Short-term outcome prediction for myasthenia gravis: an explainable machine learning model.

Background: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigability. The fluctuating nature of the disease course impedes the clinical management. Objective: The purpose of the study was to establish and validate a machine learning (ML)-based model for predicting the short-term clinical outcome in MG patients with different antibody types. Methods: We studied 890 MG patients who had regular follow-ups at 11 tertiary centers in China from 1 January 2015 to 31 July 2021 (653 patients for derivation and 237 for validation). The short-term outcome was the modified post-intervention status (PIS) at a 6-month visit. A two-step variable screening was used to determine the factors for model construction and 14 ML algorithms were used for model optimisation. Results: The derivation cohort included 653 patients from Huashan hospital [age 44.24 (17.22) years, female 57.6%, generalized MG 73.5%], and the validation cohort included 237 patients from 10 independent centers [age 44.24 (17.22) years, female 55.0%, generalized MG 81.2%]. The ML model identified patients who were improved with an area under the receiver operating characteristic curve (AUC) of 0.91 [0.89-0.93], 'Unchanged' 0.89 [0.87-0.91], and 'Worse' 0.89 [0.85-0.92] in the derivation cohort, whereas identified patients who were improved with an AUC of 0.84 [0.79-0.89], 'Unchanged' 0.74 [0.67-0.82], and 'Worse' 0.79 [0.70-0.88] in the validation cohort. Both datasets presented a good calibration ability by fitting the expectation slopes. The model is finally explained by 25 simple predictors and transferred to a feasible web tool for an initial assessment. Conclusion: The explainable, ML-based predictive model can aid in forecasting the short-term outcome for MG with good accuracy in clinical practice.

Response of waxy maize (Zea mays L. var. ceratina Kulesh) leaf photosynthesis to low temperature during the grain-filling stage.

Low temperature (LT) during the grain-filling stage is an important factor that affects the source-sink relationship and leads to yield loss in maize (Zea mays L). In this study, field and pot trials were conducted to investigate the effects of LT during the grain-filling stage on leaf photosynthesis, antioxidant system, hormones, and grain yield of waxy maize cultivars Suyunuo 5 (S5) and Yunuo 7 (Y7). The results showed that LT treatment inhibited the chlorophyll biosynthesis and reduced the photosynthetic pigment levels during grain-filling stage. Ribulose-1,5-bisphosphate carboxylase and phosphoenolpyruvate carboxylase activities, photosynthetic rate, transpiration rate, and stomatal conductance decreased under LT treatment during the grain-filling stage. Furthermore, LT treatment increased the contents of malondialdehyde and reactive oxygen species, and decreased the activities of catalase, superoxide dismutase, peroxidase, and ascorbate peroxidase in the ear leaves, which accelerated the oxidative damage of leaf. The LT treatment also raised abscisic acid content and reduced indole acetic acid content in the ear leaves during grain-filling stage. The results of field and pot trials were verified by each other, but the field effect was greater than that of pot. Overall, LT treatment reduced the waxy maize dry matter accumulation after silking by affecting the physiological and biochemical processes of leaves, and ultimately decreased grain yield.

Enhancing viability of dried lactic acid bacteria prepared by freeze drying and spray drying via heat preadaptation.

Physical injury carried by dried process was an inevitable and hostile problem which could seriously affect the quality and viability of microbial agents. In this study, heat preadaptation was successfully applied as a pretreatment to fight against the physical stresses encountered during freeze-dried and spray-dried process and develop a high activity Tetragenococcus halophilus powder. The results indicated T. halophilus cells maintained a higher viability in dried powder when cells were treated with heat preadaptation before dried process. Flow cytometry analysis illustrated that heat preadaptation contributed to maintain a high membrane integrity during dried process. Besides, glass transition temperatures of dried powder increased when cells were preheated, which further verified that higher stability was obtained in group preadaptation during shelf life. Additionally, dried powder prepared by heat shock presented a better fermentation performance, suggesting heat preadaptation may be a promising strategy to prepare bacterial powder by freeze drying or spray drying.

