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Background Coca-Cola and Cola-Cola Zero Sugar are commonly consumed beverages by healthcare professionals. Medical superstitions abound about whether Cola-Cola Zero sugar consumption affects night call outcomes. Objectives The current study aimed to determine whether Coca-Cola Zero Sugar, compared to regular Coca-Cola, is associated with any differences in inpatient admissions and mortality of patients on night calls. Methods A double-blinded randomized controlled trial was conducted in the Division of Medicine, Singapore General Hospital, Singapore involving junior doctors from January 2024 to February 2024.The primary outcome was the number of ward admissions under the night call doctor’s care. Secondary outcomes involved the number of inpatient deaths, high-dependency or intensive care admissions, the number of hours slept by the doctor, the number of steps walked by the doctor, and the level of sleepiness of the doctor on call. Results 203 participants consented and were randomized (44.9%). The data of 198 participants were included for analysis (97.5%). No significant differences were detected in the number of ward admissions between the Coca-Cola Zero Sugar group and the regular Coca-Cola group. For secondary outcomes, a significant difference was present between the two groups in the Karolinska Sleepiness Scale score ( p -value = .0413). Other secondary outcomes did not demonstrate significant differences between the two groups. Conclusions No convincing evidence was present to support the consumption of Coca-Cola Zero Sugar versus the regular Coca-Cola had significant differences in the number of inpatient admissions and mortality in night call duties.

The problem of potentially toxic metal pollution is increasingly acute with the development of human society. In this study, we investigated the remediation of nickel (Ni) and cadmium (Cd) co-contamination through inoculating rice with three new-isolated Ni- and Cd-resistant plant growth-promoting rhizobacteria (PGPR) Y3, Y4, and Y5. These three strains possessed growth-promoting properties, including 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase activity, the ability of indoleacetic acid (IAA) production, phosphate solubilization, siderophores production, and exopolysaccharide (EPS) development. According to 16S rDNA sequence homology, strains Y3, Y4, and Y5 were identified as Pseudomonas sp., Chryseobacterium sp., and Enterobacter sp., respectively. Based on the results of rice germination experiments conducted under combined toxicity, we set the contamination concentrations for Ni2+ at 20 μg mL−1 and Cd2+ at 40 μg mL−1. Then we conducted potting experiments at these concentration levels to study the effects of strains Y3, Y4, and Y5 on rice growth under synergistic Ni and Cd stress. The results indicated that the inoculated strains Y3, Y4, and Y5 were effective in promoting the growth of rice seedlings under the combined stress of Ni and Cd, and conferring tolerance to Ni and Cd by increasing the antioxidant enzyme activities of the seedlings. Among them, strain Y3 exhibited stronger ACC deaminase activity, IAA production capacity, and EPS production capacity, showing the most pronounced growth-promoting effect on rice. It was demonstrated that after inoculation with strain Y3, the germination rate of rice seeds increased by 43 %, the fresh weight of stems improved by 35 %, and the chlorophyll content enhanced by 70 % and other growth-promoting phenomena. Additionally, under Ni and Cd stress, strain Y5 performed better than strain Y4 in terms of IAA production capacity and its influence on rice root growth, suggesting that IAA production might play a specifically essential role in root growth under Ni and Cd stress.

Here we describe the first case of abscess infection caused by Nocardia beijingensis in China. The patient was immunocompetent but suffered from postoperative abscess for 6 years. This study highlights the necessity of long-term infected foci to be thoroughly examined to identify the pathogen, as well as the importance of accurate Nocardia identification and antimicrobial susceptibility tests for understanding the pathogen's epidemiology, clinical significance, and treatment strategy.

