Prenatal lipopolysaccharide exposure induces anxiety-like behaviour in male mouse offspring and aberrant glial differentiation of embryonic neural stem cells.

BACKGROUND: Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development. METHODS: We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs. RESULTS: Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA. CONCLUSIONS: Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.

Is China approaching the inflection point of the ecological Kuznets curve? Analysis based on ecosystem service value at the county level.

Accounting for the ecosystem service values (ESVs) and discussing the relationship between the ESVs and economic development can help achieve sustainable ecological development. Therefore, this paper evaluates the county-level ESVs of various land types in China, and depicts the distribution of ESVs in various urban agglomerations. In addition, the nonlinear relationship between ESVs and economic development is revealed. The main findings are as follows: (1) From 2000 to 2018, the ESVs in China decreased, and the decline rate of ESVs in urban agglomerations is much higher than that of China as a whole. (2) The decline rate of ESVs in core cities is much higher than in urban agglomerations, and the decline rate of ESVs is higher in areas close to core cities and lower in areas far from core cities. (3) The ecological Kuznets curve of China has a positive "U" shape, and the ecological Kuznets curve of urban agglomerations has an "N" shape; the ecological Kuznets curve of core cities has a positive "U" shape, while the ESVs of other cities decreases monotonically with the increase of the economic level.

The effect of economic growth pressure on green technology innovation: Do environmental regulation, government support, and financial development matter?

Green technology improvement is critical in promoting green development and mitigating negative externalities. Exploring the effect of economic growth pressure (EGP) on green technology innovation (GTI) is important for coordinated economic growth and green transformation. Using the data from 285 cities in China during 2006-2018, this study investigates the influence of EGP on GTI by taking the difference between economic growth target and previous year's actual growth rate to represent the EGP. The results indicate that EGP negatively affects GTI. When there is a 1% increase in EGP, green patent applications will fall by 3.2%. Furthermore, the heterogeneity analysis indicates that the negative effect of EGP is especially significant in western China compared with eastern and central regions. In addition, we find various nonlinear moderating effects between EGP and GTI by using panel threshold model. Specifically, EGP and GTI show an inverted U-shaped relationship with EGP increasing. Meanwhile, only when environmental regulation, government support, and financial development cross the thresholds will EGP have a significant role in promoting GTI. This study provides helpful implications for decision-makers to adopt a more reasonable combination of policy tools to achieve economic growth targets and low-carbon transformation.

Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS.

BACKGROUND: The practices used to diagnose gestational diabetes mellitus (GDM) could only be carried out around the time of detectable symptoms, and predictive capacity is little. METHODS: LC-MS/MS was conducted to explore overview proteomics for GDM complicated pregnant woman at 16-18 gestation weeks, while normal pregnant for control. Enzyme-linked immunosorbent assay was further applied in an independent cohort of 15 GDM cases and 15 controls for verification. RESULTS: The results indicated that 24 protein expression levels were significantly changed in GDM group samples, and inflammation, oxidative stress, insulin resistance, blood coagulation, and lipid homeostasis were associated with GDM. The abnormal expression of CRP and IGFBP2 was verified in the first-trimester maternal plasma in women who subsequently developed GDM. CONCLUSIONS: This study not only identified 24 potential predictive biomarkers for GDM also provided a global overview of protein rearrangements induced by GDM.

Identification of upstream transcription factors (TFs) for expression signature genes in breast cancer.

Breast cancer is a common malignancy among women with a rising incidence. Our intention was to detect transcription factors (TFs) for deeper understanding of the underlying mechanisms of breast cancer. Integrated analysis of gene expression datasets of breast cancer was performed. Then, functional annotation of differentially expressed genes (DEGs) was conducted, including Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Furthermore, TFs were identified and a global transcriptional regulatory network was constructed. Seven publically available GEO datasets were obtained, and a set of 1196 DEGs were identified (460 up-regulated and 736 down-regulated). Functional annotation results showed that cell cycle was the most significantly enriched pathway, which was consistent with the fact that cell cycle is closely related to various tumors. Fifty-three differentially expressed TFs were identified, and the regulatory networks consisted of 817 TF-target interactions between 46 TFs and 602 DEGs in the context of breast cancer. Top 10 TFs covering the most downstream DEGs were SOX10, NFATC2, ZNF354C, ARID3A, BRCA1, FOXO3, GATA3, ZEB1, HOXA5 and EGR1. The transcriptional regulatory networks could enable a better understanding of regulatory mechanisms of breast cancer pathology and provide an opportunity for the development of potential therapy.