Long-term exposure of polytetrafluoroethylene-nanoplastics on the nitrogen removal and extracellular polymeric substances in sequencing batch reactor.

The impact of polytetrafluoroethylene-nanoplastics (PTFE-NPs) on biological sewage disposal was delved, containing nitrogen remotion, microbiological activity and composition of extracellular polymer (EPS). The addition of PTFE-NPs reduced the removal efficiencies of chemical oxygen demand (COD) and ammonia nitrogen (NH4+-N) by 3.43 % and 2.35 %, respectively. In comparison with no PTFE-NPs, the specific oxygen uptake rate (SOUR), specific ammonia oxidation rate (SAOR), specific nitrite oxidation rate (SNOR) and specific nitrate reduction rate (SNRR) decreased by 65.26 %, 65.24 %, 41.77 % and 54.56 %, respectively. The PTFE-NPs inhibited the activities of nitrobacteria and denitrobacteria. It was worth noting that, nitrite oxidized bacterium was more resistant to adverse environments than ammonia oxidizing bacterium. Compared with no PTFE-NPs, the reactive oxygen species (ROS) content and lactate dehydrogenase (LDH) grew by 130 % and 50 % under PTFE-NPs pressure. The appearance of PTFE-NPs affected the normal function of microorganisms by inducing endocellular oxidative stress and destroying the completeness of the cytomembrane. The protein (PN) and polysaccharide (PS) levels in loosely bound EPS (LB-EPS) and tightly bound EPS (TB -EPS) increased by 4.96, 0.70, 3.07 and 0.71 mg g-1 VSS, under PTFE-NPs. Meanwhile, the PN/PS ratios of LB-EPS and TB -EPS increased from 6.18 and 6.41-11.04 and 9.29, respectively. The LB-EPS might provide sufficient binding sites for PTFE-NPs adsorption due to its loose and porous structure. The defense mechanism of bacteria against PTFE-NPs was mainly the PN in loosely bound EPS. Moreover, the functional groups referred to the complexation of EPS with PTFE-NPs were mainly related to N-H, CO, and C-N in proteins and O-H in polysaccharides.

Mucus-penetrating nonviral gene vaccine processed in the epithelium for inducing advanced vaginal mucosal immune responses.

Establishment of vaginal immune defenses at the mucosal interface layer through gene vaccines promise to prevent infectious diseases among females. Mucosal barriers composed of a flowing mucus hydrogel and tightly conjugated epithelial cells (ECs), which represent the main technical difficulties for vaccine development, reside in the harsh, acidic human vaginal environment. Different from frequently employed viral vectors, two types of nonviral nanocarriers were designed to concurrently overcome the barriers and induce immune responses. Differing design concepts include the charge-reversal property (DRLS) to mimic a virus that uses any cells as factories, as well as the addition of a hyaluronic acid coating (HA/RLS) to directly target dendritic cells (DCs). With a suitable size and electrostatic neutrality, these two nanoparticles penetrate a mucus hydrogel with similar diffusivity. The DRLS system expressed a higher level of the carried human papillomavirus type 16 L1 gene compared to HA/RLS in vivo. Therefore it induced more robust mucosal, cellular, and humoral immune responses. Moreover, the DLRS applied to intravaginal immunization induced high IgA levels compared with intramuscularly injected DNA (naked), indicating timely protection against pathogens at the mucus layer. These findings also offer important approaches for the design and fabrication of nonviral gene vaccines in other mucosal systems.

The use of high-flow nasal cannula in patients with chronic obstructive pulmonary disease under exacerbation and stable phases: A systematic review and meta-analysis.