Titanium tetrachloride (TiCl4) is an important raw material for preparing metallic Ti and TiO2. At present, TiCl4 is mainly produced through boiling chlorination and molten salt chlorination. However, the quality of the titanium slag (or rutile) is significantly influenced by the preparation method. The content of Ca and Mg impurities in Panzhihua ilmenite is high, and the titanium slag after smelting is suitable for the production of TiCl4 via molten salt chlorination. However, chlorinated waste salt pollutes the environment, which should be avoided to meet sustainability goals. Herein, a novel process for preparing TiCl4 from Panzhihua ilmenite involving boiling chlorination is proposed. The carbothermal reduction of the ilmenite concentrate, acid leaching separation of the reduced products, and boiling chlorination process were investigated via X-ray diffraction, mineral dissociation analysis, scanning electron microscopy, and energy-dispersive spectroscopy. The reduced products, which are rich in titanium oxycarbide, Ti2O3 and iron, were prepared after reacting at 1550 °C for 3 h. The Fe content in the reduced products was reduced from 37.85 to 3.0 wt % after leaching with 1–5 wt. % hydrochloric acid. The obtained acid insoluble substances were chlorinated at 500 °C for 25 min to prepare TiCl4, resulting in a chlorination rate of 77.4%. The chlorination residue is rich in unchlorinated rutile, which can be recovered by repeating the boiling chlorination process. Therefore, the environmentally friendly boiling chlorination of Panzhihua ilmenite can be used to prepare TiCl4 avoiding the waste of chlorinated salt.

Klebsiella michiganensis is an increasingly important bacterial pathogen causing nosocomial infections in clinical patients. In this study, we described the molecular and genomic characteristics of a carbapenem-resistant K. michiganensis strain KM166 cultured from a one-month premature baby’s blood sample. KM166 showed lower biofilm forming ability in optical density (OD) than K. pneumoniae NTUH-K2044 (0.271 ± 0.027 vs. 0.595 ± 0.054, p = 0.001), and the median lethal dose (0.684 lg CFU/mL) was lower than K. pneumoniae strain NTUH-K2044 (6.679 lg CFU/mL). A IncFII/IncFIA(HI1)/IncFIB(K) multiple replicon plasmid in KM166 was identified carrying three replicon types. It has low homology to Escherichia coli pMRY09-581ECO_1 and the highest homology similarity to the INcFIA/INcFII(p14)-type plasmid in K. michiganensis strain fxq plasmid pB_KPC, suggesting that this multiple replicon plasmid was unlikely to have been transmitted from E. coli and probably a transfer of repFIB replicon genes from other K. michiganensis strains into the INcFIA/INcFII(p14)-type plasmid of KM166 had occurred. Mapping of the gene environment revealed that blaKPC-2 in KM166 plasmid 3 had high identity and same Tn3-tnpR-IS481-blaKPC-2-klcA_1 genomic context structure with K. pneumoniae strain JKP55, plasmid pKPC-J5501, and blaKPC-2-carrying plasmid proved to be autonomously transferred under the help of mobile genetic elements into Escherichia coli 600 by plasmid conjugation experiment. In conclusion, we have characterized a K. michiganensis strain carrying multi-replicon IncFII/IncFIA(HI1)/IncFIB(K) plasmid and blaKPC-2-carrying IncFII(p14)/IncFIA plasmid in this study, which provided insights about the evolutionary diversity of plasmids carried by K. michiganensis.

Abstract. Vascular smooth muscle cells (VSMCs) have diverse biological functions that include maintaining the vascular structure and recruiting progenitors to form the embryonic vascular system. Accumulating evidence suggests that the VSMCs are not just derived from the mesoderm, as previously thought, but have diverse developmental origins. Lineage tracing analysis indicates that VSMCs have at least 7 different origins, thereby giving it the characteristic of a mosaic tissue. The crucial role of the diverse origins of the VSMCs has been recognized in relation to blood vessel function and diseases such as arteriosclerosis. The VSMC distribution in cardiovascular development and whether and how their heterogeneous origins contribute to the overall cardiovascular development continue to be topics of research. Here, we review the current state of research, mainly focusing on the role of VSMCs in cardiovascular development. We emphasize the following biological pathways: (1) normal course of development of VSMCs and their diverse origins in relation to cardiovascular development, (2) signaling regulation of progenitor cell development and differentiation into VSMCs, and (3) abnormal development of vascular smooth muscle and the associated cardiovascular malformations.