Effect of Genotype and Environment on Salvia miltiorrhiza Roots Using LC/MS-Based Metabolomics.

Salvia miltiorrhiza (S. miltiorrhiza) Bunge is broadly used as herbal medicine for the clinical treatments of cardiovascular and cerebrovascular diseases. Despite its commercial and medicinal values, few systematic studies on the metabolome of S. miltiorrhiza roots have been carried out so far. We systematically described the metabolic profiles of S. miltiorrhiza using high pressure liquid chromatography mass spectrometry (LC/MS) in conjunction with multivariate statistical analyses, aimed at monitoring their biological variations of secondary metabolites related to three locations and four S. miltiorrhiza genotypes. A total of 40 bioactive constituents were putatively annotated in S. miltiorrhiza root samples. This study found that both the same S. miltiorrhiza genotype growing at three different locations and four S. miltiorrhiza genotypes growing at the same location had significant metabonomic differences identified by the principal component analysis (PCA) approach. By using orthogonal projection to latent structure with discriminant analysis (OPLS-DA), 16 and 14 secondary metabolites can be used as potential location-specific and genotype-specific markers in S. miltiorrhiza, respectively. The specificity of LC/MS profiles offered a powerful tool to discriminate S. miltiorrhiza samples according to genotypes or locations.

[Construction of A Genetic Linkage Map in Salvia miltiorrhiza].

Objective: On the basis of previous studies, to construct a genetic map of Salvia miltiorrhiza by using EST-SSR primers, to build a platform for positioning important traits relating to genes, the cloning and molecular marker-assisted in breeding of new varieties of Salvia miltiorrhiza. Methods: A total of 411 EST-SSR primers were used for PCR amplification to screen polymorphic markers in F1 mapping population derived from a cross between Salvia miltiorrhiza, two parents of which were the cultivars of ZH74 and BH18. Combined with the molecular marker data of previous studies, Joinmap 4. 0 software was used for map integration. Results: 411EST-SSR primers were screened from two parents, a total of 328 pairs of primers were amplified stable products,164 pairs of polymorphic primers were obtained. Conclusion: A linkage map of Salvia miltiorrhiza with 150 marker high density genetic is constructed.

[Effect of Different Locations and Genotypes on Yield and Accumulation of Bioactive Constituents in Salvia miltiorrhiza].

Objective: The root yield and active constituent contents were analyzed from four Salvia miltiorrhiza cultivars grown at three different locations( Zhuyang, Changqing, and Taian, Shandong Province) to determine the influence of environmental conditions and cultivars. . Methods: Phenolic acids and tanshinones were analyzed by HPLC method. Total phenolic acids content were analyzed by FolinCiocalteu method. Klason method was used to determine the content of lignin. Results: The root yield and the active constituent contents were significantly affected by different environments and cultivars of Salvia miltiorrhiza. The root yield was negatively correlated with active constituent contents. Salvia miltiorrhiza of Zhuyang location had the highest active constituent content, but it had the lowest root yield. Salvia miltiorrhiza of Taian location had the lowest active constituent contents, while it had the highest root yield. Salvia miltiorrhiza of Changqing location had relatively higher bio-yields of phenolic acids and tanshinones, which made it suitable for Salvia miltiorrhiza cultivation. Furthermore, compared with three other cultivars,105 cultivar could remain the salvianolic acid B stable, which indicating that 105 cultivar was possible related to resistances. Conclusion: The research provides a theoretical basis for the selecting of the optimal cultivar and the optimal environmental condition.

[Construction of the first genetic linkage map of Salvia miltiorrhiza Bge. using SSR, SRAP and ISSR markers].

The first genetic linkage map of Salvia miltiorrhiza was constructed in 94 F1 individuals from an intraspecific cross by using simple sequence repeat (SSR), sequence-related amplified polymorphism (SRAP) and inter-simple sequence repeat (ISSR) markers. A total of 93 marker loci in the linkage map, consisting of 53 SSR, 38 SRAP and 2 ISSR locus were made up of eight linkage groups, covered a total length of 400.1 cm with an average distance of 4.3 cm per marker. The length of linkage groups varied from 3.3 -132 cm and each of them included 2-23 markers, separately. The result will provide important basis for QTL mapping, map-based cloning and association studies for commercially important traits in S. miltiorrhiza.

Characteristics and outcome of systemic treatment for metastatic or unresectable thymic carcinoma: A single institution experience.

