Increased opioid consumption in neoadjuvant immunotherapy plus chemotherapy for patients with non-small-cell lung cancer: A multicenter, prospective cohort study.

AIMS: PD-1 block was reported to impair opioid-induced antinociception and affect cognitive function in rodents and non-human primates. This prospective multicenter cohort study aims to investigate the possible impact of neoadjuvant immunotherapy with PD-1 antibody on perioperative analgesic effect of opioids and postoperative delirium (POD) for non-small-cell lung cancer (NSCLC) patients. METHODS: Eighty-four NSCLC patients from three medical centers with neoadjuvant chemoimmunotherapy (nCIT) or chemotherapy (nCT) were enrolled. The primary outcome is the total perioperative opioid consumption defined as the sum of intraoperative and postoperative opioid use within 3 days after surgery. Secondary outcomes compromise of incidence of POD, pain intensity, and number of analgesic pump press. Tumor prognostic parameters and perioperative change of inflammatory cytokines and soluble PD-L1 level were also recorded. RESULTS: Eighty-one patients were included in the final analysis. The total opioid consumption (sufentanil equivalent) perioperatively in the nCIT group was significantly higher than that in the nCT group, with mean difference of 60.39 µg, 95% CI (25.58-95.19), p < 0.001. Multiple linear regression analysis showed that nCIT was correlated with increased total opioid consumption (ß = 0.305; 95% CI, 0.152-0.459; p < 0.001). The incidence of moderate-to-severe pain and cumulative analgesic pump press within 72 h was significantly higher in subjects with nCIT. There is no statistical difference in incidence of POD between groups within 72 h after surgery. The pathologic complete response rate and perioperative serum IL-6 level were higher in the nCIT group than in the nCT group. CONCLUSION: Patients with NSCLC receiving nCIT warrant increased opioid consumption perioperatively and suffered from more postoperative pain. CLINICAL TRIAL REGISTRATION: NCT05273827.

Synthesis of nimbolide and its analogues and their application as poly(ADP-ribose) polymerase-1 trapping inducers.

Nimbolide, a ring seco-C limonoid natural product, was recently found to inhibit the poly(ADP)-ribosylation (PARylation)-dependent ubiquitin E3 ligase RNF114. In doing so, it induces the 'supertrapping' of both PARylated PARP1 and PAR-dependent DNA-repair factors. PARP1 inhibitors have reshaped the treatment of cancer patients with germline BRCA1/2 mutations partly through the PARP1 trapping mechanism. To this end, modular access to nimbolide analogues represents an opportunity to develop cancer therapeutics with enhanced PARP1 trapping capability. Here we report a convergent synthesis of nimbolide through a late-stage coupling strategy. Through a sulfonyl hydrazone-mediated etherification and a radical cyclization, this strategy uses a pharmacophore-containing building block and diversifiable hydrazone units to enable the modular synthesis of nimbolide and its analogues. The broad generality of our synthetic strategy allowed access to a variety of analogues with their preliminary cellular cytotoxicity and PARP1 trapping activity reported.

NIR-Remote Selectively Triggered Buprenorphine Hydrochloride Release from Microneedle Patches for the Treatment of Neuropathic Pain.

Neuropathic pain is a prevalent form of intermittent chronic pain, affecting approximately 7-10% of the global population. However, the current clinical administration methods, such as injection and oral administration, are mostly one-time administration, which cannot achieve accurate control of pain degree and drug dose. Herein, we developed near-infrared (NIR) light-responsive microneedle patches (MNPs) to spatiotemporally control the drug dose released to treat neuropathic pain according to the onset state. The mechanism of action utilizes upconversion nanoparticles to convert NIR light into visible and ultraviolet light. This conversion triggers the rapid rotation of the azobenzene molecular motor in the mesoporous material, enabling the on-demand controlled release of a drug dose. Additionally, MNs are used to overcome the barrier of the stratum corneum in a minimally invasive and painless manner, effectively promoting the transdermal penetration of drug molecules. The effectiveness of these patches has been demonstrated through significant results. Upon exposure to NIR light for five consecutive cycles, with each cycle lasting 30 s, the patches achieved a precise release of 318 µg of medication. In a mouse model, maximum pain relief was observed within 1 h of one cycle of NIR light exposure, with the effects lasting up to 6 h. The same level of precise treatment efficacy was maintained for subsequent pain episodes with similar light exposure. The NIR-controlled drugs precision-released MNPs provide a novel paradigm for the treatment of intermittent neuropathic pain.

