Ion association behaviors in the initial stage of calcium carbonate formation: An ab initio study.

In this work, we performed static density functional theory calculations and ab initio metadynamics simulations to systematically investigate the association mechanisms and dynamic structures of four kinds of ion pairs that could be formed before the nucleation of CaCO3. For Ca2+-HCO3- and Ca2+-CO32- pairs, the arrangement of ligands around Ca2+ evolves between the six-coordinated octahedral structure and the seven-coordinated pentagonal bipyramidal structure. The formation of ion pairs follows an associative ligand substitution mechanism. Compared with HCO3-, CO32- exhibits a stronger affinity to Ca2+, leading to the formation of a more stable precursor phase in the prenucleation stage, which promotes the subsequent CaCO3 nucleation. In alkaline environments, excessive OH- ions decrease the coordination preference of Ca2+. In this case, the formation of Ca(OH)+-CO32- and Ca(OH)2-CO32- pairs favors the dissociative ligand substitution mechanism. The inhibiting effects of OH- ion on the CaCO3 association can be interpreted from two aspects, i.e., (1) OH- neutralizes positive charges on Ca2+, decreases the electrostatic interactions between Ca2+ and CO32-, and thus hinders the formation of the CaCO3 monomer, and (2) OH- decreases the capacity of Ca2+ for accommodating O, making it easier to separate Ca2+ and CO32- ions. Our findings on the ion association behaviors in the initial stage of CaCO3 formation not only help scientists evaluate the impact of ocean acidification on biomineralization but also provide theoretical support for the discovery and development of more effective approaches to manage undesirable scaling issues.

Associations between adverse childhood experiences and pain in middle-aged and older adults: findings from the China Health and Retirement Longitudinal Study.

OBJECTIVE: Adverse childhood experiences (ACEs) have been associated with a range of adverse health outcomes, with pain being potentially one of them. This population-based cross-sectional study aimed to investigate the associations between Adverse Childhood Experiences (ACEs) and pain in Chinese adults and evaluate whether physical activity and demographic and socioeconomic characteristics modify this associations. METHODS: Cross-sectional data from the China Health and Retirement Longitudinal Study (CHARLS), were utilized in this study. A total of 9923 respondents with information on 12 ACE indicators and 15 self-reported body pains were included. Logistic regression models were used to assess associations of the ACEs and pain. Modification of the associations by physical activity, demographic and socioeconomic characteristics was assessed by stratified analyses and tests for interaction. RESULTS: Among the 9923 individuals included in the primary analyses, 5098 (51.4%) males and the mean (SD) age was 61.18 (10·.44) years. Compared with individuals with 0 ACEs, those who with ≥ 5 ACEs had increased risk of single pains and multiple pain. A dose-response association was found between the number of ACEs and the risk of pain (e.g. neck pain for ≥ 5 ACEs vs. none: OR, 1.107; 95% CI, 0.903-1.356; p < 0.001 for trend). In the associations of each body pain with each ACE indicator, most ACE indicators were associated with an increased risk of pain. In addition, physical activity, sociodemographic and socioeconomic characteristics, such as age, sex, educational level, area of residence, childhood economic hardship, did not demonstrate a significant modify on the associations between ACEs and pain. CONCLUSIONS: These findings indicate that cumulative ACE exposure is associated with increased odds of self-reported pain in Chinese adults, regardless of adult physical activity, sociodemographic and socioeconomic characteristics.

Label-free proteomic analysis reveals the hepatoprotective mechanism of gypenosides in liver injury rats.

Chronic liver disease, a long-term condition resulting from various causes such as alcohol abuse, metabolic disorders, and viral hepatitis, is becoming a significant global health challenge. Gypenosides (GPs), derived from the traditional Chinese medicine Gynostemma pentaphyllum (Thunb.) Makino, exhibited hepatoprotective properties in recent years, yet the precise therapeutic mechanism remains unclear. In this study, label-free and parallel reaction monitoring (PRM) proteomics were used to elucidate the hepatoprotective mechanism of GPs in liver injury rats. Through label-free proteomics, we identified 2104 differentially expressed proteins (DEPs) associated with liver injury, along with 1974 DEPs related to the effects of GPs. Bioinformatics analysis revealed that GPs primarily restored metabolic processes involving valine, leucine, and isoleucine degradation, as well as propanoate and butanoate metabolism, and steroid hormone biosynthesis during liver injury. Subsequently, overlapping the two groups of DEPs identified 1508 proteins reversed following GPs treatment, with key targets further validated by PRM. Eight target proteins were identified for GPs treatment of liver injury, including Lgals3, Psat1, Phgdh, Cyp3a9, Cyp2c11, Cyp4a2, Glul, and Ces1d. These findings not only elucidated the hepatoprotective mechanism of GPs, but may also serve as potential therapeutic targets of chronic liver disease.