BACKGROUND: High-flow nasal cannula (HFNC) has been increasingly utilized in patients with chronic obstructive pulmonary disease (COPD); however, the effects on reducing the need for intubation or reintubation remain unclear. OBJECTIVES: We aimed to investigate whether HFNC therapy was superior to conventional oxygen therapy (COT) or noninvasive ventilation (NIV) in patients with COPD. METHODS: A literature search was performed in electronic databases until October 1st, 2022. The primary outcome was the need for intubation/reintubation. All analyses were performed using R (version 4.0.3) and STATA SE (version 15.1). RESULTS: When HFNC therapy was compared with NIV in patients with COPD under initial respiratory support and postextubation, no significant differences were found in the risk of intubation (RR 0.84, 95% CI 0.36 to 1.98) and reintubation (RR 1.35, 95% CI 0.73 to 2.50). Compared to NIV, HFNC therapy did not decrease the partial pressure of carbon dioxide or increase the partial pressure of oxygen to the fraction of inspired oxygen. However, HFNC therapy was associated with a lower incidence of skin breakdown (RR 0.52, 95% CI 0.39 to 0.69) and a higher comfort score (SMD 0.90, 95% CI 0.60 to 1.20) than NIV. When HFNC therapy was compared with COT during initial respiratory treatment for COPD exacerbation, a lower risk of treatment failure was found (RR 0.58, 95% CI 0.37 to 0.89). When HFNC therapy was compared with long-term oxygen therapy, quality of life (measured by SGRQ-C) was significantly improved (SMD -0.42, 95% CI -0.69 to -0.14). CONCLUSION: HFNC therapy might be used as an alternative to NIV for COPD exacerbation with mild-moderate hypercapnia under close monitoring and is a potential domiciliary treatment for stable COPD.

Polydopamine Nanoparticles Targeting Ferroptosis Mitigate Intervertebral Disc Degeneration Via Reactive Oxygen Species Depletion, Iron Ions Chelation, and GPX4 Ubiquitination Suppression.

Intervertebral disc degeneration (IVDD)-induced lower back pain (LBP) is a common problem worldwide. The underlying mechanism is partially accredited to ferroptosis, based on sequencing analyses of IVDD patients from the gene expression omnibus (GEO) databases. In this study, it is shown that polydopamine nanoparticles (PDA NPs) inhibit oxidative stress-induced ferroptosis in nucleus pulposus (NP) cells in vitro. PDA NPs scavenge reactive oxygen species (ROS), chelate Fe2+ to mitigate iron overload, and regulate the expression of iron storage proteins such as ferritin heavy chain (FHC), ferritin, and transferrin receptor (TFR). More importantly, PDA NPs co-localize with glutathione peroxidase 4 (GPX4) around the mitochondria and suppress ubiquitin-mediated degradation, which in turn exerts a protective function via the transformation and clearance of phospholipid hydroperoxides. PDA NPs further down-regulate malondialdehyde (MDA) and lipid peroxide (LPO) production; thus, antagonizing ferroptosis in NP cells. Moreover, PDA NPs effectively rescue puncture-induced degeneration in vivo by targeting ferroptosis and inhibiting GPX4 ubiquitination, resulting in the upregulation of antioxidant pathways. The findings offer a new tool to explore the underlying mechanisms and a novel treatment strategy for IVDD-induced LBP.

Effect of oral administration of gabapentin on the minimum alveolar concentration of isoflurane in cats.