Diagnostic and Prognostic Markers for Pancreatitis and Pancreatic Ductal Adenocarcinoma.

Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.

An in vitro study of coagulation evaluation in obstetric hemorrhage for pregnancy-induced hypertension with coagulation and platelet function analyzer.

This study aimed to establish in vitro hemodilution and resupplementation assays for obstetric hemorrhage in pregnancy-induced hypertension (PIH) and to monitor the coagulation function dynamically using a coagulation and platelet function analyzer. Forty-seven singleton pregnant women were divided into normal (n = 24) and PIH (n = 23) groups. Peripheral blood samples were used to construct the assays, and the activated clotting time (ACT), clotting rate (CR), and platelet function index (PF) were measured. The results showed that the baseline ACT was higher in the PIH group (p < 0.01). Hemodilution assays showed decreased ACT and increased CR and PF, with ACT changes significantly lower in the PIH group (p < 0.05). CR changed most in both groups at lower dilution ratios (35% to 50%), while ACT changed most at a higher dilution ratio (75%). In the resupplementation assay, ACT exhibited the most significant response. The analyzer effectively detected differences between pregnant women with and without PIH. Thus, we need to pay more attention to the changes of ACT in the actual clinical application to assess the coagulation status of parturients.

PIAS3 acts as a zinc sensor under zinc deficiency and plays an important role in myocardial ischemia/reperfusion injury.

Alterations in zinc transporter expression in response to zinc loss protect cardiac cells from ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms how cardiac cells sense zinc loss remains unclear. Here, we found that zinc deficiency induced ubiquitination and degradation of the protein inhibitor of activated STAT3 (PIAS3), which can alleviate myocardial I/R injury by activating STAT3 to promote the expression of ZIP family zinc transporter genes. The RING finger domain within PIAS3 is vital for PIAS3 degradation, as PIAS3-dRing (missing the RING domain) and PIAS3-Mut (zinc-binding site mutation) were resistant to degradation in the setting of zinc deficiency. Meanwhile, the RING finger domain within PIAS3 is critical for the inhibition of STAT3 activation. Moreover, PIAS3 knockdown increased cardiac Zn2+ levels and reduced myocardial infarction in mouse hearts subjected to I/R, whereas wild-type PIAS3 overexpression, but not PIAS3-Mut, reduced cardiac Zn2+ levels, and exacerbated myocardial infarction. These findings elucidate a unique mechanism of zinc sensing, showing that fast degradation of the zinc-binding regulatory protein PIAS3 during zinc deficiency can correct zinc dyshomeostasis and alleviate reperfusion injury.

Efficacy and safety of ciprofol for sedation in outpatient gynecological procedures: a phase III multicenter randomized trial.