Signature identification based on immunogenic cell death-related lncRNAs to predict the prognosis and immune activity of patients with endometrial carcinoma.

Background: Endometrial carcinoma (EC) is one of the most prevalent gynecologic malignancies and requires further classification for treatment and prognosis. Long non-coding RNAs (lncRNAs) and immunogenic cell death (ICD) play a critical role in tumor progression. Nevertheless, the role of lncRNAs in ICD in EC remains unclear. This study aimed to explore the role of ICD related-lncRNAs in EC via bioinformatics and establish a prognostic risk model based on the ICD-related lncRNAs. We also explored immune infiltration and immune cell function across prognostic groups and made treatment recommendations. Methods: A total of 552 EC samples and clinical data of 548 EC patients were extracted from The Cancer Genome Atlas (TCGA) database and University of California Santa Cruz (UCSC) Xena, respectively. A prognostic-related feature and risk model was developed using the least absolute shrinkage and selection operator (LASSO). Subtypes were classified with consensus cluster analysis and validated with t-Distributed Stochastic Neighbor Embedding (tSNE). Kaplan-Meier analysis was conducted to assess differences in survival. Infiltration by immune cells was estimated by single sample gene set enrichment analysis (ssGSEA), Tumor IMmune Estimation Resource (TIMER) algorithm. Quantitative polymerase chain reaction (qPCR) was used to detect lncRNAs expression in clinical samples and cell lines. A series of studies was conducted in vitro and in vivo to examine the effects of knockdown or overexpression of lncRNAs on ICD. Results: In total, 16 ICD-related lncRNAs with prognostic values were identified. Using SCARNA9, FAM198B-AS1, FKBP14-AS1, FBXO30-DT, LINC01943, and AL161431.1 as risk model, their predictive accuracy and discrimination were assessed. We divided EC patients into high-risk and low-risk groups. The analysis showed that the risk model was an independent prognostic factor. The prognosis of the high- and low-risk groups was different, and the overall survival (OS) of the high-risk group was lower. The low-risk group had higher immune cell infiltration and immune scores. Consensus clustering analysis divided the samples into four subtypes, of which cluster 4 had higher immune cell infiltration and immune scores. Conclusions: A prognostic signature composed of six ICD related-lncRNAs in EC was established, and a risk model based on this signature can be used to predict the prognosis of patients with EC.

Identification of predictive markers of Pneumocystis jirovecii pneumonia in kidney transplant recipients.

BACKGROUND: Kidney transplantation has emerged as the most effective treatment for patients with uremia. Advances in immunosuppressant medications have significantly reduced the risk of rejection. However, a notable increase in opportunistic infections, such as Pneumocystis jirovecii pneumonia (PJP), demands special attention in clinical practice. Our study aims to evaluate risk factors and identify predictive markers associated with PJP in kidney transplantation recipients. METHODS: We conducted a case-control study (1:2 ratio) involving kidney transplant recipients with and without PJP, matched based on the same surgical date. The study was carried out at Zhongnan Hospital of Wuhan University, China. RESULTS: Ninety-three participants were enrolled at Zhongnan Hospital of Wuhan University, comprising 31 with PJP and 62 without PJP. All patients tested negative for HIV. Our findings indicate that PJP patients exhibited lower levels of serum albumin (P = 0.001), reduced counts of total and CD3+ (P < 0.001), CD4+ (P = 0.001), and CD8+ T lymphocytes (P < 0.001), and a lower rate of prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) usage compared to non-PJP patients (P = 0.02). Conversely, urea levels in PJP patients were significantly higher than in non-PJP controls (P < 0.001). We developed a model combining CD8+ T cell count (< 241.11/µL, P < 0.001) and ALB levels (< 35.2 g/L, P = 0.003), which demonstrated excellent discriminatory power in distinguishing PJP from non-PJP cases, with an area under the curve (AUC) of 0. 920 (95% CI, 0.856-0.989). CONCLUSIONS: Our study suggests that a baseline CD8+ T cell count (< 241.11/µL) and serum ALB levels (< 35.2 g/L) offer robust predictive value for the occurrence of PJP infections in kidney transplant recipients.