Objective: To determine if oral gabapentin decreases the minimum alveolar concentration (MAC) of isoflurane in cats. Study design: Prospective, randomized, blinded, crossover, and experimental study. Animals: A total of six healthy adult cats (three male, three female) aged 18-42 months, weighing 3.31 ± 0.26 kg. Methods: Cats were randomly given oral gabapentin (100 mg cat-1) or placebo 2 h before starting MAC determination, with the crossover treatment given at least 7 days apart. Anesthesia was induced and maintained with isoflurane in oxygen. Isoflurane MAC was determined in duplicate using an iterative bracketing technique and tail clamp method. Hemodynamic and other vital variables were recorded at each stable isoflurane concentration and were compared between gabapentin and placebo treatments at lowest end-tidal isoflurane concentration when cats did not respond to tail clamping. A paired t-test was used to compare normally distributed data, and a Wilcoxon signed-rank test was applied for non-normally distributed data. Significance was set at p < 0.05. Data are mean ± standard deviation. Results: Isoflurane MAC in the gabapentin treatment was 1.02 ± 0.11%, which was significantly lower than that in the placebo treatment (1.49 ± 0.12%; p < 0.001), decreasing by 31.58 ± 6.94%. No significant differences were found in cardiovascular and other vital variables between treatments. Conclusion and clinical relevance: Oral administration of gabapentin 2 h before starting MAC determination had a significant isoflurane MAC-sparing effect in cats with no observed hemodynamic benefit.

Postsurgical wound management and prevention of triple-negative breast cancer recurrence with a pryoptosis-inducing, photopolymerizable hydrogel.

Surgical removal remains the predominant treatment strategy for triple-negative breast cancer (TNBC). However, risks that include high locoregional recurrence and remote metastasis threaten patient survival and quality of life after surgery. In this study, a hydrogel based on poly (ethylene glycol) dimethacrylate and sericin methacryloyl was fabricated by photopolymerization to fill the resection cavity and prevent recurrence. The obtained hydrogel exhibited mechanical properties compatible with breast tissue and facilitated postsurgical wound management by promoting tissue regeneration. The DNA methylation inhibitor decitabine (DEC) and poly (lactic-co-glycolic acid)-encapsulated phytochemical gambogic acid (GA) were loaded into the hydrogel. The as-prepared hydrogel promoted fast release of DEC and sustained release of GA, leading to gasdermin E-mediated tumor cell pyroptosis and activating antitumor immune responses. Inducing postsurgical tumor cell pyroptosis inhibited local tumor recurrence and lung metastasis. While the dual-drug-loaded hydrogel system cured less than half of tumor-bearing mice, the cured mice survived for over half a year. These findings indicate that our hydrogel system is an excellent biocompatible platform for postsurgical TNBC therapy.

Spermatophore development in drones indicates the metabolite support for sperm storage in honey bees (Apis cerana).

Developing effective long-term sperm storage strategies to maintain activity requires an understanding of the underlying spermatophore developmental phase in drones. Here we compared the developmental processes and metabolites about seminal vesicles of drones from different parentages (0-24 d)in honeybee colonies, including mated queens, virgin queens, and worker bees. The results showed a similar developmental trend of seminal vesicles in thethree groups of drones on the whole, although there were significant differences in developmental levels, as well as in other indicators. Correlation analysis showed significant positive correlations between seminal vesicle width and sperm viability. The metabolomics of the seminal vesicles in drones from mated queens showed differences of the metabolites in each stage. Particularly, squalene identified among them was validated a protective effect on sperm vitality in vitro experiments. Together the results of these assays support that there were significant differences in the developmental levels of seminal vesicles among the three groups of drones in honeybees, wherein a significant correlation between sperm viability and the developmental levels of seminal vesicles were dissected. The metabolomics analysis and semen storage experiments in vitro display signatures of squalene that may act as an effective protective agent in maintaining sperm viability. Collectively, our findings indicate that spermatophore development in drones provides metabolite support, which contributes to research on the differences of sperm viability among drones in the future.

Investigation of Catalytic Co-Pyrolysis Characteristics and Synergistic Effect of Oily Sludge and Walnut Shell.