Objective: Ciprofol (also known as cipepofol and HSK3486), is a compound similar to propofol in chemical structure and hypnotic effect. Herein we evaluated the efficacy and safety of ciprofol for sedation in outpatient gynecological procedures. Methods: This phase III multicenter randomized trial with a non-inferiority design was conducted in nine tertiary hospitals. We enrolled 135 women aged 18-65 years who were scheduled for ambulatory gynecological procedures. Patients were randomly assigned to receive either ciprofol (0.4 mg/kg for induction and 0.2 mg/kg for maintenance) or propofol (2.0 mg/kg for induction and 1.0 mg/kg for maintenance) sedation in a 2:1 ratio. Patients and investigators for data collection and outcome assessment were blinded to study group assignments. The primary outcome was the success rate of sedation, defined as completion of procedure without remedial anesthetics. The non-inferiority margin was set at -8%. Secondary outcomes included time to successful induction, time to full awake, time to meet discharge criteria, and satisfaction with sedation assessed by patients and doctors. We also monitored occurrence of adverse events and injection pain. Results: A total of 135 patients were enrolled; 134 patients (90 patients received ciprofol sedation and 44 patients propofol sedation) were included in final intention-to-treat analysis. The success rates were both 100% in the two groups (rate difference, 0.0%; 95% CI, -4.1 to 8.0%), i.e., ciprofol was non-inferior to propofol. When compared with propofol sedation, patients given ciprofol required more time to reach successful induction (median difference [MD], 2 s; 95% CI, 1 to 7; p < 0.001), and required more time to reach full awake (MD, 2.3 min; 95% CI, 1.4 to 3.1; p < 0.001) and discharge criteria (MD, 2.3 min; 95% CI, 1.5 to 3.2; p < 0.001). Fewer patients in the ciprofol group were dissatisfied with sedation (relative risk, 0.21; 95% CI, 0.06 to 0.77; p = 0.024). Patients given ciprofol sedation had lower incidences of treat-emergent adverse events (34.4% [31/90] vs. 79.5% [35/44]; p < 0.001) and injection pain (6.7% [6/90] vs. 61.4% [27/44]; p < 0.001). Conclusion: Ciprofol for sedation in ambulatory gynecological procedures was non-inferior to propofol, with less adverse events and injection pain. Clinical trial registration: ClinicalTrials.gov, identifier NCT04958746.

Preoperative recovery sleep ameliorates postoperative cognitive dysfunction aggravated by sleep fragmentation in aged mice by enhancing EEG delta-wave activity and LFP theta oscillation in hippocampal CA1.

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

Euchromatin histone-lysine N-methyltransferase 2 regulates the expression of potassium-sodium-activated channel subfamily T member 1 in primary sensory neurons and contributes to remifentanil-induced pain sensitivity.

Intraoperative remifentanil administration has been linked to increased postoperative pain sensitivity. Recent studies have identified the involvement of euchromatic histone-lysine N-methyltransferase 2 (Ehmt2/G9a) in neuropathic pain associated with the transcriptional silencing of many potassium ion channel genes. This study investigates whether G9a regulates the potassium sodium-activated channel subfamily T member 1 (Slo2.2) in remifentanil-induced post-incisional hyperalgesia (RIH) in rodents. We performed remifentanil infusion (1 µg·kg-1·min-1 for 60 min) followed by plantar incision to induce RIH in rodents. Our results showed that RIH was accompanied by increased G9a and H3K9me2 production and decreased Slo2.2 expression 48 h postoperatively. Deletion of G9a rescued Slo2.2 expression in DRG and reduced RIH intensity. Slo2.2 overexpression also reversed this hyperalgesia phenotype. G9a overexpression decreased Slo2.2-mediated leak current and increased excitability in the small-diameter DRG neurons and laminal II small-diameter neurons in the spinal dorsal horn, which was implicated in peripheral and central sensitization. These results suggest that G9a contributes to the development of RIH by epigenetically silencing Slo2.2 in DRG neurons, leading to decreased central sensitization in the spinal cord. The findings may have implications for the development of novel therapeutic targets for the treatment of postoperative pain.

SfREPAT38, a pathogen response gene (REPAT), is involved in immune response of Spodoptera frugiperda larvae through mediating Toll signalling pathway.