Background/objective: Coronavirus disease 2019 (COVID-19) is a disaster in human medical history and glucocorticoids remain the most promising therapy. Osteonecrosis is a disease caused by reduced intraosseous blood flow to bones in the joints, which will rapidly induce joint destruction. Approximately one-third patients with severe acute respiratory syndrome (SARS) who received high cumulative doses and long treatment durations of glucocorticoids occurred osteonecrosis. Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics, and therapeutic strategies, it is particularly desirable to investigate whether osteonecrosis will become a common sequela among convalescent COVID-19 patients. Methods: This multi-strategy study was designed by integrating different research methods, such as meta-analysis, systematic review, and cross-sectional investigations to address above study objectives. At first, two meta-analyses were performed on the osteonecrosis incidence among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in Wuhan city of China were also conducted. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis patients with COVID-19 infection were further presented and discussed. Results: Our meta-analysis showed that 32% of SARS patients had developed osteonecrosis after receiving glucocorticoid treatment with high dose, and our system review supported that low level glucocorticoid exposure might also lead to the occurrence of osteonecrosis. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in Wuhan city of China found that the average of cumulative glucocorticoid exposure level was 504 ​mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case was identified from 1406 patients with COVID-19 during our cross-sectional investigation, implying that preventive management of osteonecrosis should be better started with regular clinical follow-up observation. Conclusion: Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to establish risk-classification-based early screening and to introduce early prevention protocol of its associated osteonecrosis that will be of clinical significance in favor of improved prognosis of this disease. The translational potential of this article: To establish risk-classification-based early screening and to introduce early prevention protocol of glucocorticoid-induced osteonecrosis will be of clinical significance in favor of improved prognosis of COVID-19.

This paper presents an SOC (State of Charge) prediction method based on a chaotic time series Volterra adaptive filter. This method first verifies the chaotic characteristics of the SOC time series of lithium-ion batteries and then implements the phase space reconstruction method to reorganize the voltage and current data into multi-dimensional data. Furthermore, we use the Volterra adaptive filter to predict the SOC of the lithium-ion battery pack on the reconstructed multi-dimensional data. This method can effectively solve the problem that the SOC estimation error increases due to the poor real-time performance of battery voltage, current, and other parameters of vehicular lithium-ion battery packs in electric vehicles obtained by the battery management system. According to the simulation and test results, the error of the SOC estimation algorithm studied in this paper is less than 0.6%, which indicates that the Volterra adaptive filter based on chaotic time series comprehensively uses the linear and non-linear parameter characteristics of lithium-ion batteries and recombines the voltage and current data into multi-dimensional data through phase space reconstruction technology. It can reveal the relationship between the battery SOC and other variables better, achieve higher precision lithium-ion battery SOC prediction, and have better realizability.

ABSTRACT Bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious and urgent threat for hospitalized patients. This study aims to describe the clinical and molecular characteristics of CRKP causing BSI in a tertiary-care hospital in Beijing, China. A total of 146 CRKP strains and 39 carbapenem-susceptible K. pneumoniae (CSKP) strains collected in the hospital from 2017 to 2020 were sent for whole-genome sequencing. Univariate and multivariate analyses were used to evaluate risk factors for in-hospital mortality of CRKP-BSI cases. Thirty (20.5%) of 146 CRKP-BSI patients and three (7.7%) of 39 CSKP-BSI patients died at discharge (χ2 = 3.471, P = 0.062). Multivariate logistic regression analysis indicated that age and use of urinary catheters were independent risk factors for the death of CRKP-BSI. The 146 CRKP isolates belonged to 9 sequence types (STs) and 11 serotypes, while the 39 CSKP isolates belonged to 23 STs and 27 serotypes. The mechanism of carbapenem resistance for all the CRKP strains was the acquisition of carbapenemase, mainly KPC-2 (n = 127). There were 2 predominant serotypes for ST11 CRKP, namely, KL47 (n = 82) and KL64 (n = 42). Some virulent genes, including rmpA2, iucABCD and iutA, and repB gene, which was involved in plasmid replication, were detected in all ST11-KL64 strains. Evolutionary transmission analysis suggested that ST11 CRKP strains might have evolved from KL47 into KL64 and were accompanied by multiple outbreak events. This study poses an urgent need for enhancing infection control measures in the hospital, especially in the intensive care unit where the patients are at high-risk for acquiring CRKP-BSI. IMPORTANCE CRKP-BSI is demonstrated to cause high mortality. In this study, we demonstrated that ST11 CRKP strains might carry many virulent genes. Meanwhile, outbreak events occurred several times in the strains collected. Carbapenemase acquisition (mainly KPC-2 carbapenemase) was responsible for carbapenem resistance of all the 146 CRKP strains. As 2 predominant strains, all ST11-KL64 strains, but not ST11-KL47 strains, carried rmpA2, iucABCD, iutA, as well as a plasmid replication initiator (repB). Our study suggested that the occurrence of region-specific recombination events manifested by the acquisition of some virulence genes might contribute to serotype switching from ST11-KL47 to ST11-KL64. The accumulation of virulent genes in epidemic resistant strains poses a great challenge for the prevention and treatment of BSI caused by K. pneumoniae in high-risk patients.

