Objective The prevalence of drug-resistant Mycobacterium tuberculosis (Mtb) strains is exacerbating the global burden of tuberculosis (TB), highlighting the urgent need for new treatment strategies for TB. Methods The recombinant adenovirus vaccine expressing cyclic di-adenosine monophosphate (c-di-AMP) phosphodiesterase B (CnpB) (rAd-CnpB), was administered to normal mice via mucosal immunization, either alone or in combination with drug therapy, to treat Mtb respiratory infections in mice.Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of antibodies in serum and bronchoalveolar lavage fluid (BALF). Real-time quantitative PCR was performed to assess the transcription levels of cytokines interferon γ(IFN-γ) and interleukin 10(IL-10) in mouse lungs. Flow cytometry was used to determine the proportions of CD4⁺ and CD8⁺ T cell subsets in the lungs and spleens. ELISA was employed to measure the levels of cytokines IFN-γ, IL-2, IL-10, inflammatory factors IL-6, and tumor necrosis factor α (TNF-α) secreted by spleen cells following antigen stimulation. The bacteria loads in the lungs and spleens of Mtb-infected mice were enumerated by plate counting methods. Resluts Intranasal immunization with rAd-CnpB induced high titers of IgG in mouse serum and the production of IgG and IgA in BALF, along with alterations in T lymphocyte subsets in the lungs and spleens. Administration of rAd-CnpB, either alone or in combination with drugs, to Mtb-infected mice significantly increased serum IgG levels as well as IgA and IgG levels in BALF. rAd-CnpB immunization promoted the secretion of CnpB-specific cytokines and inflammatory factors by splenocytes in Mtb-infected mice. However, rAd-CnpB immunotherapy, either alone or combined with drugs, did not significantly affect the bacterial loads in the lungs and spleens of mice with Mtb respiratory infections. Conclusion Mucosal immunization with rAd-CnpB induced significant mucosal, humoral and cellular immune responses in mice, and significantly enhanced CnpB-specific cellular immune responses in Mtb-infected mice.
Animals ; Adenoviridae/immunology* ; Mycobacterium tuberculosis/genetics* ; Mice ; Female ; Phosphoric Diester Hydrolases/genetics* ; Tuberculosis Vaccines/administration & dosage* ; Tuberculosis/prevention & control* ; Mice, Inbred BALB C ; Cytokines ; Lung/microbiology* ; Immunization ; Bronchoalveolar Lavage Fluid/immunology* ; Immunity, Mucosal

Computational analysis can accurately detect drug-gene interactions (DGIs) cost-effectively. However, transductive learning models are the hotspot to reveal the promising performance for unknown DGIs (both drugs and genes are present in the training model), without special attention to the unseen DGIs (both drugs and genes are absent in the training model). In view of this, this study, for the first time, proposed an inductive learning-based model for the precise identification of unseen DGIs. In our study, by integrating disease nodes to avoid data sparsity, a multi-relational drug-disease-gene (DDG) graph was constructed to achieve effective fusion of data on DDG intro-relationships and inter-actions. Following the extraction of graph features by utilizing graph embedding algorithms, our next step was the retrieval of the attributes of individual gene and drug nodes. In this way, a hybrid feature characterization was represented by integrating graph features and node attributes. Machine learning (ML) models were built, enabling the fulfillment of transductive predictions of unknown DGIs. To realize inductive learning, this study generated an innovative idea of transforming known node vectors derived from the DDG graph into representations of unseen nodes using node similarities as weights, enabling inductive predictions for the unseen DGIs. Consequently, the final model was superior to existing models, with significant improvement in predicting both external unknown and unseen DGIs. The practical feasibility of our model was further confirmed through case study and molecular docking. In summary, this study establishes an efficient data-driven approach through the proposed modeling, suggesting its value as a promising tool for accelerating drug discovery and repurposing.

