Mature astrocytes as source for astrocyte repopulation after deletion in the medial prefrontal cortex: Implications for depression.

The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.

Double Half Purse-String Sutures Plus "8" Pattern of Stitching for Prevention of Duodenal Stump Fistula after Laparoscopic Gastrectomy.

Background: Duodenal stump fistula represents an infrequent but serious complication after laparoscopic radical gastrectomy with Billroth II or Roux-en-Y reconstruction for gastric cancer. The present study was designed to evaluate the effectiveness of laparoscopic double half purse-string sutures plus "8" pattern of stitching for reinforcement of duodenal stump. Methods: The data of patients undergoing laparoscopic radical gastrectomy with Billroth II or Roux-en-Y reconstruction were retrospectively analyzed between August 2022 and June 2023. According to the different reinforcement methods of duodenal stump, included patients were subdivided into three groups as follows: Group A, duodenal stump was treated with double half purse-string sutures plus "8" pattern of stitching; Group B, duodenal stump was reinforced by continuous suture using a barbed suture; and Group C, duodenal stump without any additional processing. The incidences of duodenal stump fistula between three groups were documented and compared. Moreover, the independent risk factors associated with duodenal stump fistula were analyzed using the logistic regression analysis. Results: No postoperative duodenal stump fistula occurred in Group A, which was significantly different from Group B and Group C (P = .007). In the multivariate analysis, age (odds ratio [OR], 1.191; 95% confidence interval [CI], 1.088-1.303), body mass index (OR, 0.824; 95% CI, 0.727-0.935), and American Society of Anesthesiologists score (OR, 4.495; 95% CI, 1.264-15.992) were the risk factors for duodenal stump fistula. Conclusion: Double half purse-string sutures plus "8" pattern of suture can be conducted in a relatively short operation period and could prevent the incidence of duodenal stump fistula to some extent.

Extracellular ATP Is a Homeostatic Messenger That Mediates Cell-Cell Communication in Physiological Processes and Psychiatric Diseases.

Neuronal activity is the basis of information encoding and processing in the brain. During neuronal activation, intracellular ATP (adenosine triphosphate) is generated to meet the high-energy demands. Simultaneously, ATP is secreted, increasing the extracellular ATP concentration and acting as a homeostatic messenger that mediates cell-cell communication to prevent aberrant hyperexcitability of the nervous system. In addition to the confined release and fast synaptic signaling of classic neurotransmitters within synaptic clefts, ATP can be released by all brain cells, diffuses widely, and targets different types of purinergic receptors on neurons and glial cells, making it possible to orchestrate brain neuronal activity and participate in various physiological processes, such as sleep and wakefulness, learning and memory, and feeding. Dysregulation of extracellular ATP leads to a destabilizing effect on the neural network, as found in the etiopathology of many psychiatric diseases, including depression, anxiety, schizophrenia, and autism spectrum disorder. In this review, we summarize advances in the understanding of the mechanisms by which extracellular ATP serves as an intercellular signaling molecule to regulate neural activity, with a focus on how it maintains the homeostasis of neural networks. In particular, we also focus on neural activity issues that result from dysregulation of extracellular ATP and propose that aberrant levels of extracellular ATP may play a role in the etiopathology of some psychiatric diseases, highlighting the potential therapeutic targets of ATP signaling in the treatment of these psychiatric diseases. Finally, we suggest potential avenues to further elucidate the role of extracellular ATP in intercellular communication and psychiatric diseases.

Dopamine D2 receptors in pyramidal neurons in the medial prefrontal cortex regulate social behavior.

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.

The Memory Orchestra: Contribution of Astrocytes.

For decades, memory research has centered on the role of neurons, which do not function in isolation. However, astrocytes play important roles in regulating neuronal recruitment and function at the local and network levels, forming the basis for information processing as well as memory formation and storage. In this review, we discuss the role of astrocytes in memory functions and their cellular underpinnings at multiple time points. We summarize important breakthroughs and controversies in the field as well as potential avenues to further illuminate the role of astrocytes in memory processes.

Prediction of pathological complete response to neoadjuvant chemotherapy in patients with breast cancer using a combination of contrast-enhanced ultrasound and dynamic contrast-enhanced magnetic resonance imaging.