The co-pyrolysis of oily sludge and walnut shell is a reliable method for solid waste treatment and waste recycling. In this paper, a thermogravimetric analysis was used to study the thermodynamics and synergy effect of oily sludge (OS) and walnut shell (WS) at four heating rates (10, 20, 30, and 40 °C/min) in the temperature range from 50-850 °C. Two model-free methods (FWO and KAS) were used to calculate the activation energy. The results showed that the heating rate had no significant effect on the pyrolysis process. The addition of walnut shell improved the pyrolysis process of the samples. Mixture 1OS3WS had a synergy effect, while other blends showed an inhibitory effect. The synergy effect of co-pyrolysis was strongest when the mass ratio of oily sludge was 25%. The activation energy of the Zn-ZSM-5/25 catalyst was the lowest, and the residual substances were the least, indicating that the Zn-ZSM-5/25 was beneficial to the co-pyrolysis of oily sludge and walnut shell. The analysis of catalytic pyrolysis products by Py-GC/MS found that co-pyrolysis was beneficial to the generation of aromatic hydrocarbons. This study provided a method for the resource utilization of hazardous waste and biomass waste, which was conducive to the production of aromatic chemicals with added value while reducing environmental pollution.

Dismantling the Component-Specific Effects of Yogic Breathing: Feasibility of a Fully Remote Three-Arm RCT with Virtual Laboratory Visits and Wearable Physiology.

Despite the growing research base examining the benefits and physiological mechanisms of slow-paced breathing (SPB), mindfulness (M), and their combination (as yogic breathing, SPB + M), no studies have directly compared these in a "dismantling" framework. To address this gap, we conducted a fully remote three-armed feasibility study with wearable devices and video-based laboratory visits. Eighteen healthy participants (age 18-30 years, 12 female) were randomized to one of three 8-week interventions: slow-paced breathing (SPB, N = 5), mindfulness (M, N = 6), or yogic breathing (SPB + M, N = 7). The participants began a 24-h heart rate recording with a chest-worn device prior to the first virtual laboratory visit, consisting of a 60-min intervention-specific training with guided practice and experimental stress induction using a Stroop test. The participants were then instructed to repeat their assigned intervention practice daily with a guided audio, while concurrently recording their heart rate data and completing a detailed practice log. The feasibility was determined using the rates of overall study completion (100%), daily practice adherence (73%), and the rate of fully analyzable data from virtual laboratory visits (92%). These results demonstrate feasibility for conducting larger trial studies with a similar fully remote framework, enhancing the ecological validity and sample size that could be possible with such research designs.

Rapid quantitative detection of Klebsiella pneumoniae in infants with severe infection disease by point-of-care immunochromatographic technique based on nanofluorescent microspheres.

Background: Klebsiella pneumoniae (KP, K. pneumoniae) is one of the most important nosocomial pathogens that cause severe respiratory infections. As evolutionary high-toxic strains with drug resistance genes increase year by year, the infections caused by it are often accompanied by high mortality, which may be fatal to infants and can cause invasive infections in healthy adults. At present, the traditional clinical methods for detecting K. pneumoniae are cumbersome and time-consuming, and the accuracy and sensitivity are not high. In this study, nanofluorescent microsphere (nFM)-based immunochromatographic test strip (ICTS) quantitative testing platform were developed for point-of-care testing (POCT) method of K. pneumoniae. Methods: 19 clinical samples of infants were collected, the genus-specific gene of mdh was screened from K. pneumoniae. Polymerase chain reaction (PCR) combined with nFM-ICTS based on magnetic purification assay (PCR-ICTS) and strand exchange amplification (SEA) combined with nFM-ICTS based on magnetic purification assay (SEA-ICTS) were developed for the quantitative detection of K. pneumoniae. The sensitivity and specificity of SEA-ICTS and PCR-ICTS were demonstrated by the existing used classical microbiological methods, the real-time fluorescent quantitative PCR (RTFQ-PCR) and PCR assay based on agarose gel electrophoresis (PCR-GE). Results: Under optimum working conditions, the detection limits of PCR-GE, RTFQ-PCR, PCR-ICTS and SEA-ICTS are 7.7 × 10-3, 2.5 × 10-6, 7.7 × 10-6, 2.82 × 10-7 ng/µL, respectively. The SEA-ICTS and PCR-ICTS assays can quickly identify K. pneumoniae, and could specifically distinguish K. pneumoniae samples from non-K. pneumoniae samples. Experiments have shown a diagnostic agreement of 100% between immunochromatographic test strip methods and the traditional clinical methods on the detection of clinical samples. During the purification process, the Silicon coated magnetic nanoparticles (Si-MNPs) were used to removed false positive results effectively from the products, which showed of great screening ability. The SEA-ICTS method was developed based on PCR-ICTS, which is a more rapid (20 min), low-costed method compared with PCR-ICTS assay for the detection of K. pneumoniae in infants. Only need a cheap thermostatic water bath and takes a short detection time, this new method can potentially serve as an efficient point-of-care testing method for on-site detection of pathogens and disease outbreaks without fluorescent polymerase chain reaction instruments and professional technicians operation.