Objective To analyze the clinical characteristics and the antimicrobial resistance of respiratory tract infection in children in Baoshan City,guide clinicians to rationally apply antibiotics,and improve the success rate of treatment.Methods Retrospective analysis of the distribution characteristics and drug sensitivity results of 1039 strains of pathogens detected in pediatric inpatients of hospitals from 2019 to 2022 was conducted.Results The main pathogens causing the respiratory infections in children in Baoshan area were Streptococcus pneumoniae,Escherichia coli,Staphylococcus aureus,Haemophilus influenzae,Klebsiella pneumoniae and Pseudomonas aeruginosa.Analysis of the drug sensitivity results of pathogenic bacteria with a detected quantity greater than 80 revealed that Streptococcus pneumoniae had a high resistance rate to erythromycin,clindamycin,and compound sulfamethoxazole.The resistance rates of penicillin,ceftriaxone,cefotaxime,and meropenem were P<0.05,and the difference was statistically significan.Methicillin-resistant Staphylococcus aureus(MRSA)was11.1%;CTX/CRO-R-ECO,CTX/CRO-R-KPN,CR-ECO and CR-KPN were lower than the 2021 ISPED level;The P.aeruginosa drug resistance rate and H.influenzae's ampicillin and ampicillin/sulbactam were higher than the 2021 ISPED level.Conclusion The treatment of respiratory tract infections in pediatric patients faces great challenges.The non-standard use of empirical medication has led to the emergence of multidrug-resistant bacteria,and the selection of anti infection treatment drugs is limited.Therefore,it is imperative to grasp the epidemic characteristics and drug resistance of pathogenic bacteria in the local area.

The family readiness for discharge of premature infants in the Neonatal Intensive Care Unit (NICU) is an important index to evaluate the safe discharge of premature infants, and a good family discharge readiness is the basic guarantee for the smooth recovery and healthy growth of premature infants. This article summarizes the concept, influencing factors, and intervention strategies of family discharge readiness for premature infants in NICU, in order to provide reference for the formulation and improvement of discharge readiness measures for premature infants in NICU.

ObjectiveTo explore the effect of oleanolic acid （OA） on water metabolism in mice with water-dampness retention caused by spleen deficiency and the mechanism. MethodThe 60 SPF Kunming （KM） mice were randomized into blank group （n=10） and modeling group （n=50）. Through long-term living in damp place and irregular diet， water-dampness retention caused by spleen deficiency was induced in modeling mice. Then the model mice were randomly classified into model group， natural recovery group， and low-dose， medium-dose， and high-dose OA groups. The mice in the blank group， model group， and natural recovery group were given （ig） 10 mL·kg^-1·d^-1 normal saline， and mice in the low-dose， medium-dose， and high-dose OA groups received 50， 100， 200 mg·kg^-1·d^-1 OA， respectively. The intervention lasted 7 days. Before and after modeling and administration， the general conditions of the mice were observed and body weight of mice was measured. The water content in feces and tissues was detected with the oven-drying method， and water load index and organ coefficient were measured with the weighing method. Enzyme-linked immunosorbent assay （ELISA） was employed to detect the urinary D-xylose excretion， serum gastrin （GAS）， total protein （TP）， albumin （ALB）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， interleukin-6 （IL-6）， antidiuretic hormone （AVP）， aquaporin 1 （AQP1） in renal medulla， and liver Na⁺-K⁺-ATPase. At the same time， OA was docked with ALB， IL-6， AQP1， and Na⁺-K⁺-ATPase. ResultCompared with the blank group， the model group showed withered hair， emaciation， laziness， bradykinesia， slow weight growth， infrequent spontaneous activities， high water content in feces and tissues， low weight loss after water loading， high coefficient of each organ （P<0.05， P<0.01）. Moreover， the model group had less urinary D-xylose excretion， lower serum levels of GAS， TP， ALB， and HDL-C， higher levels of TC， LDL-C， AVP， and IL-6， lower expression of Na⁺-K⁺-ATPase in the liver， and higher expression of AQP1 in renal medulla than the blank group （P<0.05， P<0.01）. The three OA groups demonstrated better general conditions， faster weight gain， more frequent spontaneous activities， lower water content in feces and tissues， larger weight loss after water loading， and lower coefficient of each organ than the model group （P<0.05， P<0.01）. Moreover， compared with the model group， the three OA groups had high D-xylose excretion， high serum levels of GAS， TP， ALB， and HDL-C， low serum levels of TC， LDL-C， AVP， and IL-6， high expression of Na⁺-K⁺-ATPase in liver， and low expression of AQP1 in renal medulla （P<0.05， P<0.01）. The recovery in each OA group was better than that in natural recovery group. Molecular docking results also confirmed that OA had high binding affinity with ALB， IL-6， AQP1， and Na⁺-K⁺-ATPase. ConclusionOA can alleviate the abnormal water metabolism in mice with water-dampness retention caused by spleen deficiency， which lays a basis for its potential clinical application.