Efficient Ozone Elimination Over MnO2 via Double Moisture-Resistance Protection of Active Carbon and CeO2.

The widespread ozone (O3) pollution is extremely hazardous to human health and ecosystems. Catalytic decomposition into O2 is the most promising method to eliminate ambient O3, while the fast deactivation of catalysts under humid conditions remains the primary challenge for their application. Herein, we elaborately developed a splendidly active and stable Mn-based catalyst with double hydrophobic protection of active carbon (AC) and CeO2 (CeMn@AC), which possessed abundant interfacial oxygen vacancies and excellent desorption of peroxide intermediates (O22-). Under extremely humid (RH = 90%) conditions and a high space velocity of 1200 L h-1 g-1, the optimized CeMn@AC achieved nearly 100% O3 conversion (140 h) at 5 ppm, showing unprecedented catalytic activity and moisture resistance toward O3 decomposition. In situ DRIFTS and theory calculations confirmed that the exceptional moisture resistance of CeMn@AC was ascribed to the double protection effect of AC and CeO2, which cooperatively prevented the competitive adsorption of H2O molecules and their accumulation on the active sites of MnO2. AC provided a hydrophobic reaction environment, and CeO2 further alleviated moisture deterioration of the MnO2 particles exposed on the catalyst surface via the moisture-resistant oxygen vacancies of MnO2-CeO2 crystal boundaries. This work offers a simple and efficient strategy for designing moisture-resistant materials and facilitates the practical application of the O3 decomposition catalysts in various environments.

Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.

BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression. METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS. RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice. LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored. CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.

Identification of a gene expression signature of vascular invasion and recurrence in stage I lung adenocarcinoma via bulk and spatial transcriptomics.

Microscopic vascular invasion (VI) is predictive of recurrence and benefit from lobectomy in stage I lung adenocarcinoma (LUAD) but is difficult to assess in resection specimens and cannot be accurately predicted prior to surgery. Thus, new biomarkers are needed to identify this aggressive subset of stage I LUAD tumors. To assess molecular and microenvironment features associated with angioinvasive LUAD we profiled 162 resected stage I tumors with and without VI by RNA-seq and explored spatial patterns of gene expression in a subset of 15 samples by high-resolution spatial transcriptomics (stRNA-seq). Despite the small size of invaded blood vessels, we identified a gene expression signature of VI from the bulk RNA-seq discovery cohort (n=103) and found that it was associated with VI foci, desmoplastic stroma, and high-grade patterns in our stRNA-seq data. We observed a stronger association with high-grade patterns from VI+ compared with VI- tumors. Using the discovery cohort, we developed a transcriptomic predictor of VI, that in an independent validation cohort (n=60) was associated with VI (AUROC=0.86; p=5.42×10-6) and predictive of recurrence-free survival (HR=1.98; p=0.024), even in VI- LUAD (HR=2.76; p=0.003). To determine our VI predictor's robustness to intra-tumor heterogeneity we used RNA-seq data from multi-region sampling of stage I LUAD cases in TRACERx, where the predictor scores showed high correlation (R=0.87, p<2.2×10-16) between two randomly sampled regions of the same tumor. Our study suggests that VI-associated gene expression changes are detectable beyond the site of intravasation and can be used to predict the presence of VI. This may enable the prediction of angioinvasive LUAD from biopsy specimens, allowing for more tailored medical and surgical management of stage I LUAD.

Image recovery method for underwater targets with complex polarization characteristics.

Polarization imaging techniques have been effective in improving the clarity of turbid underwater images affected by water scattering. These techniques offer valuable additional information compared to traditional methods. However, previous descattering methods have mostly been designed for targets with uniform distribution of polarimetric characteristics. Therefore, targets with complex polarization characteristics have non-uniform distribution of polarization characteristics when dealing with such problems, additional parameter estimation errors can limit the results of image recovery. This paper proposes what we believe is a novel approach to address this issue. The method involves obtaining a new set of images using the polarization images vector space transformation method. The angle of polarization (AOP) of the target reflected light is estimated using the additivity law of the Stokes vector. This information is then combined with the physical model of underwater imaging to recover the underwater images affected by scattering. Experimental results conducted under varying levels of water turbidity validate the effectiveness of the proposed method. Moreover, the proposed method significantly broadens the range of application scenarios.