BACKGROUND: Thymic carcinoma is a rare disease with an incidence of around 0.5 cases per million with a poor prognosis. The aim of this study was to assess patient outcomes with advanced thymic carcinoma receiving first-line chemotherapy. METHODS: In our retrospective cohort study, we included patients who underwent treatment for metastatic thymic carcinoma between January 2013 to December 2019 in our hospital. Overall survival, progression-free survival (PFS), objective response rates (ORR) and chemotherapy regimens were assessed and analyzed. RESULTS: A total of 27 patients were retrospectively analyzed. All patients received a platinum (cisplatin or carboplatin) based regimen as first-line chemotherapy (29.6% received ADOC, 11.1% received PE, 40.7% received CP, 14.8% received CAP). The median PFS on first-line chemotherapy was 199 days. The response rate was 40.7%. Median overall survival (OS) was 585 days. Positive CD5 staining was associated with better PFS. CONCLUSION: We highlight the critical role of platinum-based chemotherapy agents as a primary treatment modality in advanced thymic carcinoma, underscoring the efficacy of platinum as a first-line option for recurrent disease, even in cases previously treated with platinum. Additionally, our findings indicate that CD5 positivity could be associated with improved PFS, suggesting its potential as a prognostic marker.

Integrated Microfluidic-Transistor Sensing System for Multiplexed Detection of Traumatic Brain Injury Biomarkers.

Traumatic brain injury (TBI) is widely recognized as a global public health crisis, affecting millions of people each year, leading to permanent neurologic, emotional, and occupational disability, and highlighting the urgent need for rapid, sensitive, and early assessment. Here, we design a novel and simple lithography-free method for preparing dual-channel graphene-based field-effect transistors (G-FETs) and integrating them with microfluidic channels for simultaneously multiplexed detection of key blood TBI biomarkers: neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP). The G-FET utilizes an ingenious dual-channel electrode array design, where the source is shared between channels and the drains are independent of each other, which is the key to achieving simultaneous output of dual detection signals. At the same time, the microfluidic chip realizes microscale fluidic control and fast sample response time. This integrated detection system shows excellent sensitivity in biological fluids for the TBI biomarkers with detection limits as low as 55.63 fg/mL for NFL and 144.45 fg/mL for GFAP in phosphate-buffered saline (PBS) buffer, respectively. Finally, the clinical sample analysis shows promising performance for TBI detection, with an area under the curve (AUC) of 0.98 for the two biomarkers. And the combined dual-protein assay is also a good predictor of intracranial injury findings on computed tomography (CT) scans (AUC = 0.907). The integrated microfluidic G-FET device with a dual-signal output strategy has important potential for application in clinical practice, providing more comprehensive information for brain injury assessment.

Monoclonal Antibodies as a Therapeutic Strategy against Multidrug-Resistant Bacterial Infections in a Post-COVID-19 Era.

The development of severe multidrug-resistant bacterial infections has recently intensified because of the COVID-19 pandemic. According to the guidelines issued by the World Health Organization (WHO), routine antibiotic administration is not recommended for patients with supposed or confirmed mild SARS-CoV-2 infection or pneumonia, unless bacterial infection is clinically suspected. However, recent studies have pointed out that the proportion of non-essential antibiotic use in patients infected with SARS-CoV-2 remains high. Therefore, the silent pandemic of antibiotic resistance remains a pressing issue regardless of the present threats presented by the COVID-19 pandemic. To prevent or delay entry into the postulated post-antibiotic era, the long-term advocacy for the rational use of antibiotics, the optimization of infection control procedures, and the development of new antibacterial agents and vaccines should be underscored as vital practices of the antibacterial toolbox. Recently, the development of vaccines and monoclonal antibodies has gradually received attention following the advancement of biotechnology as well as enhanced drug discovery and development in cancer research. Although decent progress has been made in laboratory-based research and promising results have been obtained following clinical trials of some of these products, challenges still exist in their widespread clinical applications. This article describes the current advantages of antibacterial monoclonal antibodies, the development of associated clinical trials, and some perceived future perspectives and challenges. Further, we anticipate the development of more therapeutic agents to combat drug-resistant bacterial infections as well as to increase the resilience of current or novel agents/strategies.

Performance of the digital cell morphology analyzer MC-100i in a multicenter study in tertiary hospitals in China.