REPAT (response to pathogen) is an immune-associated gene family that plays important roles in insect immune response to pathogens. Although nine REPAT genes have been identified in Spodoptera frugiperda (Lepidoptera: Noctuidae) currently, their functions and mechanisms in the immune response to pathogens still remain unclear. Therefore, SfREPAT38, a pathogen response gene (REPAT) of S. frugiperda, was characterised and its function was analysed. The results showed that SfREPAT38 contains a signal peptide and a transcription activator MBF2 (multi-protein bridging factor 2) domain. Quantitative real-time polymerase chain reaction analysis showed that SfREPAT38 was highly expressed in the sixth-instar larvae (L6) and was the highest in expression in the midgut of L6. We found that the expression of SfREPAT38 could be activated by challenge with four microbial pathogens (Bacillus thuringiensis, Metarhizium anisopliae, Spodoptera exigua nuclearpolyhedrosis and Escherichia coli), except 12 h after E. coli infection. Furthermore, the SfREPAT38 expression levels significantly decreased at 24, 48 and 72 h after SfREPAT38 dsRNA injection or feeding. Feeding with SfREPAT38 dsRNA significantly decreased the weight gain of S. frugiperda, and continuous feeding led to the death of S. frugiperda larvae from the fourth day. Moreover, SfREPAT38 dsRNA injection resulted in a significant decrease of weight gain on the fifth day. Silencing SfREPAT38 gene down-regulated the expression levels of immune genes belonging to the Toll pathway, including SPZ, Myd88, DIF, Cactus, Pell and Toll18W. After treatment with SfREPAT38 dsRNA, S. frugiperda became extremely sensitive to the B. thuringiensis infection, and the survival rate dramatically increased, with 100% mortality by the eighth day. The weight of S. frugiperda larvae was also significantly lower than that of the control groups from the second day onwards. In addition, the genes involved in the Toll signalling pathway and a few antibacterial peptide related genes were down-regulated after treatment. These results showed that SfREPAT38 is involved in the immune response of S. frugiperda larvae through mediating Toll signalling pathway.

Quadratus lumborum block vs. transversus abdominis plane block for postoperative pain control in patients with nephrectomy: A systematic review and network meta-analysis.

STUDY OBJECTIVE: This systematic review and network meta-analysis aimed to compare the analgesic efficacy of transversus abdominis plane block (TAPB) and quadratus lumborum block (QLB) on nephrectomy. DESIGN: Systematic review and network meta-analysis. PATIENTS: Patients undergoing nephrectomy. INTERVENTIONS: TAPB and QLB for postoperative analgesia. MEASUREMENTS: The primary outcome was 24 h morphine-equivalent consumptions after surgery. Secondary outcomes included postoperative pain scores, postoperative opioid consumption, postoperative rescue analgesia, postoperative nausea and vomiting (PONV), length of hospital stay after surgery, and patient satisfaction. MAIN RESULTS: Fourteen studies involving 883 patients were included. Seven studies compared TAPB to control, six studies compared QLB to control, and one study compared TAPB to QLB. For direct meta-analysis of the post-surgical 24 h morphine-equivalent consumption, QLB was lower than control (mean difference [95%CI]: -18.16 [-28.96, -7.37]; I2 = 88%; p = 0.001), while there was no difference between TAPB and control (mean difference [95%CI]: -8.34 [-17.84, 1.17]; I2 = 88%; p = 0.09). Network meta-analysis showed similar findings that QLB was ranked as the best anesthetic technique for reducing postoperative 24 h opioid consumption (p-score = 0.854). Moreover, in direct meta-analysis, as compared to control, the time of first postoperative rescue analgesia was prolonged after QLB (mean difference [95%CI]: 165.00 [128.99, 201.01]; p < 0.00001), but not TAPB (mean difference [95%CI]: 296.82 [-91.92, 685.55]; p = 0.13). Meanwhile, QLB can effectively reduce opioid usages at intraoperative period, as well as at postoperative 6 h and 48 h, while TAPB can only reduce opioid consumption at 6 h after surgery. As compared to control, both TAPB and QLB exhibited the reduction in PONV and pain scores at post-surgical some timepoints. Also, QLB (mean difference [95%CI]: -0.29 [-0.49, -0.08]; p = 0.006) but not TAPB (mean difference [95%CI]: 0.60 [-0.25, 1.45]; p = 0.17) exhibited the shorter postoperative length of hospital stay than control. CONCLUSIONS: QLB is more likely to be effective in reducing postoperative opioid use than TAPB, whereas both of them are superior to control with regard to the reduction in postoperative pain intensity and PONV. TRIAL REGISTRATION: PROSPERO identifier: CRD42022358464.