Innate lymphoid cell-based immunomodulatory hydrogel microspheres containing Cutibacterium acnes extracellular vesicles for the treatment of psoriasis.

Psoriasis is a chronic skin inflammation influenced by dysregulated skin microbiota, with the role of microbiota in psoriasis gaining increasing prominence. Bacterial extracellular vesicles (bEVs) serve as crucial regulators in the interaction between hosts and microbiota. However, the mechanism underlying the therapeutic potential of bEVs from commensal bacteria in psoriasis remains unclear. Here, we investigated the therapeutic role of Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs) in psoriasis treatment. To prolong the active duration of CA-EVs, we encapsulated them in gelatin methacrylate (GelMA) to fabricate hydrogel microspheres (CA-EVs@GHM) with sustained release properties. As GelMA degraded, CA-EVs were gradually released, maintaining a high concentration in mouse skin even 96 h post-treatment. In human keratinocyte cells (HaCaT), CA-EVs@GHM enhanced resistance to Staphylococcus aureus (S. aureus), promoted proliferation and migration of HaCaT cells exposed to S. aureus, and significantly reduced the expression of inflammatory genes such as interleukin (IL)-6 and C-X-C motif chemokine ligand 8 (CXCL8). In vivo, CA-EVs@GHM, more potent than CA-EVs alone, markedly attenuated proinflammatory gene expression, including tumor necrosis factor (TNF), Il6, Il17a, Il22 and Il23a in imiquimod (IMQ)-induced psoriasis-like mice, and restored skin barrier function. 16S rRNA sequencing revealed that CA-EVs@GHM might provide therapeutic effects against psoriasis by restoring microbiota diversity on the back skin of mice, reducing Staphylococcus colonization, and augmenting lipid metabolism. Furthermore, flow cytometry analysis showed that CA-EVs@GHM prevented the conversion of type 2 innate lymphoid cells (ILC2) to type 3 innate lymphoid cells (ILC3) in psoriasis-like mouse skin, reducing the pathogenic ILC3 population and suppressing the secretion of IL-17 and IL-22. In summary, our findings demonstrate that the long-term sustained release of CA-EVs alleviated psoriasis symptoms by controlling the transformation of innate lymphoid cells (ILCs) subgroups and restoring skin microbiota homeostasis, thus offering a promising therapy for psoriasis treatment. STATEMENT OF SIGNIFICANCE: Cutibacterium acnes, which is reduced in psoriasis skin, has been reported to promote skin homeostasis by regulating immune balance. Compared to live bacteria, bacterial extracellular vesicles (bEVs) are less prone to toxicity and safety concerns. bEVs play a pivotal role in maintaining bacterial homeostasis and modulating the immune system. However,bEVs without sustained release materials are unable to function continuously in chronic diseases. Therefore, we utilized hydrogel microspheres to encapsulate Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs), enabling long term sustained release. Our findings indicate that, CA-EVs loaded gelatin methacrylate hydrogel microspheres (CA-EVs@GHM) showed superior therapeutic effects in treating psoriasis compared to CA-EVs. CA-EVs@GHM exhibited a more significant regulation of pathological type 3 innate lymphoid cells (ILC3) and skin microbiota, providing a promising approach for microbiota-derived extracellular vesicle therapy in the treatment of skin inflammation.

Evaluation of hair transplantation for improving unnatural hairlines after laser hair removal: A multicenter retrospective study.

CONTEXT: Laser hair removal treatment for hairlines with an unsatisfactory appearance often leads to an unnatural appearance; however, few studies have reported treatment outcomes. OBJECTIVE: To explore the satisfaction rate of laser hair removal involving the hairline. DESIGN: Retrospective analysis. SETTING: Data from 5 clinical institutions. PATIENTS: Patients (915; 630 female and 285 male) who underwent laser hair removal. INTERVENTIONS: Issues associated with hair removal were classified, and their proportions were calculated. Hair transplantation was performed to improve the appearance of different hairline issues. MAIN OUTCOME MEASURES: Relevant indicators of hair transplantation and postoperative effects. RESULTS: Overall, 82 patients were unsatisfied with their hairline appearance; of these patients, 58 underwent hair transplantation to improve the hairline. Additionally, demographic statistics showed that 68% and 32% of patients were in the 20 to 30 and 30 to 40 years age groups, respectively; there were no patients in the 40 to 50 years age group. Among female patients who underwent hair transplantation, 25% had a poor hairline position, 64% had a stiff hairline appearance, and 11% experienced both issues. Among male patients, 50% had a stiff hairline appearance, 28% had temporal absence, and 22% experienced both issues. Surgical treatment included moving the hairline forward and rebuilding the frontal curves. All patients were satisfied with hair transplantation outcomes. CONCLUSIONS: Laser hair removal can result in diverse types of unnatural hairlines. Hair transplantation has been proven to effectively improve the aesthetic appearance of the hairline.