To prepare a lipid nanoparticle (LNP)-based subunit vaccine of Mycobacterium tuberculosis (Mtb) antigen EsxV and study its immunological characteristics, the LNP containing EsxV and c-di-AMP (EsxV: C: L) was prepared by thin film dispersion method, and its encapsulation rate, LNP morphology, particle size, surface charge and polyphase dispersion index were measured. BALB/c mice were immunized with EsxV: C: L by nasal drops. The levels of serum and mucosal antibodies, transcription and secretion of cytokines in lung and spleen, and the proportion of T cell subsets were detected after immunization. EsxV: C: L LNPs were obtained with uniform size and they were spherical and negatively charged. Compared with EsxV: C immunization, EsxV: C: L mucosal inoculation induced increased sIgA level in respiratory tract mucosa. Levels of IL-2 secreted from spleen and ratios of memory T cells and tissue-resident T cells in mice were also elevated. In conclusion, EsxV: C: L could induce stronger mucosal immunity and memory T cell immune responses, which may provide better protection against Mtb infection.
Animals ; Mice ; Mycobacterium tuberculosis ; Antigens, Bacterial ; Immunization ; Nanoparticles ; Vaccines, Subunit ; Mice, Inbred BALB C

Immunoscenescence plays a key role in the initiation and development of tumors. Furthermore, immunoscenescence also impacts drug delivery and cancer therapeutic efficacy. To reduce the impact of immunosenescence on anti-tumor therapy, this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid (SA)-modified liposomes into the tumor, kill tumor cells via SA-mediated photochemotherapy, enhance infiltration of neutrophils into the tumor, induce immunogenic death of tumor cells with chemotherapy, enhance infiltration of CD8⁺ T cells into the tumor-draining lymph nodes and tumors of immunosenescent mice, and achieve SA-mediated photochemotherapy. We found that CD8⁺ T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2- and 8-month-old mice; 16-month-old mice exhibited immunosenescence. The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice, and tumors recurred after scabbing. SA-mediated photochemotherapy enhanced tumor infiltration by CD8⁺ T cells and neutrophils, induced crusting and regression of tumors in 8-month-old mice, inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective To investigate the consistency between colonoscopic Boston bowel preparation score and the bowel cleanliness evaluated by pre-endoscopy naked eye faecal observation,so as to provide a guidance on bowel preparation.Methods From September 2018 to June 2019,convenience sampling method was used to select 150 inpatients who underwent colonoscopy in the Department of Gastroenterology of a tertiary hospital in Guangzhou as the research objects.Before colonoscopy,the compound polyethylene glycol electrolyte powder was taken orally according to the bowel preparation plan for cleaning the colorectum.Before the colonoscopic examination,the naked eye observation method by nurses was used to observe the transparency of the excreta to evaluate the cleanliness of colorectum.Then the colorectal cleanliness was evaluated by endoscope by the operator using the Boston bowel preparation assessment scale(BBPS)during colonoscopy.Results A total of 145 patients completed the study.The cleanliness of bowel preparation was 93.1%with the naked eye observation and 88.27%with colonoscopy.There was no significant difference between the two assessment methods in judging the effectiveness of bowel preparation(P<0.05).The sensitivity of naked eye observation in judging bowel preparation was 96.10%with a 29.41%of specificity.The positive predictive value was 91.11%,and the negative predictive value was 50%(Kappa=0.310,P<0.001).Conclusion The naked eye observation and evaluation method for bowel preparation has advantages in high sensitivity,low specificity,high positive predictive value and low negative predictive value.It can be used as a preliminary evaluation method for cleanliness of colorectum before colonoscopy.

Objective:To analyze the detection rate and related factors of depressive and anxious symptoms comorbidity in 2021 and 2022.Methods:Based on the results of the Seventh National Population Census in 2021,the residents of 32 provinces,municipalities,and autonomous regions were sampled by gender and age.The gender and age of the samples were in line with the characteristics of China's population.A face-to-face interview survey was conducted in community residents in each province in 2021(n=11 005)and 2022(n=30 421)with the Gen-eralized Anxiety Questionnaire-7 and Patient Health Questionnaire-9.Results:The detection rates of depressive and anxious symptoms comorbidity were 10.67％in 2021 and 11.72％in 2022.The prevalence of depressive and anxi-ety comorbidity were higher in male,younger(age≤17 years),divorced,lower BMI(BMI＜18.5 kg/m2),higher education(graduate),students,and residents with chronic medical history(Ps＜0.001).In 2022,32.06％of people with depressive symptoms had anxious symptoms and 47.62％of people with anxious symptoms had depressive symptoms.Conclusion:In 2021 and 2022,the detection rates of depressive and anxious symptoms comorbidity were both about 10％,and half of patients with anxious symptoms were accompanied by depressive symptoms,So atten-tion should be paid to the comorbidity of depression and anxiety symptoms.