Calcineurin B-like protein (CBL)-interacting protein kinases (CIPKs) are a group of Ser/Thr protein kinases, playing a crucial role in the growth, development, and stress responses of plants. CIPKs can undergo autophosphorylation or target the phosphorylation of other signaling factors in responses to biotic and abiotic stresses. In addition, they are involved in the signaling pathways of plant hormones such as abscisic acid (ABA), gibberellic acid (GA), ethylene (ETH), and salicylic acid (SA) to regulate plant growth and development. Furthermore, CIPKs respond to stresses such as salinity, drought, cold, and heavy metals by forming complexes through specific interactions with CBLs. In this study, we summarized the discovery, structures, classification, regulatory mechanisms, and roles of CIPKs in plant responses to stresses and made an outlook on the future research directions. This review is expected to provide genetic resources and theoretical foundations for the genetic improvement and breeding of crops with stress tolerance.
Stress, Physiological/physiology* ; Protein Serine-Threonine Kinases/genetics* ; Signal Transduction/physiology* ; Plant Growth Regulators/metabolism* ; Plant Proteins/genetics* ; Plants/metabolism*

Objective Explore the molecular mechanism by which long chain non-coding(lncRNA)MEG8 regulates the development of chronic obstructive pulmonary disease(COPD)mediated by miR-367-3p/phos-phatase and tensin homolog(PTEN).Methods Real time fluorescence quantitative polymerase chain reaction(qPCR)was used to detect the expression level of lncRNA MEG8 in 16HBE cells and clinical tissues of chron-ic obstructive pulmonary disease(COPD).MEG8 was overexpressed in 16HBE cells stimulated by cigarette smoke extract(CSE),and MEG8 or PTEN were simultaneously knocked down after the addition of miR-367-3p inhibitor,then MTT assay,flow cytometry,enzyme-linked immunosorbent assay,and immunoblotting were used to detect changes in cell apoptosis,proliferation,and levels of inflammatory factors.The targeting rela-tionships of MEG8,miR-367-3p,and PTEN was verified by using the dual luciferase reporting system.Results MEG8 expression was reduced in CSE stimulated 16HBE cells and COPD clinical tissue samples(P<0.05).Compared to the CSE group,overexpression of MEG8 stimulated apoptosis and inflammatory fac-tor interleukin(IL)-1β,IL-6 and tumor necrosis factor(TNF)-αlevels decreased(P<0.05)in 16HBE cells stimulated by CSE.The expression levels of proapoptotic proteins Bax,Caspase3,and Cleared caspase3 de-creased(P<0.05),and the expression level of apoptosis inhibitory factor Bcl-2 increased(P<0.05).The double luciferase Reporter gene experiment verified that MEG8 can target to inhibit miR-367-3p(P<0.05),and miR-367-3p can target to inhibit the expression of PTEN(P<0.05),thereby inhibiting the apoptosis and inflammatory response of 16HBE cells stimulated by CSE(P<0.05).Under CSE stimulation,compared to the Control group,the addition of miR-367-3p inhibitor significantly upregulated the protein expression level of PTEN in 16HBE cells(P<0.05),enhanced cell proliferation activity(P<0.05),reduced cell apoptosis(P<0.05),significantly downregulated the expression levels of proapoptotic proteins Bax,Caspase 3,and Cleared caspase 3(P<0.05),upregulated the expression level of anti apoptotic protein Bcl-2(P<0.05),and suppressed the inflammatory factor IL-1 β,IL-6 and TNF-α Knocking down MEG8 or PTEN can restore the protein expression level of PTEN(P<0.05),inhibit cell proliferation activity(P<0.05),reverse cell apoptosis caused by miR-367-3p inhibitor(P<0.05),and regulate apoptosis related proteins(P<0.05),and enhance the in-flammatory factor IL-1 β,IL-6 and TNF-α The level of(P<0.05).Conclusion MEG8 inhibits the apoptosis and inflammatory response of 16HBE cells stimulated by CSE by regulating miR-367-3p/PTEN molecular ax-is,and may provide a potential molecular target for the treatment of COPD.