SlGAD2 is the target of SlTHM27, positively regulates cold tolerance by mediating anthocyanin biosynthesis in tomato.

Cold stress significantly limits the yield and quality of tomato. Deciphering the key genes related to cold tolerance is important for selecting and breeding superior cold-tolerant varieties. γ-aminobutyric acid (GABA) responds to various types of stress by rapidly accumulating in plant. In this study, glutamic acid decarboxylase (GAD2) was a positive regulator to enhance cold stress tolerance of tomato. Overexpression of SlGAD2 decreased the extent of cytoplasmic membrane damage and increased the endogenous GABA content, antioxidant enzyme activities, and reactive oxygen species (ROS) scavenging capacity in response to cold stress, whereas Slgad2 mutant plants showed the opposite trend. In addition, SlGAD2 induced anthocyanin biosynthesis in response to cold stress by increasing the content of endogenous GABA. Further study revealed that SlGAD2 expression was negatively regulated by the transcription factor SlTHM27. However, the transcript levels of SlTHM27 were repressed under cold stress. Antioxidant enzyme activities, SlGAD2 transcript levels, GABA and anthocyanin contents were significantly increased in Slthm27 mutant plants. Further, our study demonstrated that SlTHM27 decreases SlGAD2-promoted cold resistance in tomato by repressing SlGAD2 transcription. Overall, our results showed that the SlTHM27-SlGAD2 model regulates the cold tolerance in tomato by regulating GABA and anthocyanin.

Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

Risk Factors and Hazards of Recipient-Area Perifollicular Erythema After Hair Transplantation: A Multicenter Retrospective Cohort Study.

BACKGROUND: Recipient-area perifollicular erythema (RPE) may delay graft growth after hair transplantation. However, there is currently a lack of observational clinical studies of RPE. OBJECTIVE: To study the clinical features and risk factors associated with RPE while analyzing its correlation with graft growth. METHODS: We conducted a multicenter retrospective cohort study between June 2020 and January 2023. RESULTS: A total of 1090 participants were included, 178 (16.33%) showed mild RPE, 56 (5.14%) showed moderate RPE, and 10 (0.92%) showed severe RPE. Patients with RPE had severe hair shaft shedding (P < 0.001) and a lower survival rate (P < 0.001) of grafts. Logistic regression analysis showed that folliculitis is a significant risk factor for mild RPE (OR 6.061, 95% CI 3.343-10.991, P < 0.001) and moderate RPE (OR 3.397, 95% CI 1.299-8.882, P = 0.013). Besides, untimely first postoperative hair washing was associated with the development of moderate RPE (OR 0.724, 95% CI 0.553-0.947, P = 0.018) and severe RPE (OR 1.553, 95% CI 1.156-2.086, P = 0.003). CONCLUSION: RPE is a postoperative complication closely related to high hair shaft shedding proportion and low graft survival rate. Both postoperative folliculitis and untimely first postoperative hair washing may induce the occurrence of RPE. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Integrative molecular and spatial analysis reveals evolutionary dynamics and tumor-immune interplay of in situ and invasive acral melanoma.

In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE+/CD163+ macrophages. In vitro and ex vivo experiments further demonstrate that APOE+CD163+ macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.

Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.

BACKGROUND: Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2-BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2-BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate. METHODS: In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2-BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2-BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan-Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2-BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay. RESULTS: By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2-BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2-BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function. CONCLUSION: In conclusion, the study we presented demonstrated that NK cells in ER+/HER2-BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Deep Brain Stimulation Modulates the Visual Pathway to Improve Freezing of Gait in Parkinson's Disease Patients.