A novel prognostic model of breast cancer based on cuproptosis-related lncRNAs.

OBJECTIVE: Breast cancer (BC) is a deadly form of malignancy responsible for the death of a large number of women every year. Cuproptosis is a newly discovered form of cell death that may have implications for the prognosis of BC. Long non-coding RNAs (lncRNAs) have been shown to be involved in the progression and development of BC. Here within, a novel model capable of predicting the prognosis of patients with BC was established based on cuproptosis-related lncRNAs. METHODS: Data of breast cancer patients was downloaded, including clinical information from The Cancer Genome Atlas (TCGA) database and lncRNAs related to cuproptosis were isolated. In total, nine lncRNAs related to copper death were obtained by Cox regression model based on Least Absolute Shrinkage and Selector Operation (LASSO) algorithm for model construction. The model was verified by overall survival (OS), progression-free survival (PFS) and receiver operating characteristic (ROC) curve. The differences in immune function, tumor mutation burden (TMB) and tumor immune dysfunction and exclusion (TIDE) between patients with different risk scores were analyzed. RESULTS: Based on cuproptosis-related lncRNAs, a prognostic model for predicting BC was constructed. Each patient was assigned a risk score based on our model formula. We found that patients with higher risk scores had significantly lower OS and PFS, increased TMB, and higher sensitivity to immunotherapy. CONCLUSIONS: The model established in this study based on cuproptosis-related lncRNAs may be capable of improving the OS of patients with BC.

LCN2 and ELANE overexpression induces sepsis.

Sepsis is a syndrome characterized by a systemic inflammatory response due to the invasion of pathogenic microorganisms. The relationship between Lipocalin-2 (LCN2), elastase, neutrophil expressed (ELANE) and sepsis remains unclear. The sepsis datasets GSE137340 and GSE154918 profiles were downloaded from gene expression omnibus generated from GPL10558. Batch normalization, differentially expressed Genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, construction and analysis of protein-protein interaction (PPI) networks, Comparative Toxicogenomics Database (CTD) analysis were performed. Gene expression heatmaps were generated. TargetScan was used to screen miRNAs of DEGs. 328 DEGs were identified. According to Gene Ontology (GO), in the Biological Process analysis, they were mainly enriched in immune response, apoptosis, inflammatory response, and immune response regulation signaling pathways. In cellular component analysis, they were mainly enriched in vesicles, cytoplasmic vesicles, and secretory granules. In Molecular Function analysis, they were mainly concentrated in hemoglobin binding, Toll-like receptor binding, immunoglobulin binding, and RAGE receptor binding. In Kyoto Encyclopedia of Genes and Genomes (KEGG), they were mainly enriched in NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, TNF signaling pathway, P53 signaling pathway, and legionellosis. Seventeen modules were generated. The PPI network identified 4 core genes (MPO, ELANE, CTSG, LCN2). Gene expression heatmaps revealed that core genes (MPO, ELANE, CTSG, LCN2) were highly expressed in sepsis samples. CTD analysis found that MPO, ELANE, CTSG and LCN2 were associated with sepsis, peritonitis, meningitis, pneumonia, infection, and inflammation. LCN2 and ELANE are highly expressed in sepsis and may serve as molecular targets.

Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this signal generated a cell-specific response in ASCL1 degradation, leading to the identification of HUWE1 expression as a predictive biomarker for PARPi. Combining PARPi with agents targeting these pathways markedly improved therapeutic response in SCLC. The degradation of lineage-specific oncoproteins therefore represents a previously unidentified mechanism for PARPi efficacy in SCLC.