This study aimed to evaluate the value of dynamic contrast-enhanced ultrasound (CEUS) combined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting pathological complete response (pCR) in patients with breast cancer receiving neoadjuvant chemotherapy (NAC). Fifty-seven female patients with breast cancer (mean age, 50.46 years; range, 32-66 years) scheduled for NAC were recruited. CEUS and DCE-MRI were performed before and after NAC. Imaging features and their changes were compared with postoperative pathological results. After the clinical differences were balanced using propensity score matching, univariate and multiple logistic regression analyses were used to derive the characteristics independently associated with pCR. Receiver operating characteristic curve analysis was performed to assess diagnostic performance. After six to eight cycles of NAC, 24 (42.1%) patients achieved pCR, while 33 (57.9%) did not. Multivariate analysis showed that enhancement order on CEUS and DCE-MRI before NAC, reduction in diameter and enhancement shape on CEUS, maximum diameter on DCE-MRI, and the type of progressive dynamic contrast enhancement after NAC were independently associated with pCR after NAC. The area under the receiver operating characteristic curve for CEUS+DCE-MRI was 0.911 (95% confidence interval, 0.826-0.997), and the specificity and positive predictive values were 87.0% and 87.5%. CEUS and DCE-MRI have the potential for assessing the pathological response to NAC in patients with breast cancer; their combination showed the best diagnostic performance. CEUS+DCE-MRI has proved beneficial for comprehensive assessment and personalizing treatment strategies for patients with breast cancer.

The efficacy of topical 0.1% mometasone furoate for treating symptomatic severe phimosis: A comparison of two treatment regimens.

Background: Twice daily 0.1% mometasone furoate is an effective treatment for phimosis in children. However, mometasone furoate has an important therapeutic advantage because it is effective in once-daily applications. This study was to compare the efficacy of two different topical 0.1% mometasone furoate regimens for the treatment of symptomatic severe phimosis in pediatric patients. Methods: A total of 1,689 patients with symptomatic severe phimosis classified by the Kikiros system were prospectively enrolled in the study from March 2018 to February 2021. A total of 855 patients received 0.1% mometasone furoate twice-daily (BID group) and 834 patients received 0.1% mometasone furoate once-daily (QD group) for 4 weeks. Results: A total of 1,595 boys completed the treatment (798 and 797 in the BID and QD groups, respectively). The success rate of the BID group was higher than that of the QD group at the end of week 2 (44.8% vs. 33.3%, P < 0.05), while there was no difference in the success rate at 4 weeks and 3 months between the two groups (70.7% vs. 69.7%, and 66.8% vs. 64.9%, respectively) (P > 0.05). In both treatment groups, the success rate of grade 5 phimosis was lower than that of grade 4 at 2 weeks, 4 weeks, and 3 months. A total of 83 patients experienced recurrence of phimosis. Only fifteen patients had local mild adverse drug reactions. Conclusion: Topical application of 0.1% mometasone furoate once-daily or twice-daily for 4 weeks had comparable efficacy in children with symptomatic severe phimosis. A once a day regimen may be more suitable for children. Topical steroid application is more effective in children with low-grade phimosis than those with high-grade phimosis.

Rational Design, Synthesis, and Biological Evaluation of Fluorine- and Chlorine-Substituted Pyrazol-5-yl-benzamide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

To develop novel succinate dehydrogenase inhibitors (SDHIs), two series of novel N-4-fluoro-pyrazol-5-yl-benzamide and N-4-chloro-pyrazol-5-yl-benzamide derivatives were designed and synthesized, and their antifungal activities were evaluated against Valsa mali, Sclerotinia sclerotiorum, FusaHum graminearum Sehw, Physalospora piricola, and Botrytis cinerea. The bioassay results showed that some of the target compounds exhibited good antifungal activities in vitro against V. mali and S. sclerotiorum. Remarkably, compound 9Ip displayed good in vitro activity against V. mali with an EC50 value of 0.58 mg/L. This outcome was 21-fold greater than that of fluxapyroxad (12.45 mg/L) and close to that of the commercial fungicide tebuconazole (EC50 = 0.36 mg/L). In addition, in vivo experiments proved that compound 9Ip has good protective fungicidal activity with an inhibitory rate of 93.2% against V. mali at 50 mg/L, which was equivalent to that of the positive control tebuconazole (95.5%). The results of molecular docking indicated that there were obvious hydrogen bonds and p-π interactions between compound 9Ip and succinate dehydrogenase (SDH), which could explain the probable action mechanism. In addition, the SDH enzymatic inhibition assay was carried out to further prove its mode of action. Our studies suggest that compound 9Ip could be a fungicidal lead to discover more potent SDHIs for crop protection.

The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway.

BACKGROUND: Depression is the most common mental illness. Mounting evidence suggests that dysregulation of extracellular ATP (adenosine triphosphate) is involved in the pathophysiology of depression. However, the cellular and neural circuit mechanisms through which ATP modulates depressive-like behavior remain elusive. METHODS: By use of ex vivo slice electrophysiology, chemogenetic manipulations, RNA interference, gene knockout, behavioral testing, and two depression mouse models, one induced by chronic social defeat stress and one caused by a IP3R2-null mutation, we systematically investigated the cellular and neural circuit mechanisms underlying ATP deficiency-induced depressive-like behavior. RESULTS: Deficiency of extracellular ATP in both defeated susceptible mice and IP3R2-null mutation mice led to reduced GABAergic (gamma-aminobutyric acidergic) inhibition and elevated excitability in lateral habenula-projecting, but not dorsal raphe-projecting, medial prefrontal cortex (mPFC) neurons. Furthermore, the P2X2 receptor in GABAergic interneurons mediated ATP modulation of lateral habenula-projecting mPFC neurons and depressive-like behavior. Remarkably, chemogenetic activation of the mPFC-lateral habenula pathway induced depressive-like behavior in C57BL/6J mice, while inhibition of this pathway was sufficient to alleviate the behavioral impairment in both defeated susceptible and IP3R2-null mutant mice. CONCLUSIONS: Overall, our study provides compelling evidence that ATP level in the mPFC is critically involved in regulating depressive-like behavior in a pathway-specific manner. These results shed new light on the mechanisms underlying depression and the antidepressant effect of ATP.