Objective:To explore the challenges in the implementation of drug centralized volume-based procurement policies in hospitals and propose corresponding optimization suggestions.Methods:From August to December 2023, a purposive sampling was conducted to select 11 pharmaceutical experts from tertiary hospitals in China for Delphi method. The survey content included " policy recommendations for promoting the acceleration and expansion of national drug centralized procurement and retaining surplus medical insurance funds for centralized procurement" .Results:Survey participants gave feedback on a set of existing problems found in the implementation of drug centralized procurement policies and proposed corresponding optimization methods. Kendall′s W coefficient of the specialist consultation was 0.332( P<0.05), demonstrating good consistency and concentration of the expert opinions. Among the problems, the score of drug supply guarantee was the highest(mean value of importance was 4.45). At the same time, the recommendation of strengthening monitoring and early warning, coordination and dispatch, and effectively ensuring the supply of centralized drug procurement had the highest score and concentration(mean value of importance was 4.91, coefficient of variation was 0.06). Conclusions:Through Delphi method, this study revealed issues and optimization methods in the implementation of drug centralized procurement policies in hospitals. The findings could provide valuable insights for improvements in the pharmaceutical sector and future policy adjustments.

Objective To clarify the mechanism that HIV infection mediates mitochondrial damage of CD4⁺ T lymphocytes (CD4⁺ T cells) through mitogen-activated protein kinase (MAPK) pathway. Methods From October 1st, 2022 to March 31st, 2023, 47 HIV-infected people who received antiretroviral therapy (ART) for 4 years were recruited, including 22 immune non-responders (INR) and 25 responders (IR); and 26 sex and age-matched control participants (HC) who were negative for HCV, HBV, and HIV infections. The immune parameters were analyzed by flow cytometry. Finally, peripheral blood mononuclear cells (PBMCs) from HC or HIV patients were treated with MAPK pathway inhibitor SB203580, and the changes of mitochondrial function of CD4⁺ T cells were observed. Results Compared with HC group, the proportion of CD4⁺ T cells in PBMCs in INR group and IR group was significantly lower, and the proportion of CD4⁺ T cells in PBMCs in INR group was significantly lower than that in IR group. In addition, the proportion of naive (CD45RA⁺CD27⁺)T cells in PBMCs in INR group was significantly lower than that in HC group and IR group. Compared with HC group and IR group, the proportions of CD4⁺PD-1⁺, CD4⁺Av⁺ and CD4⁺MO⁺ in PBMCs in INR group and the proportions of CD45RA⁺CD27⁺PD-1⁺, CD45RA⁺CD27⁺Av⁺, CD45RA⁺CD27⁺MO⁺ in CD4⁺ T cell subsets increased significant. Compared with HC-con group, the basal respiration, maximal respiration and adenosine triphosphate(ATP) production of CD4⁺ T cells in HIV-con group decreased significantly, and JC-1 (green/red) in CD4⁺ T cells increased significantly. Compared with HIV-con group, the basal respiration, maximal respiration, ATP production and respiratory potential of CD4⁺ T cells in HIV-SB203580 group increased significantly, and the JC-1 (green/red) in CD4⁺ T cells decreased significantly. Conclusion Abnormal activation of the MAPK signaling pathway is observed in HIV patients receiving ART treatment, especially in CD4⁺ T cells of INR patients, which may lead to impaired mitochondrial function and abnormal CD4⁺ T cell homeostasis.
Humans ; HIV Infections/immunology* ; Male ; Mitochondria/drug effects* ; Female ; CD4-Positive T-Lymphocytes/metabolism* ; Adult ; Middle Aged ; MAP Kinase Signaling System/drug effects* ; Pyridines/pharmacology* ; Imidazoles/pharmacology* ; Leukocytes, Mononuclear/immunology*