Meeting Report on the 3rd Chinese American Society for Mass Spectrometry Conference-Advancing Biological and Pharmaceutical Mass Spectrometry.

Following the highly successful Chinese American Society for Mass Spectrometry (CASMS) conferences in the previous 2 years, the 3rd CASMS Conference was held virtually on August 28-31, 2023, using the Gather.Town platform to bring together scientists in the MS field. The conference offered a 4-day agenda with a scientific program consisting of two plenary lectures, and 14 parallel symposia in which a total of 70 speakers presented technological innovations and their applications in proteomics and biological MS and metabo-lipidomics and pharmaceutical MS. In addition, 16 invited speakers/panelists presented at two research-focused and three career development workshops. Moreover, 86 posters, 12 lightning talks, 3 sponsored workshops, and 11 exhibitions were presented, from which 9 poster awards and 2 lightning talk awards were selected. Furthermore, the conference featured four young investigator awardees to highlight early-career achievements in MS from our society. The conference provided a unique scientific platform for young scientists (i.e. graduate students, postdocs, and junior faculty/investigators) to present their research, meet with prominent scientists, learn about career development, and job opportunities (http://casms.org).

The locus coeruleus-dorsal hippocampal CA1 pathway is involved in depression-induced perioperative neurocognitive disorders in adult mice.

BACKGROUND: Patients undergoing surgical anesthesia increasingly suffer from preoperative depression. Clinical studies have shown that depression is a risk factor for perioperative neurocognitive disorders (PNDs) in elder patients. However, the underlying mechanism, especially at the neural circuit level, remains poorly understood. METHODS: Right carotid artery separation under sevoflurane and chronic social defeat stress (CSDS) in adult mice were used to establish surgical anesthesia and chronic depression models. Cognitive function was assessed by the Y maze and novel object recognition tests. A chemogenetic approach was used to modulate the locus coeruleus-dorsal hippocampal CA1 (LC-dCA1) circuit. Hippocampal synaptic alterations were evaluated by Golgi staining and whole-cell patch clamp recording. RESULTS: We found that CSDS induced synaptic impairments in dorsal hippocampal CA1 pyramidal neurons and cognitive deficits in adult mice after surgery under sevoflurane. Chemogenetic activation of the LC-dCA1 pathway significantly alleviated the CSDS-induced synaptic impairments and cognitive dysfunction. On the contrary, inhibition of this pathway could mimic CSDS-induced deficits. Furthermore, we showed that dopamine played an important role in CSDS-induced PNDs in adult mice after surgery/sevoflurane. CONCLUSION: Overall, our results have demonstrated a vital role for the LC-dCA1 pathway in CSDS-induced PNDs in adult mice undergoing surgery with sevoflurane anesthesia.

Complete Mitochondrial Genome Characterization of Schrankia costaestrigalis (Insecta: Erebidae: Hypenodinae) and Its Phylogenetic Implication.

The pinion-streaked snout Schrankia costaestrigalis is a new potato pest that has recently been recorded in China. In this study, we analyzed the complete mitochondrial genome of S. costaestrigalis. The results revealed the mitogenome (GenBank: OQ181231) to occur as a circular DNA molecule of 16,376 bp with 51.001% AT content, including 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and 1 control region. Notably, the PCGs exhibited typical ATN (Met) start codons, including cox1, which deviated from the usual CGA start codon observed in other lepidopteran mitogenomes, and followed the conventional TAN stop codons. The 22 tRNA genes demonstrated the ability to form a cloverleaf structure, with the exception of trnS1-NCU, which lacked the DHU arm present in other Erebidae mitogenomes. Additionally, conserved motifs like "ATAGA + poly-T (19 bp) stretch" and five microsatellite-like elements (TA) were identified in the AT-rich region. The phylogenetic trees revealed that the Hypenodinae subfamily forms an independent lineage closely related to Erebinae and Catocalinae. The comprehensive mitogenome of S. costaestrigalis will greatly enhance future studies focused on the molecular classification and phylogenetic understanding of the Hypenodinae subfamily within the larger family Erebidae.

