple Cox regression analyses. Riskscores, Kaplan-Meier curves, receiver operating characteristic (ROC) curves, and independent prognostic analyses validated the prognostic value of the immune-related-7-gene assessment model. As suggested by GSEA, there was a prominent difference in cytokine-related pathways between high- and low-risk groups. As the analysis went further, we discovered a statistically significant difference in the expression of human leukocyte antigen (HLA) proteins and costimulatory molecules expressed on the surface of CD274, CD152, and T lymphocytes in different groups. In a word, we started with immune-related genes to construct the prognostic model for SCLC, which could effectively evaluate the clinical outcomes and offer guidance for the treatment and prognosis of SCLC patients.

Characteristics of a new carotenoid cleavage dioxygenase NtCCD10 derived from Nicotiana tabacum.

MAIN CONCLUSION: A new carotenoid cleavage dioxygenase NtCCD10 from tobacco was characterized. There is some difference between NtCCD10 and CCD1 in structure. NtCCD10 can cleave the C5-C6 (C5'-C6') and C9-C10 (C9'-C10') double bonds of carotenoids and has high catalytic activity. Carotenoid cleavage dioxygenases (CCDs) cleave carotenoids to produce a variety of apocarotenoids, which have important biological functions for organisms in nature. There are eleven CCDs subfamilies in the plant kingdom, many of which have been extensively characterized in their functions. However, as a newly classified subfamily, the function of CCD10 has rarely been studied. In this work, the function of an NtCCD10 gene from dicotyledonous Nicotiana tabacum was cloned and characterized, and its phylogeny, molecular structural modeling and protein structure were also systematically analyzed. Like other CCDs, NtCCD10 also possesses a seven bladed ß-propeller with Fe2+ cofactor in its center constituting the active site of the enzyme. The Fe2+ is also coordinated bonding with four conserved histidine residues. Meanwhile, NtCCD10 also has many unique features, such as its α1 and α3 helixes are not anti-parallel, a special ß-sheet and a longer access tunnel for substrates. When expressed in engineered Escherichia coli (producing phytoene, lycopene, ß-carotene, and zeaxanthin) and Saccharomyces cerevisiae (producing ß-carotene), NtCCD10 could symmetrically cleave phytoene and ß-carotene at the C9-C10 and C9'-C10' positions to produce geranylacetone and ß-ionone, respectively. In addition, NtCCD10 could also cleave the C5-C6 and C5'-C6' double bonds of lycopene to generate 6-methyl-5-heptene-2-one (MHO). NtCCD10 has higher catalytic activity than PhCCD1 in yeast, which provides a good candidate CCD for biosynthesis of ß-ionone and has potential applications in biotechnological industry. This study identified the taxonomic position and catalytic activity of the first NtCCD10 in dicotyledonous plants. This will provide a reference for the discovery and functional identification of CCD10 enzymes in dicotyledons.

Co-transfer of mcr-8 with blaNDM-1 or tmexCD1-toprJ1 by plasmid hybridisation.

Carbapenems, tigecycline and colistin are three important antimicrobial agents for the treatment of clinical infections caused by multidrug-resistant Enterobacteriaceae. Here we characterised the formation of hybrid plasmids containing mcr-8 and blaNDM-1 or tmexCD1-toprJ1 that could confer resistance to colistin and carbapenems or tigecycline. More specifically, these clinically important genes could be co-transferred through IS26- and ltrA-mediated plasmid fusion to clinical isolates during conjugation under single drug (colistin) selection, following which the recipient strains became carbapenem- or tigecycline-resistant. The transferability and stability of these hybrid multidrug resistance (MDR) plasmids depend on the bacterial host and the presence of antibiotics. Further evolution and adaptation of these hybrid plasmids may facilitate their emergence and spread, which is of great concern for clinical therapy.

A Nomogram for Predicting the Risk of Pulmonary Hypertension for Patients with Chronic Obstructive Pulmonary Disease.

Background: Pulmonary hypertension (PH) is a life-threatening complication of chronic obstructive pulmonary disease (COPD). Timely diagnosis of PH in COPD patients is vital to achieve proper treatment; however, there is no algorithm to identify those at high risk. We aimed to develop a predictive model for PH in patients with COPD that provides individualized risk estimates. Methods: A total of 527 patients with COPD who were admitted to our hospital between May 2019 and December 2020 were retrospectively enrolled in this study. Using echocardiographic results as a standard, patients were stratified into a moderate- or high-PH probability group and a low-PH probability group. They were randomly grouped into either the training set (n = 368 patients) or validation set (n = 159 patients) in a ratio of 7:3. We utilized the least absolute shrinkage and selection operator (LASSO) regression model to select the feature variables. The characteristic variables selected in the LASSO regression were analyzed using multivariable logistic regression to construct the predictive model. The predictive model was displayed using a nomogram. We used the receiver operating characteristic curve, calibration curve, and clinical decision curve analysis (DCA) to evaluate model performance, and internal validation was assessed. Results: The predictive factors included in the prediction model were Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, emphysema, PaCO2, NT-pro-BNP, red blood cell (RBC) distribution width-standard deviation (RDW-SD), and neutrophil/lymphocyte ratio (NLR). The predictive model yielded an area under the curve (AUC) of 0.770 (95% confidence interval [CI], 0.719-0.820); in the internal validation, the AUC was 0.741 (95% CI, 0.659-0.823). The predictive model was well calibrated, and the DCA showed that the proposed nomogram had strong clinical applicability. Conclusion: This study showed that a simple nomogram could be used to calculate the risk of PH in patients with COPD which can be useful for the individualized clinical management of COPD patients who may be occur with PH. Further studies need to be confirmed by larger sample sizes and validated in the stable COPD population.