Clinical and Therapeutic Factors Vary by Prognosis in Patients with Pathological Complete Response After Neoadjuvant Therapy for Breast Cancer.

PURPOSE: To determine clinical predictors of recurrence and metastasis in patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NCT). METHODS: Patients treated with NCT who achieved pCR (n=285) were classified into three groups according to pre-NCT clinical stage (cStage): group I (IIa-IIb), group II (IIIa), and group III (IIIb-IIIc). Survival was analysed using the Kaplan-Meier method. The relationships between clinicopathological factors and recurrence were determined using Cox regression analysis. RESULTS: The median follow-up was 31 months. The 3-year disease-free survival and overall survival rates in groups I, II, and III were 92.7%, 87.8%, and 66.7% (P < 0.01) and 98.6%, 98.3%, and 90.6% (P=0.370), respectively. Lymph node status and tumour size were independent risk factors for recurrence and metastasis after NCT. In the human epidermal growth factor receptor 2-positive subgroup, advanced cStage and lymph node metastasis were associated with recurrence (P < 0.01). In the hormone receptor-positive subgroup, disease-free survival rates differed for cStages I-II compared to cStage III (P=0.049) and clinical node status 0-2 compared to clinical node status 3 (P=0.037). CONCLUSION: Pre-NCT cStage predicted the prognosis of pCR for different breast cancer subtypes. Patients with advanced cStage, lymph node metastasis, and large tumour sizes had a higher risk of recurrence or metastasis.

Upregulated NMDAR-mediated GABAergic transmission underlies autistic-like deficits in Htr3a knockout mice.

Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven γ-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV+) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV+ interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism.

Application of conventional ultrasonography combined with contrast-enhanced ultrasonography in the axillary lymph nodes and evaluation of the efficacy of neoadjuvant chemotherapy in breast cancer patients.

OBJECTIVE: Axillary lymph node status assessment has always been an important issue in clinical treatment of breast cancer. However, there has been no effective method to accurately predict the pathological complete response (pCR) of axillary lymph node after neoadjuvant chemotherapy (NAC). The objective of our study was to investigate whether conventional ultrasonography combined with contrast-enhanced ultrasonography (CEUS) can be used to evaluate axillary lymph node status of breast cancer patients after NAC. METHODS: A total of 74 patients who underwent NAC were recruited for the present study. Prior to and after NAC, examinations of conventional ultrasonography and CEUS were performed. After evaluating the images of conventional ultrasonography, four characteristics were recorded: lymph node medulla boundary, cortex of lymph node, lymph node hilus, and lymph node aspect ratio. Two additional imaging characteristics of CEUS were analyzed: CEUS way and CEUS pattern. Receiver operating characteristiccurve analysis was applied to evaluate their diagnostic performance. RESULTS: After 6~8 cycles of NAC, 46 (71.9%) patients had negative axillary lymph node, and 18 (28.1%) patients turned out non-pCR. According to statistical analysis, lymph node medulla, lymph node aspect ratio and CEUS way were independently associated with pCR of axillary lymph node after NAC. The area under the curve of the prediction model with three imaging characteristics was 0.882 (95% confidence interval: 0.608-0.958), and the accuracy to predict the patients' lymph node status was 78.1% (p < 0.01). CONCLUSIONS: Conventional ultrasonography combined with CEUS technology can accurately predict axillary lymph nodes status of breast cancer patients after NAC. ADVANCES IN KNOWLEDGE: The usefulness of CEUS technology in predicting pCR after neoadjuvant chemotherapy is highlighted.

Clinical Significance of Oncoplastic Breast-Conserving Surgery and Application of Volume-Displacement Technique.

ABSTRACT: Oncoplastic breast-conserving surgery for breast cancer has been continuously developing in recent years, and it has become an important part of breast cancer surgery. Its safety and aesthetics have been widely recognized by domestic and foreign experts. However, due to the complexity and diversity of individuals and diseases, and the need for integrating the thinking of breast surgery and plastic surgery, it is still a challenge for breast surgeons. This review summarizes the pros and cons of its clinical application through a comprehensive discussion of hot issues in oncoplastic breast-conserving surgery and introduces common volume-displacement techniques in the clinic for reference by doctors in daily work.