Objective To investigate the predictive value of preoperative fibrinogen/albumin ratio (FAR) and systemic immune inflammation index (SII) on the postoperative prognosis of patients with pancreatic ductal adenocarcinoma. Methods An ROC curve was used in determining the best cutoff values of FAR and SII and then grouped. The Cox proportional hazards model was used in analyzing the prognostic factors of radical pancreatic cancer surgery, and then a Nomogram prognostic model was established. C-index, AUC, and calibration curve were used in evaluating the discrimination and calibration ability of the Nomogram. DCA curves were used in assessing the clinical validity of the Nomograms. Results The optimal cutoff values for preoperative FAR and SII were 0.095 and 532.945, respectively. FAR≥ 0.095, SII≥ 532.945, CA199≥ 450.9 U/ml, maximum tumor diameter≥ 4 cm, and the absence of postoperative chemotherapy were independent risk factors for the poor prognosis of pancreatic cancer (P<0.05). The discrimination ability, calibration ability, and clinical effectiveness of Nomogram prognostic model were better than those of the TNM staging system. Conclusion The constructed Nomogram prognostic model has higher accuracy and level of discrimination and more clinical benefits than the TNM staging prognostic model.

Objective:To screen the key exosomal long non-coding RNAs (lncRNAs) molecules that cause nasopharyngeal carcinoma cells to develop chemoradiotherapy resistance.Methods:In vitro, a model of concurrent chemoradiotherapy for human nasopharyngeal carcinoma cells was constructed, and the continuous shock method of high-dose concurrent chemoradiotherapy was used to induce the establishment of chemoradiotherapy-resistant nasopharyngeal carcinoma cell lines, and its resistance formation was verified. Exosomes produced by chemoradiotherapy-resistant cell lines and respective mother cell lines for nasopharyngeal carcinoma were extracted and identified. Finally, biochip technology was used to detect the differential expression levels of exosomal lncRNAs. Results:After 10 repeated treatments of concurrent chemoradiotherapy, CNE-1 CRR and CNE-2 CRR were successfully obtained. Compared with the mother cell lines, CNE-1 CRR and CNE-2 CRR had a tendency to transform from epithelial to interstitial morphology, and the number of cell clones was higher, and the values of average lethal dose (D 0), quasi-threshould dose (D q), survival fraction after 2 Gy irradiation (SF 2) and cell survival rate were higher. Nasopharyngeal carcinoma cells were detected by PCR chip of exosomal lncRNAs. Compared with their respective mother cell lines, 18 lncRNAs in CNE-1 CRR exosomes were significantly up-regulated and 31 lncRNAs were significantly down-regulated, and 15 lncRNAs were significantly up-regulated and 38 lncRNAs were significantly down-regulated in CNE-2 CRR exosomes. CNE-1 CRR also had similar expression profiles to CNE-2 CRR. Conclusion:There are significantly up-regulated and down-regulated lncRNAs in the exosomes of CNE-1 CRR and CNE-2 CRR.

BACKGROUND: Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV). METHODS: We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development. RESULTS: We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (<-2 standard deviations [SDs]), and 14 had significantly increased WBDV (>+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs . 75.0% [30/40], P  = 0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes ( P  = 1.656e -9 ). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron. CONCLUSION Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.
Child ; Humans ; Neurodevelopmental Disorders/epidemiology* ; Genetic Testing ; Phenotype ; Brain/pathology* ; Genetic Background ; SOX Transcription Factors/genetics*

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Mice ; Animals ; Transcriptome ; Aging/metabolism* ; Cochlea ; Stria Vascularis ; Presbycusis