Abstract Background Coarctation of the aorta (CoA) is a serious innate heart disease. Although surgery results are generally good, some complications such as recoarctation and aortic aneurysm or persistent hypertension were serious threats to patient’s health. To better understand the pathology of CoA and its underlying molecular mechanism is particularly important for early diagnosis and preventing the occurrence of its complications. However, the mechanisms of CoA remain unclear, especially for infants. Methods RNA sequencing (RNA-seq) was used to identify the differentially expressed genes (DEGs) in vascular tissues of 12 patients with CoA and 10 normal participants form 3- to 34-month-old infants. The characteristic of DEGs were validated by quantitative reverse transcription–polymerase chain reaction (qRT-PCR) and immunochemical staining (IHC) in vessels of patients with CoA and normal infants. Results A total of 2491 DEGs with the false discovery rate less than 0.05(> 1.5-fold, P

Battery capacity is an important metric for evaluating and predicting the health status of lithium-ion batteries. In order to determine the answer, the battery’s capacity must be, with some difficulty, directly measured online with existing methods. This paper proposes a multi-dimensional health indicator (HI) battery state of health (SOH) prediction method involving the analysis of the battery equivalent circuit model and constant current discharge characteristic curve. The values of polarization resistance, polarization capacitance, and initial discharge resistance are identified as the health indicators reflective of the battery’s state of health. Moreover, the retention strategy genetic algorithm (e-GA) selects the optimal voltage drop segment, and the corresponding equal voltage drop discharge time is also used as a health indicator. Based on the above health indicator selection strategy, a battery SOH prediction model based on particle swarm optimization (PSO) and LSTM neural network is constructed, and its accuracy is validated. The experimental results demonstrate that the suggested strategy is accurate and generalizable. Compared with the prediction model with single health indicator input, the accuracy is increased by 0.79%.

The line pipes with large diameter, thick wall and high steel grade are preferred to meet the requirements of extremely high gas transmission rate (380 × 108 m3/a) in the Sino–Russian eastern route project. In this paper, the technical standards of line pipes at home and abroad were comparatively analyzed after the research and formulation process of technical specifications of X80 line pipes (OD 1422 mm) used in the above-mentioned project was introduced. The key technical indexes such as chemical components, crack–arrest-toughness values, etc. and its formulation process were discussed. In addition, the development process and product performance of the X80 line pipes (OD 1422 mm) were described. It is proved by trial production and product tests that using X80 line pipes (OD 1422 mm) in this gas project is a rational and effective solution to the following technical issues such as chemical composition control, fracture control and welding stability maintenance. This type of line pipes is proved not only to meet project requirements, but to suit for production cases. As a result, the safety of Sino–Russian eastern route gas pipeline will be guaranteed essentially. The research results in this paper provide a strong technical support for the application of X80 line pipes (OD 1422 mm) in the Sino–Russian eastern route project, and play a guiding role in drawing up the technical specifications of other gas pipeline projects.