Conditioned medium of PC­3 prostate cancer cells affects microRNA and mRNA profiles in mechanically strained osteoblasts.

Bone is the main site of metastasis from prostate cancer; therefore, it is important to investigate the microRNAs (miRNAs) and mRNA associated with bone metastases from prostate cancer. Since an appropriate mechanical environment is important in the growth of bone, in the present study, the miRNA, mRNA, and long non-coding RNA (lncRNA) profiles of mechanically strained osteoblasts treated with conditioned medium (CM) from PC-3 prostate cancer cells were studied. MC3T3-E1 osteoblastic cells were treated with the CM of PC-3 prostate cancer cells and were simultaneously stimulated with a mechanical tensile strain of 2,500 µÎµ at 0.5 Hz; the osteoblastic differentiation of the MC3T3-E1 cells was then assessed. In addition, the differential expression levels of mRNA, miRNA and lncRNA in MC3T3-E1 cells treated with the CM of PC-3 cells were screened, and some of the miRNAs and mRNAs were verified by reverse transcription-quantitative PCR (RT-qPCR). The signal molecules and signaling pathways associated with osteogenic differentiation were predicted by bioinformatics analysis. The CM of PC-3 prostate cancer cells suppressed osteoblastic differentiation of MC3T3-E1 cells. A total of seven upregulated miRNAs and 12 downregulated miRNAs were selected by sequencing and further verified using RT-qPCR, and related differentially expressed genes (11 upregulated and 12 downregulated genes) were also selected by sequencing and further verified using RT-qPCR; subsequently, according to the enrichment of differentially expressed genes in signaling pathways, nine signaling pathways involved in osteogenic differentiation were screened out. Furthermore, a functional mRNA-miRNA-lncRNA regulatory network was constructed. The differentially expressed miRNAs, mRNAs and lncRNAs may provide a novel signature in bone metastases of prostate cancer. Notably, some of the signaling pathways and related genes may be associated with pathological osteogenic differentiation caused by bone metastasis of prostate cancer.

Preparation of Anorthite/Mullite In Situ and Phase Transformation in Porcelain.

A high sintering temperature is required to acquire excellent performance in the production of porcelain but results in high fuel consumption. To prepare the porcelain with outstanding performance at a lower temperature, a self-produced additive containing calcium (CaK) was added into a three-component system of kaolinite-feldspar-quartz. XRD and SEM were used to characterize the samples. The toughening mechanism and Gibbs free energy were investigated. After introducing the CaK, the bending strength of the porcelain fired at 1513 K increased from 56.32 ± 0.65 MPa to 95.31 ± 0.63 MPa, which was 21.83% higher than that of the porcelain without CaK at an optimal firing temperature of 1603 K. The main crystal phase of the sample comprised mullite and quartz in the raw materials at 1453~1603 K. The anorthite was observed at 1453 K and interlocked with needle-shaped mullite at 1513 K in the porcelain after adding CaK, which resulted in the higher bending strength. Quantitative analysis indicated that the amount of anorthite decreased at 1513 K and disappeared at 1543 K; the amount of mullite increased with temperature. The Gibbs free energy of the reaction (CaO•Al2O3•2SiO2 + 2(Al2O3•2SiO2) → 3Al2O3•2SiO2 + CaO + 4SiO2) at high temperature was negative, which suggested that the formation of mullite (3Al2O3•2SiO2) from anorthite (CaO•Al2O3•2SiO2) was possible. These findings implied that the addition of CaK contributed to the appropriate phase composition and microstructure, and the excellent performance of the porcelain at a lower temperature. In addition, the transformation between anorthite and mullite was possible in the special raw material system. The results are of interest in producing anorthite/mullite ceramics at reduced sintering temperatures and the conversion between anorthite and mullite.