Objective:To investigate the predictive value of preoperative lymphocyte-to-monocyte ratio (LMR) combined with platelet-to-lymphocyte ratio (PLR) (LMR-PLR) scoring model for prognosis of pancreatic ductal adenocarcinoma (PDAC) after radical resection.Methods:The retrospective cohort study was conducted. The clinicopathological data of 116 patients with PDAC who were admitted to the Second Hospital of Lanzhou University from January 2015 to December 2019 were collected. There were 73 males and 43 females, aged 61.5(range, 29.0-75.0)years. All patients underwent radical resection for PDAC. Observation indicators: (1) optimal cut-off value of LMR and PLR; (2) clinicopathological features of patients with different scores of preoperative LMR-PLR scoring model; (3) follow-up and survival; (4) influencing factors for prognosis of PDAC patients; (5) construction and verification of nomogram prediction model. Measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the Mann-Whitney U test. The Graphpad prism 8 was used to draw survival curve, the Kaplan-Meier method was used to calculate survival rate, and the Log-Rank test was used for survival analysis. The COX proportional hazard regression model was used for univariate and multivariate analyses. The X-tile software was used to determine the optimal cut-off values of LMR and PLR. The nomogram prediction model was conducted based on the results of multivariate analysis, and the receiver operating characteristic (ROC) curve was drawn. The area under curve (AUC) was used to evaluate the discrimination of nomogram prediction model. The calibration curve was used to evaluate the consistency of nomogram prediction model and the decision curve was used to evaluate the clinical benefits. Results:(1) Optimal cut-off value of LMR and PLR. The optimal cut-off values of LMR and PLR were 1.9 and 156.3. (2) Clinicopathological features of patients with different scores of preoperative LMR-PLR scoring model. Cases with LMR-PLR scoring as 0, 1, 2 were 11, 42, 63. Cases with CA125 <12.4 U/mL, cases postoperative with vascular invasion, cases with postoperative chemotherapy in patients with 0, 1, 2 of LMR-PLR scoring were 1, 8, 24, 9, 27, 27, 3, 26, 43, showing significant differences among them ( χ2=6.73, 8.37, 6.68, P<0.05). (3) Follow-up and survival. All 116 patients were followed up for 39(range, 2-86)months. The 1-, 2-, 3-year survival rate of 116 PDAC patients was 50.9%, 37.9%, 19.3%, respectively, with a survival time of 13(range, 1-85)months. The survival time of patients with LMR-PLR scoring as 0, 1, 2 was 3(range, 1-9)months, 7(range, 2-56)months, 26(range, 2-85)months, respectively, showing a significant difference among them ( χ2=48.78, P<0.05). (4) Influencing factors for prognosis of PDAC patients. Results of multivariate analysis showed that carcinoembryonic antigen (CEA), CA19-9, LMR-PLR score, tumor diameter were independent factors affecting prognosis of patients ( hazard ratio=1.61, 1.88, 0.27, 1.87, 95% confidence interval as 1.02-2.54, 1.18-3.00, 0.19-0.39, 1.13-3.09, P<0.05). (5) Construction and verification of nomogram prediction model. The nomogram prediction model was constructed based on CEA, CA19-9, LMR-PLR score and tumor diameter. The AUC of ROC curve in predicting 1-, 2-, 3-year survival rate of patients was 0.86 (95% confidence interval as 0.79-0.93, P<0.05), 0.86 (95% confidence interval as 0.79-0.92, P<0.05), 0.87 (95% confidence interval as 0.78-0.95, P<0.05), respectively. Results of calibration curve showed that the predicted survival rate of nomogram prediction model was consistent with the actual survival rate, with the consistency index as 0.74. Results of decision curve showed that the predictive performance of nomogram prediction model was superior to that of a single factor at a risk threshold of 0.12-0.85. Conclusions:CEA, CA19-9, LMR-PLR score, tumor diameter are independent factors affecting prognosis of patients undergoing radical resection for PDAC, and the nomogram prediction model can predict postoperative survival rate. The predicted survival rate of nomogram prediction model is consistent with the actual survival rate, and the predictive performance of nomogram prediction model is superior to that of a single factor at a risk threshold of 0.12-0.85.