Multidrug resistant microbes present in the environment are a potential public health risk. In this study, we investigate the presence of New Delhi metallo-β-lactamase 1 (NDM-1) producing bacteria in the 99 water samples in Beijing City, including river water, treated drinking water, raw water samples from the pools and sewage from 4 comprehensive hospitals. For the bla NDM-1 positive isolate, antimicrobial susceptibility testing was further analyzed, and Pulsed Field Gel Electrophoresis (PFGE) was performed to determine the genetic relationship among the NDM-1 producing isolates from sewage and human, as well as the clinical strains without NDM-1. The results indicate that there was a higher isolation of NDM-1 producing Acinetobacter baumannii from the sewage of the hospitals, while no NDM-1 producing isolates were recovered from samples obtained from the river, drinking, or fishpond water. Surprisingly, these isolates were markedly different from the clinical isolates in drug resistance and pulsed field gel electrophoresis profiles, suggesting different evolutionary relationships. Our results showed that the hospital sewage may be one of the diffusion reservoirs of NDM-1 producing bacteria.

Kindlin 2, as an integrin-associated protein, is required for myocyte elongation and fusion. However, the association of Kindlin 2 with muscle differentiation-related signaling pathways is unknown. Here, we identified a mechanism that Kindlin 2 regulates myogenic regulatory factors myogenin via a canonical Wnt/β-catenin signaling. We found that knockdown of Kindlin 2 leads to the abolishment of β-catenin/TCF4-mediated transcription in C2C12 cells, followed by the impairment of myogenic differentiation. Mechanistically, nuclear translocation of both Kindlin 2 and β-catenin is induced during myogenic differentiation. In particular, Kindlin 2 forms a tripartite complex with active β-catenin and TCF4, and hence co-occupied on the promoter of myogenin to enhance its expression. Functionally, depletion of Kindlin 2 impairs myogenic differentiation via downregulation of myogenin. Taken together, our data reveal that Kindlin 2 is required for Wnt signaling-regulated myogenic differentiation, providing a mechanistic insight into the role of Kindlin-2 in muscle development.

The effects of plastic deformation on the microstructure evolution of grade X100 pipeline were investigated by SEM, TEM and EBSD tests. The result shows that quasipolygon ferrite deforms firstly under plastic strain initial stage, then both acicular ferrite and granular bainite change remarkably with the value of plastic strain increase. When the tension stress reaches the tensile strength, microcracks nucleate around the inclusion and M/A constitute, expand with the plastic deformation increases, and finally cracks connection causes the crack penetration until the expiration. Furthermore, the microscopic orientation concentrates in {110} 〈111〉 direction before the deformation, while crystal orientation in {110} and {112} direction enhanced after the deformation.

Abstract Neurodegenerative diseases, characterized by impairments in cognition, memory, and movement, are becoming increasingly prevalent due to population aging, posing a significant threat to public health. Extensive evidence suggests that neuroinflammation, mediated by microglia, plays a crucial role in the development of these diseases. Notably, the vitamin D receptor (VDR) has been shown to regulate microglia activation by controlling the function of neuroprotective vitamin D. This study aims to elucidate the potential of VDR in modulating neuroinflammation. To mimic neuroinflammation, BV2 cells were treated with lipopolysaccharide (LPS) for 12 h. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the release of cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, MCP-1, and TNF-α. Western blot assays were performed to assess relative protein expressions and succinylation modifications. Co-immunoprecipitation (Co-IP) experiments were conducted to determine the interaction between VDR and carnitine palmitoyltransferase 1A (CPT1A). Immunofluorescence staining was used to analyze the localization of VDR, CPT1A, COX-2, and CD11b. Our findings demonstrated that VDR expression was upregulated in BV2 cells exposed to LPS. Ectopic expression of VDR attenuated the inflammatory response and microglia activation. We discovered that carnitine palmitoyltransferase 1A (CPT1A) promoted VDR succinylation. Further investigations revealed that CPT1A enhanced VDR stability by binding to VDR, with lysine K117 being the primary succinylation site. Importantly, depletion of CPT1A abrogated the protective effects of VDR overexpression on microglia-mediated neuroinflammation. Our study highlighted that CPT1A functioned as a suppressor in neuroinflammation by facilitating VDR succinylation, offering potential therapeutic targets for the management of neurodegenerative diseases.