Effects of tryptophan and phenylalanine on tryptophol production in Saccharomyces cerevisiae revealed by transcriptomic and metabolomic analyses.

Tryptophol (TOL) is a metabolic derivative of tryptophan (Trp) and shows pleiotropic effects in humans, plants and microbes. In this study, the effect of Trp and phenylalanine (Phe) on TOL production in Saccharomyces cerevisiae was determined, and a systematic interpretation of TOL accumulation was offered by transcriptomic and metabolomic analyses. Trp significantly promoted TOL production, but the output plateaued (231.02-266.31 mg/L) at Trp concentrations ≥ 0.6 g/L. In contrast, Phe reduced the stimulatory effect of Trp, which was strongly dependent on the Phe concentration. An integrated genomic, transcriptomic, and metabolomic analysis revealed that the effect of Trp and Phe on TOL production was mainly related to the transamination and decarboxylation of the Ehrlich pathway. Additionally, other genes, including thiamine regulon genes (this), the allantoin catabolic genes dal1, dal2, dal4, and the transcriptional activator gene aro80, may play important roles. These findings were partly supported by the fact that the thi4 gene was involved in TOL production, as shown by heterologous expression analysis. To the best of our knowledge, this novel biological function of thi4 in S. cerevisiae is reported here for the first time. Overall, our findings provide insights into the mechanism of TOL production, which will contribute to TOL production using metabolic engineering strategies.

A Small KPC-2-Producing Plasmid in Klebsiella pneumoniae: Implications for Diversified Vehicles of Carbapenem Resistance.

The convergence of hypervirulence to carbapenem-resistant K. pneumoniae (CRKP) in a highly transmissible ST11 clone poses a great challenge to public health and anti-infection therapy. Recently, we revealed that an expanding repertoire of diversified KPC-2-producing plasmids occurs in these high-risk clones. Here, we report a clinical case infected with a rare isolate of ST437 CRKP, K186, which exhibited KPC-2 production. Apart from its 5,322,657-bp long chromosome, whole-genome sequencing of strain K186 elucidated three distinct resistance plasmids (designated pK186_1, pK186_2, and pK186_KPC, respectively). Unlike the prevalently larger form of KPC-2-producing plasmids (~120 to ~170 kb) earlier we observed, pK186_KPC is an IncN-type, small plasmid of 26,012bp in length. Combined with the colinear alignment of plasmid genome, the analyses of insertion sequences further suggested that this carbapenem-resistant pK186_KPC might arise from the cointegration of its ancestral IncN and IncFII plasmids, exclusively relying on IS26-based transposition events. Taken together, the result represents an unusual example of blaKPC-2-bearing small plasmids, and highlights an ongoing arsenal of diversified carriers benefiting the transferability of KPC-2 carbapenem resistance. IMPORTANCE A rare ST437 isolate termed K186 was clinically determined which was unlike ST11, the dominant sequence type of CRKP. Whole-genome sequencing enabled us to discover three distinct resistance plasmids, namely, pK186_1, pK186_2, and pK186_KPC. Among them, pK186_KPC appears as a unique plasmid ~26 kb in size, much smaller than the prevalent forms (~120 to ~170 kb). Intriguingly, genetic analysis suggests that it might originate from Proteus mirabilis. This result constitutes an additional example of differentiated plasmid vehicles dedicated to the emergence and dissemination of KPC-2 carbapenem resistance.

Local temporal Rac1-GTP nadirs and peaks restrict cell protrusions and retractions.

Cells probe their microenvironment using membrane protrusion-retraction cycles. Spatiotemporal coordination of Rac1 and RhoA GTP-binding activities initiates and reinforces protrusions and retractions, but the control of their finite lifetime remains unclear. We examined the relations of Rac1 and RhoA GTP-binding levels to key protrusion and retraction events, as well as to cell-ECM traction forces at physiologically relevant ECM stiffness. High RhoA-GTP preceded retractions and Rac1-GTP elevation before protrusions. Notable temporal Rac1-GTP nadirs and peaks occurred at the maximal edge velocity of local membrane protrusions and retractions, respectively, followed by declined edge velocity. Moreover, altered local Rac1-GTP consistently preceded similarly altered traction force. Local optogenetic Rac1-GTP perturbations defined a function of Rac1 in restricting protrusions and retractions and in promoting local traction force. Together, we show that Rac1 plays a fundamental role in restricting the size and durability of protrusions and retractions, plausibly in part through controlling traction forces.