BACKGROUND: This study investigated the performance of the MC-100i, a pre-commercial digital morphology analyzer utilizing a convolutional neural network algorithm, in a multicentric setting involving up to 11 tertiary hospitals in China. METHODS: Blood smears were analyzed by MC-100i, verified by morphologists, and manually differentiated. The classification performance on WBCs and RBCs was evaluated by comparing the classification results using different methods. The PLT and PLT clump counting performance was also assessed. The total assay time including hands-on time was evaluated. RESULTS: The agreements between pre- and post-classification were high for normal WBCs (κ > 0.96) and lower for overall abnormal WBCs (κ = 0.90). The post-classification results correlated well with manual differentials for both normal and abnormal WBCs (r > 0.93), except for basophils (r = 0.8480) and atypical lymphocytes (r = 0.8211). The clinical sensitivity and specificity of each RBC abnormality after verification were above 90 % using microscopy reviews as the reference. The PLTs counted by the MC-100i before and after verification correlated well with those measured by the PLT-O mode (r = 0.98). Moreover, PLT clumps were successfully classified by the analyzer in EDTA-dependent pseudothrombocytopenia blood samples. CONCLUSIONS: The MC-100i is an accurate and reliable digital cell morphology analyzer, offering another intelligent option for hematology laboratories.

Modified Experimental Conditions for Noise-Induced Hearing Loss in Mice and Assessment of Hearing Function and Outer Hair Cell Damage.

An animal model of noise-induced hearing loss (NIHL) is useful for pathologists, therapists, pharmacologists, and hearing researchers to thoroughly understand the mechanism of NIHL, and subsequently optimize the corresponding treatment strategies. This study aims to create an improved protocol for developing a mouse model of NIHL. Male C57BL/6J mice were used in this study. Unanesthetized mice were exposed to loud noises (1 and 6 kHz, presented simultaneously at 115-125 dB SPL-A) continuously for 6 h per day for 5 consecutive days. Auditory function was assessed 1 day and 1 week after noise exposure, using auditory brainstem response (ABR). After the ABR measurement, the mice were sacrificed, and their organs of Corti were collected for immunofluorescence staining. From the auditory brainstem response (ABR) measurements, significant hearing loss was observed 1 day after noise exposure. After 1 week, the hearing thresholds of the experimental mice decreased to ~80 dB SPL, which was still a significantly higher level than the control mice (~40 dB SPL). From the results of immunofluorescence imaging, outer hair cells (OHCs) were shown to be damaged. In summary, we created a model of NIHL using male C57BL/6J mice. A new and simple device for generating and delivering pure-tone noise was developed and then employed. Quantitative measurements of hearing thresholds and morphological confirmation of OHC damage both demonstrated that the applied noise successfully induced an expected hearing loss.

Protocol for constructing GQD-PMO functionalized FET-biosensor for ultrasensitive exosomal miRNA detection.

Here, we present a protocol for constructing an ultrasensitive biosensor for exosomal-miRNA detection. We describe steps for preparing graphene quantum dot-phosphorodiamidate morpholino oligomer hybrids, depositing them onto the reduced graphene oxide field surface, hybridizing analyte miRNA with the sensor probe, and capturing and calculating electrical signals. We also detail procedures for optimizing biosensor construction and evaluating performance. By quantifying plasma exosomal miRNA21, this protocol can identify cancer patients from healthy individuals. For complete details on the use and execution of this protocol, please refer to Li et al.1.

Early cholecystectomy following percutaneous transhepatic gallbladder drainage is effective for moderate to severe acute cholecystitis in the octogenarians.

BACKGROUND: Acute cholecystitis (AC) is a life-threatening infectious/inflammatory disease in older patients. This study aimed to investigate the safety and optimal timing of surgery in patients aged ≥ 80 years with moderate to severe AC who received percutaneous transhepatic gallbladder drainage (PTGBD). METHODS: From January 2008 to February 2021, 152 patients were retrospectively enrolled. Clinical outcomes were compared among patients who received laparoscopic cholecystectomy (LC), open cholecystectomy (OC), and conversion surgery, and between those who received early (< 6 weeks after PTGBD) and delayed cholecystectomy (≥ 6 weeks after PTGBD). Logistic regression analysis was used to identify risk factors for recurrent AC, further biliary events, conversion, and perioperative complications. RESULTS: Sixty-seven patients underwent LC, 62 underwent OC, and 23 underwent conversion surgery. Operation-related complications and mortality rates did not differ among the types of surgery; however, LC group had shorter operative time than the other groups. Eighty-two patients underwent early cholecystectomy, while 70 underwent delayed cholecystectomy. There were no differences in operative time, operation-related complications, and mortality rates between the groups. However, higher rates of recurrent AC and biliary events were observed in the delayed cholecystectomy group (52.9% vs. 4.9% and 57.1% vs. 8.5%, p < 0.001). On multivariate analysis, delayed cholecystectomy was a significant risk factor for recurrent AC (odds ratio [OR] = 19.42, p < 0.001) and further biliary events (OR = 15.95, p < 0.001). CONCLUSIONS: Early cholecystectomy is recommended for patients aged ≥ 80 years with moderate to severe AC following PTGBD.