Abstract Background Nervous system toxicity (NST) is a frequent and serious adverse event (AE) associated with blinatumomab, the first bispecific antibody drug targeting CD19 and CD3. Real-world data are needed to better understand the incidence and characteristics of NST in clinical practice. Methods Data were obtained from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence interval progressive neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms were utilized for data mining. Results A total of 5,962 blinatumomab-related cases were analyzed. NSTs were more frequent in males (44.01%) and younger individuals (18–45 years, 28.39%), with a higher prevalence in the USA (77.99%). Forty-three signals of NST were identified, of which neurotoxicity, neurological symptoms, agnosia, intention tremor, and immune effector cell-associated neurotoxicity syndrome had the highest ROR values. Concomitant use of medication for age, musculoskeletal system, genitourinary system, and sexual hormones were independent risk factors for NST, and age was an independent protective factor for fatal NST. The median time to onset (TTO) for neurological events was 3 days (range, 1 ~ 21). The highest fatality rate for neurological events was observed for increased intracranial pressure disorders, which also had the highest co-occurrence rate with cytokine release syndrome (CRS). Conclusions Age is an independent protective factor for fatal NST, and CRS leads to a higher fatality rate for NST patients treated with blinatumomab. Thorough medication evaluation should be conducted before administering blinatumomab, especially for high-risk patients with preexisting neurological conditions.

Follicular lymphoma (FL) is a common B-cell lymphoma and typically affects the elderly population. It is urgently required to enhance our comprehension of disease-specific outcomes in elderly FL patients and identify a reliable predictive indicator to assess patient risk and guide treatment options for them. Therefore, we retrospectively analysed clinical data of 128 elderly patients (aged 60 years or older) with FL treated at Tianjin Medical University Cancer Institute & Hospital from 2002 to 2020. Univariate and multivariate analyses were performed to identify high risk prognostic factors, and we evaluated the predictive capacity of several prognostic scoring models by survival analysis and receiver operating characteristic (ROC) curves. Our analysis revealed that the age ≥70 was a significant independent predictor for both OS and PFS. FLIPI2 model can classify elderly FL patients into two risk groups with different prognoses, but the FLIPI and PRIMA-PI scoring systems may not be as applicable to this specific patient population. Based on the above results, we modified the FLIPI2 scoring system to set age ≥70 years as a risk factor and developed a novel prognostic index called the Age-adjusted FLIPI2 (A-FLIPI2), which effectively classified older FL patients into three distinct groups with significantly different outcomes. Among the four scoring systems evaluated, A-FLIPI2 showed the highest AUC for predicting risk of death (0.793) and disease progression (0.678). And the performance of A-FLIPI2 is validated in an external validation cohort. Thus, A-FLIPI2 is a better prognostic model for elderly FL patients. In conclusion, the newly developed prognostic index A-FLIPI2 in this study offers improved risk stratification for elderly FL patients.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease severely affecting life quality with its prevalence rising as the population ages, yet there is still no effective treatment available. Cell therapy has emerged as a promising option for IPF, however, the absence of mature and stable animal models for IPF immunodeficiency hampers preclinical evaluations of human cell therapies, primarily due to rapid immune clearance of administered cells. This study aims to establish a reliable pulmonary fibrosis (PF) model in immunodeficient mice that supports autologous cell therapy and to investigate underlying mechanism. Methods We utilized thirty 5-week-old male NOD/SCID mice, categorizing them into three age groups: 12weeks, 32 weeks and 43 weeks, with 6 mice euthanized randomly from each cohort for lung tissue analysis. We assessed fibrosis using HE staining, Masson’s trichrome staining, α-SMA immunohistochemistry and hydroxyproline content measurement. Further, β-galactosidase staining and gene expression analysis of MMP9, TGF-β1, TNF-α, IL-1β, IL-6, IL-8, SOD1, SOD2, NRF2, SIRT1, and SIRT3 were performed. ELISA was employed to quantify protein levels of TNF-α, TGF-β1, and IL-8. Results When comparing lung tissues from 32-week-old and 43-week-old mice to those from 12-week-old mice, we noted a marked increase in inflammatory infiltration, fibrosis severity, and hydroxyproline content, alongside elevated expression levels of α-SMA and MMP9. Notably, the degree of fibrosis intensified with age. Additionally, β-galactosidase staining became more pronounced in older mice. Quantitative PCR analyses revealed age-related, increases in the expression of senescence markers (GLB1, P16, P21), and proinflammatory genes (TGF-β1, TNF-α, IL-1β, IL-6, and IL-8). Conversely, the expression of anti-oxidative stress-related genes (SOD1, SOD2, NRF2, SIRT1, and SIRT3) declined, showing statistically significant differences (*P

Abstract Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1+ NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target.