CuS quantum dots activated DNAzyme for ratiometric electrochemical detection of telomerase activity.

Telomerase activity detection has attracted much attention concerning its importance for early cancer diagnosis. Here, we established a ratiometric electrochemical biosensor for telomerase detection based on CuS quantum dots (CuS QDs) dependent DNAzyme-regulated dual signals. The telomerase substrate probe was used as the linker to combine the DNA fabricated magnetic beads and CuS QDs. In this way, telomerase extended the substrate probe with repeated sequence to from hairpin structure, releasing CuS QDs as an input to DNAzyme modified electrode. DNAzyme was cleaved with high current of ferrocene (Fc) and low current of methylene blue (MB). On the basis of the obtained ratiometric signals, telomerase activity detection was achieved in the range of 1.0 × 10-12-1.0 × 10-6 IU/L, with the limit of detection down to 2.75 × 10-14 IU/L. Moreover, telomerase activity from HeLa extracts was also tested to verify the clinical application.

Transcriptomics-based investigation of molecular mechanisms underlying synergistic antimicrobial effects of AgNPs and Domiphen on the human fungal pathogen Aspergillus fumigatus.

Critically ill patients have higher risk of serious fungal infections, such as invasive aspergillosis (IA) which is mainly caused by the human fungal pathogen Aspergillus fumigatus. Triazole drugs are the primary therapeutic agents for the first-line treatment of IA, which could easily cause drug resistance problems. Here, we assess the potential of AgNPs synthesized with Artemisia argyi leaf extract and domiphen as new antifungal agents to produce synergistic antimicrobial effects on Aspergillus fumigatus, and dissect possible molecular mechanisms of action. Plate inoculation assays combined with drug susceptibility test and cytotoxicity test showed that the combination of AgNPs and domiphen has synergistic antimicrobial effects on A. fumigatus with low cytotoxicity. Gene Ontology (GO) enrichment analysis showed that AgNPs and domiphen inhibit the growth of A. fumigatus by suppressing nitrate assimilation, and purine nucleobase metabolic process and amino acid transmembrane transport, respectively. When the two drugs are combined, AgNPs has epistatic effects on domiphen. Moreover, the combination of AgNPs and domiphen primarily influence secondary metabolites biosynthesis, steroid biosynthesis and nucleotide sugar metabolism of A. fumigatus via Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Furthermore, protein-protein interactions (PPI) analysis combined with validation experiments showed that the combination of AgNPs and domiphen could enhance the expression of copper transporter and inhibit nitrogen source metabolism. In addition, the synergistic antimicrobial effects could be enhanced or eliminated depending on exogenous addition of copper and nitrogen source, respectively. Taken together, the results of this study provide a theoretical basis and a new strategy for the treatment of IA.

The hTERT-p50 homodimer inhibits PLEKHA7 expression to promote gastric cancer invasion and metastasis.