Elizabethkingia anophelis outer membrane vesicles as a novel vaccine candidate against infection: insights into immune response and potential for passive immunity.

IMPORTANCE: Elizabethkingia anophelis, a Gram-negative pathogen, causes infections such as bacteraemia, pneumonia, and neonatal meningitis. The pathogen resists most antimicrobial classes, making novel approaches urgently needed. In natural settings, Gram-negative bacteria secrete outer membrane vesicles (OMVs) that carry important molecules in the bacterial life cycle. These OMVs are enriched with proteins involved in virulence, survival, and carbohydrate metabolism, making them a promising source for vaccine development against the pathogen. This study investigated the efficacy of imipenem-induced OMVs (iOMVs) as a vaccine candidate against E. anophelis infection in a mouse pneumonia model. Mice immunized with iOMVs were completely protected during lethal-dose challenges. Passive immunization with hyperimmune sera and splenocytes conferred protection against lethal pneumonia. Further investigation is needed to understand the mechanisms underlying the protective effects of iOMV-induced passive immunity, such as the action on specific antibody subclasses or T cell subsets.

Transport Infrastructure, High-Quality Development and Industrial Pollution: Fresh Evidence from China.

To achieve high-quality development, transport infrastructure will play a crucial role in China's economic growth, but its damage to the ecological environment has not been paid enough attention. This study was based on panel data for 30 Chinese provinces for the period of 2004-2017. A comprehensive index system for high-quality development based on the new development concept was developed. This high-quality development index used the entropy weight method and integrated transport infrastructure, high-quality development, and industrial pollution into a comprehensive framework, and systematically examined the effects of transport infrastructure and high-quality development on industrial pollution emissions. It was found that transport infrastructure significantly contributed to industrial pollution emissions, and there was a regional heterogeneity and time lag, with high-quality development and industrial pollution having an inverted "U"-shaped relationship. Further analysis showed that transport infrastructure significantly affected high-quality development and industrial pollution through industrial agglomeration, reduced the inhibitory effect on high-quality development by promoting industrial agglomeration, and reduced industrial pollution emissions by promoting industrial agglomeration.

How does digital economy affect carbon emissions? Evidence from global 60 countries.

The digital economy is of great significant for countries to achieve carbon neutrality and carbon peak. Using country-level panel data from 2008 to 2018, this study empirically examined the impact of the development of the digital economy on carbon emissions and the associated transmission mechanisms by using the intermediary effect model. Our main findings are as follows. (1) The level of digital economy development varies greatly between countries, and the difference between "hyper-digitalized countries" and "under-connected countries" is increasingly obvious. (2) Development of the digital economy significantly reduces the carbon emission intensity, but promotes increases in the per capita carbon emissions. (3) Analysis shows that economic growth, financial development, and industrial structure upgrading play mediating roles between the digital economy and carbon emissions. Our study not only advances the study on digital economy and carbon emissions, but also provides a significant reference for policy makers to achieve carbon peak and carbon neutrality.

Outcomes of patients with malignant esophagogastric junction obstruction receiving metallic stents: A single-center experience.

BACKGROUND: Malignancies-related esophagogastric junction (EGJ) obstruction is usually diagnosed in inoperable status with poor clinical outcomes. Metallic stent placement at EGJ could improve dysphagia for these patients. However, studies regarding the outcomes in these patients receiving metallic stents are still limited. This study aimed to investigate the outcomes of metallic stent placement in malignant EGJ obstruction. METHODS: Forty-one patients with inoperable malignant EGJ obstruction receiving metallic stent placement were retrospectively enrolled. The clinical outcomes between different stents and deployment techniques were analyzed. RESULTS: The overall technical success rate was 97.6% and clinical success rate was 92.1%. The median overall survival time was 77 (4-893) days, and the patency time was 71 (4-893) days, respectively. Poststent radiotherapy significantly prolonged survival and stent patency. Between patients receiving uncovered or partially covered metal stents, there was no difference in procedure-related complications, survival time, and stent patency time. Moreover, the clinical outcomes in patients receiving duodenal stents for malignant EGJ obstruction are not inferior to those receiving esophageal stents. CONCLUSION: This study provides crucial information for endoscopists to establish individualized stenting strategies for malignant EGJ obstruction.