Klebsiella michiganensis is an increasingly important bacterial pathogen causing nosocomial infections in clinical patients. In this study, we described the molecular and genomic characteristics of a carbapenem-resistant K. michiganensis strain KM166 cultured from a one-month premature baby's blood sample. KM166 showed lower biofilm forming ability in optical density (OD) than K. pneumoniae NTUH-K2044 (0.271 ± 0.027 vs. 0.595 ± 0.054, p = 0.001), and the median lethal dose (0.684 lg CFU/mL) was lower than K. pneumoniae strain NTUH-K2044 (6.679 lg CFU/mL). A IncFII/IncFIA(HI1)/ IncFIB(K) multiple replicon plasmid in KM166 was identified carrying three replicon types. It has low homology to Escherichia coli pMRY09-581ECO_1 and the highest homology similarity to the INcFIA/INcFII(p14)-type plasmid in K. michiganensis strain fxq plasmid pB_KPC, suggesting that this multiple replicon plasmid was unlikely to have been transmitted from E. coli and probably a transfer of repFIB replicon genes from other K. michiganensis strains into the INcFIA/INcFII(p14)-type plasmid of KM166 had occurred. Mapping of the gene environment revealed that blaKPC-2 in KM166 plasmid 3 had high identity and same Tn3-tnpR-IS481-blaKPC-2-klcA_1 genomic context structure with K. pneumoniae strain JKP55, plasmid pKPC-J5501, and blaKPC- 2-carrying plasmid proved to be autonomously transferred under the help of mobile genetic elements into Escherichia coli 600 by plasmid conjugation experiment. In conclusion, we have characterized a K. michiganensis strain carrying multi-replicon IncFII/IncFIA(HI1)/IncFIB(K) plasmid and blaKPC-2- carrying IncFII(p14)/IncFIA plasmid in this study, which provided insights about the evolutionary diversity of plasmids carried by K. michiganensis. [ABSTRACT FROM AUTHOR]

Abstract Surface reconstruction plays an essential role in electrochemical catalysis. The structures, compositions, and functionalities of the real catalytic species and sites generated by reconstruction, however, are yet to be clearly understood, for the metastable or transit state of most reconstructed structures. Herein, a series of NiFe oxalates (NixFe1‐xC2O4, x = 1, 0.9, 0.7, 0.6, 0.5, and 0) are synthesized for overall water splitting electrocatalysis. Whilst NixFe1‐xC2O4 shows great hydrogen evolution reaction (HER) activity, the in situ reconstructed NixFe1‐xOOH exhibits outstanding oxygen evolution reaction (OER) activity. As identified by the in situ Raman spectroscopy and quasi‐in situ X‐ray absorption spectroscopy (XAS) techniques, reconstructions from NixFe1‐xC2O4 into defective NixFe1‐xOOH and finally amorphous NixFe1‐xOOH active species (R‐NixFe1‐xOOH) are confirmed upon cyclic voltammetry processes. Specifically, the fully reconstructed R‐Ni0.6Fe0.4OOH demonstrates the best OER activity (179 mV to reach 10 mA cm−2), originating from its abundant real active sites and optimal d‐band center. Benefiting from the reconstruction, an alkaline electrolyzer composed of a Ni0.6Fe0.4C2O4 cathode and an in situ reconstructed R‐Ni0.6Fe0.4OOH anode achieves a superb overall water splitting performance (1.52 V@10 mA cm−2). This work provides an in‐depth structure‐property relationship understanding on the reconstruction of catalysts and offers a new pathway to designing novel catalyst.