Although accumulating evidence has highlighted the molecular mechanisms by which hTERT promotes tumour cell invasion and metastasis, the molecular mechanisms of the properties enabling hTERT to contribute to invasion and metastasis have not been clearly illustrated. Here, we report that hTERT promotes gastric cancer invasion and metastasis by recruiting p50 to synergistically inhibit PLEKHA7 expression. We observed that the expression of PLEKHA7 in gastric cancer was significantly negatively associated with the TNM stage and lymphatic metastasis and that decreased PLEKHA7 expression dramatically increased invasion and metastasis in gastric cancer cells. Further mechanistic research showed that hTERT directly regulates PLEKHA7 expression by binding p50 and recruiting the hTERT/p50 complex to the PLEKHA7 promoter. Increased hTERT dramatically decreased PLEKHA7 expression and promoted invasion and metastasis in gastric cancer cells. The hTERT-mediated invasion/metastasis properties at least partially depended on PLEKHA7. Our work uncovers a novel molecular mechanism underlying invasion/metastasis in gastric cancer orchestrated by hTERT and p50.

Identification of Distinct Clinical Phenotypes of Heterogeneous Mechanically Ventilated ICU Patients Using Cluster Analysis.

This retrospective study aimed to derive the clinical phenotypes of ventilated ICU patients to predict the outcomes on the first day of ventilation. Clinical phenotypes were derived from the eICU Collaborative Research Database (eICU) cohort via cluster analysis and were validated in the Medical Information Mart for Intensive Care (MIMIC-IV) cohort. Four clinical phenotypes were identified and compared in the eICU cohort (n = 15,256). Phenotype A (n = 3112) was associated with respiratory disease, had the lowest 28-day mortality (16%), and had a high extubation success rate (~80%). Phenotype B (n = 3335) was correlated with cardiovascular disease, had the second-highest 28-day mortality (28%), and had the lowest extubation success rate (69%). Phenotype C (n = 3868) was correlated with renal dysfunction, had the highest 28-day mortality (28%), and had the second-lowest extubation success rate (74%). Phenotype D (n = 4941) was associated with neurological and traumatic diseases, had the second-lowest 28-day mortality (22%), and had the highest extubation success rate (>80%). These findings were validated in the validation cohort (n = 10,813). Additionally, these phenotypes responded differently to ventilation strategies in terms of duration of treatment, but had no difference in mortality. The four clinical phenotypes unveiled the heterogeneity of ICU patients and helped to predict the 28-day mortality and the extubation success rate.

The short-term effects of air pollution exposure on preterm births in Chongqing, China: 2015-2020.

Accumulating evidence suggested that the risk of preterm births (PTBs) following prenatal exposure to air pollution was inconclusive. The aim of this study is to investigate the relationship between air pollution exposure in the days before delivery and PTB and assess the threshold effect of short-term prenatal exposure to air pollution on PTB. This study collected data including meteorological factors, air pollutants, and information in Birth Certificate System from 9 districts during 2015-2020 in Chongqing, China. Generalized additive models (GAMs) with the distributed lag non-linear models were conducted to assess the acute impact of air pollutants on the daily counts of PTB, after controlling for potential confounding factors. We observed that PM2.5 was related to increased occurrence of PTB on lag 0-3 and lag 10-21 days, with the strongest on the first day (RR = 1.017, 95%CI: 1.000-1.034) and then decreasing. The thresholds of PM2.5 for lag 1-7 and 1-30 days were 100 µg/m3 and 50 µg/m3, respectively. The lag effect of PM10 on PTB was very similar to that of PM2.5. In addition, the lagged and cumulative exposure of SO2 and NO2 was also associated with the increased risk of PTB. The lag relative risk and cumulative relative risk of CO exposure were the strongest, with a maximum RR at lag 0 (RR = 1.044, 95%CI: 1.018, 1.069). Importantly, the exposure-response curve of CO showed that RR increased rapidly when the concentration exceeded 1000 µg/m3. This study indicated significant associations between air pollution and PTB. The relative risk decreases with day lag, while the cumulative effect increases. Thus, pregnant women should understand the risk of air pollution and try to avoid high concentration exposure.