Effects of the PI3K/Akt/HO-1 pathway on autophagy in a sepsis-induced acute lung injury mouse model.

Sepsis-induced lung injury is an acute hypoxic respiratory insufficiency caused by systemic infectious factors that results in alveolar epithelial cell and capillary endothelial cell injury, diffuse pulmonary interstitial edema, and alveolar edema. Heme oxygenase (HO)-1 is usually associated with inflammation and has anti-inflammatory effects. Autophagy is a degradation pathway that eliminates cellular metabolic waste and plays an important protective role during stress. The phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) signaling pathway plays a key role in mediating cellular responses to inflammatory reactions. Therefore, we hypothesized that HO-1 is associated with autophagy and regulated by the PI3K/Akt signaling pathway in mice with sepsis-induced lung injury. Sepsis-induced lung injury was induced in mice using cecal ligation and puncture (CLP). Hemin or Sn-protoporphyrin IX (SnPP) was administered via intraperitoneal injection before surgery. Survival rates were observed during days 1-7 after the surgery; lung histology was discerned 24 h after the surgery; pro-inflammatory and anti-inflammatory factors in plasma and lung tissue were measured using enzyme-linked immunosorbent assay (ELISA); HO-1, Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, p62 and lysosome associated membrane protein (LAMP)2 protein expression levels were measured 24 h after the surgery; HO-1 and LC3B-II protein expression levels were observed using immunofluorescence 24 h after the surgery; and autophagosomes were detected using electron microscopy 24 h after the surgery. Furthermore, when PI3K inhibitors LY294002, PI3K activators Recilisib and hemin were administered before the surgery, Akt, p-Akt, HO-1, and LC3-II levels were measured 24 h post-surgery. We found that HO-1 overexpression increased the survival rate and inhibited sepsis-induced lung injury. HO-1 overexpression attenuated the levels of proinflammatory cytokines (TNF-α, IL-1ß) and increased the anti-inflammatory cytokine (IL-10, HO-1) overexpression. Moreover, HO-1 overexpression was also associated with increased expression of Beclin-1, LC3B-II and LAMP2 protein expression; decreased p62 protein expression; and significantly increased autophagosome formation. The results for HO-1-downregulated mice contrasted with those mentioned above. LY294002 inhibited p-Akt/Akt, HO-1, and LC3B-II protein expression; and hemin reversed the inhibitory effect of LY294002. The protective effect of HO-1 was involved in the mediation of autophagy, which may be regulated by the PI3K/Akt signaling pathway during sepsis-induced lung injury in mice.

Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer.

Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with BRCA mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.

Potential biomarker for diagnosis and therapy of sepsis: Lactylation.

INTRODUCTION: As a disease that has plagued human health for decades, sepsis has so far had no specific diagnostic or therapeutic indicators. The discovery of lactylation modifications not only uncovered the deep-rooted causes of changing between lactate level and pathophysiology and immunology of sepsis, but also reaffirmed the inevitable link between metabolic reprogramming and epigenetic reprogramming in sepsis. Lactylation modification became a potential marker for diagnosis and guiding the treatment of sepsis. AIM: In this paper, we will summarize the discovery and regulation of lactylation modifications, discuss the study of lactylation modifications in sepsis, and evaluate their possibility and potential as diagnostic and therapeutic indicators of sepsis. CONCLUSION: Lactylation modification is directly regulated by glycolysis and lactate, and inhibition of glycolytic pathway-related enzymes can regulate the level of lactylation modification, and more importantly, lactylation modification can act on these enzymes to regulate their functions and feedback regulate the level of glycolysis, this finding provides more ideas for clinical treatment of sepsis. We use "epigenetic modification", "glycolysis", "lactate", "lactylaiton" and "sepsis" as keywords and search the relevant literature through Pubmed and Web of science up to 2023.