BackgroundThere is currently no accurate, readily available, or validated biomarker for assessing disease severity and survival outcomes in sepsis-induced acute kidney injury (SAKI), which limits the ability to conduct effective therapeutic interventions. The neutrophil extracellular traps (NETs) may be involved in the pathophysiology of SAKI. The present study investigated the predictive value of plasma NETs for the survival outcome of patients with SAKI.MethodsThis observational study included 136 SAKI patients, all of whom underwent a 28-day follow-up. According to the follow-up records, SAKI patients were divided into two groups: the non-survivor group (60 subjects) and the survivor group (76 subjects). Blood samples were collected after the diagnosis of AKI to measure three NET markers and 12 inflammatory indices. Correlation analysis, logistic regression analysis, receiver operating characteristic curve analysis, and survival analysis were performed.ResultsCompared to survivors, non-survivors among SAKI patients exhibited significantly higher levels of three plasma NET markers (all p

Abstract Ischemic stroke (IS) is of increasing concern given the aging population and prevalence of unhealthy lifestyles, with older females exhibiting higher susceptibility. This study aimed to identify practical diagnostic markers, develop a diagnostic model for immunogenic cell death (ICD)-associated IS, and investigate alterations in the immune environment caused by hub genes. Differentially expressed genes associated with ICD in IS were identified based on weighted gene co-expression network analysis and the identification of significant modules. Subsequently, machine learning algorithms were employed to screened hub genes, which were further assessed using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. A nomogram mode lwas then constructed for IS diagnosis, and its diagnostic value was assessed using a receiver operating characteristic curve. Finally, alterations in immune cell infiltration were assessed within patients with IS, and the pan-cancer expression patterns of hub genes were evaluated. Three hub genes associated with ICD (PDK4, CCL20, and FBL) were identified. The corresponding nomogram model for IS diagnosis could effectively identify older female patients with IS (area under the curve (AUC) = 0.9555). Overall, the three hub genes exhibit good diagnostic value (AUC > 0.8). CCL20 and FBL are significantly associated with the extent of immune cells infiltration. Moreover, a strong link exists between hub gene expression and pan-cancer prognosis. Cumulatively, these results indicate that ICD-related hub genes critically influence IS progression in older females, presenting novel diagnostic and therapeutic targets for personalized treatment.

ObjectiveCerebral ischemia can cause mild damage to local brain nerves due to hypoxia and even lead to irreversible damage due to neuronal cell death. However, the underlying pathogenesis of this phenomenon remains unclear. This study utilized bioinformatics to explore the role of cuproptosis in cerebral ischemic disease and its associated biomarkers.MethodR software identified the overlap of cerebral ischemia and cuproptosis genes, analyzed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and explored hub genes. Expressions and localizations of hub genes in brain tissue, cells, and immune cells were analyzed, along with predictions of protein structures, miRNAs, and transcription factors. A network was constructed depicting hub gene co-expression with miRNAs and interactions with transcription factors. Ferredoxin 1 (FDX1) expression was determined using qRT-PCR.ResultsTen cuproptosis-related genes in cerebral ischemia were identified, with GO analysis revealing involvement in acetyl-CoA synthesis, metabolism, mitochondrial function, and iron–sulfur cluster binding. KEGG highlighted processes like the tricarboxylic acid cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. Using the Human Protein Atlas, eight hub genes associated with cuproptosis were verified in brain tissues, hippocampus, and AF22 cells. Lipoyl(octanoyl) transferase 1 (LIPT1), was undetected, while others were found in mitochondria or both nucleus and mitochondria. These genes were differentially expressed in immune cells. FDX1, lipoic acid synthetase (LIAS), dihydrolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 component subunit alpha 1 (PDHA1), PDHB, and glutaminase (GLS) were predicted to target 111 miRNAs. PDHA1, FDX1, LIPT1, PDHB, LIAS, DLAT, GLS, and dihydrolipoamide dehydrogenase (DLD) were predicted to interact with 11, 10, 10, 9, 8, 7, 5, and 4 transcription factors, respectively. Finally, FDX1 expression was significantly upregulated in the hippocampus of ovariectomized rats with ischemia.ConclusionThis study revealed an association between cerebral ischemic disease and cuproptosis, identifying eight potential target genes. These findings offer new insights into potential biomarkers for the diagnosis, treatment, and prognosis of cerebral ischemia, and provide avenues for the exploration of new medical intervention targets.

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.