OBJECTIVE: To investigate the involvement of the visual cortex in improving freezing of gait (FoG) after subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) patients using whole-brain seed-based functional connectivity. METHODS: A total of 66 PD patients with FoG who underwent bilateral STN-DBS were included in our study. Patients were divided into a FoG responder group and an FoG nonresponder group according to whether FoG improved 1 year after DBS. We compared the differences in clinical characteristics, brain structural imaging, and seed-based functional connectivity between the 2 groups. The locations of active contacts were further analyzed. RESULTS: All PD patients benefited from STN-DBS. No significant differences in the baseline characteristics or brain structures were found between the 2 groups. Seed-based functional connectivity analysis revealed that better connectivity in bilateral primary visual areas was associated with better clinical improvement in FoG (P < 0.05 familywise error corrected). Further analysis revealed that this disparity was associated with the location of the active contacts within the rostral region of the sensorimotor subregion in the FoG responder group, in contrast to the findings in the FoG nonresponder group. CONCLUSIONS: This study suggested that DBS in the rostral region of the STN sensorimotor subregion may alleviate FoG by strengthening functional connectivity in primary visual areas, which has significant implications for guiding surgical strategies for FoG in the future.

Comparing survival outcomes between neoadjuvant and adjuvant chemotherapy within T2N1M0 stage hormone receptor-positive, HER2-negative breast cancer: a retrospective cohort study based on SEER database.

BACKGROUND: Guideline recommendations for the application of neoadjuvant chemotherapy (NACT) in T2N1M0 stage hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer are ambiguous. The debate continues regarding whether NACT or adjuvant chemotherapy (ACT) offers superior survival outcomes for these patients. MATERIALS AND METHODS: Female patients diagnosed with HR + /HER2- breast cancer at T2N1M0 stage between 2010 and 2020, were identified from the Surveillance, Epidemiology, and End Results database and divided into two groups, the NACT group and the ACT group. Propensity score matching (PSM) was utilized to establish balanced cohorts between groups, considering baseline features. Kaplan-Meier (K-M) analysis and the Cox proportional hazards model were executed to assess the efficacy of both NACT and ACT in terms of overall survival (OS) and breast cancer-specific survival (BCSS). A logistic regression model was employed to examine the association between predictive variables and response to NACT. RESULTS: After PSM, 4,682 patients were finally included. K-M curves showed that patients receiving NACT exhibited significantly worse OS and BCSS when compared with patients undergoing ACT. Multivariable Cox analysis indicated that not achieving pathologic complete response (non-pCR) after NACT (versus ACT), was identified as an adverse prognostic factor for OS (HR 1.58, 95% CI 1.36-1.83) and BCSS (HR 1.70, 95% CI 1.44-2. 02). The logistic regression model revealed that low tumor grade independently predicted non-pCR. CONCLUSION: Among T2N1M0 stage HR + /HER2- patients, OS and BCSS of NACT were inferior to ACT. Patients who attained non-pCR after NACT demonstrated significantly worse survival outcomes compared with those who received ACT.

Efficacy and Safety of Gabapentinoids for Acute Herpes Zoster Neuralgia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: This study aimed to systematically evaluate the clinical efficacy of gabapentin and pregabalin in the treatment of acute herpes zoster (HZ) neuralgia, including pain control and the occurrence of adverse effects. METHODS: A systematic computerized search was conducted in October 2023 in PubMed, Embase, Web of Science, Cochrane Library, VIP, CNKI, and Wanfang databases. Data from randomized controlled trials (RCTs) comparing gabapentin analogs for the treatment of acute HZ neuralgia were searched. Endpoints were visual analog scores (Visual Analog Scale) and adverse effects at 1, 2, and 4 weeks. Data from studies that met the inclusion criteria were extracted for meta-analysis and sensitivity analysis using Revman 5.4 and Stata16. RESULTS: The study included 292 patients from 6 RCTs. Of these, 118 were in the gabapentin-treated group, 37 were in the pregabalin-treated group, and 137 were in the placebo-controlled group. The gabapentin group showed superior pain reduction compared with the placebo group ( P < 0.05), but adverse events were more frequent. CONCLUSION: Gabapentin can effectively reduce acute HZ neuralgia in patients. Pregabalin requires additional RCTs to supplement the analysis.

Retinoic acid drives hair follicle stem cell activation via Wnt/ß-catenin signalling in androgenetic alopecia.

BACKGROUND: Depletion or permanent quiescence of the hair follicle stem cell (HFSC) pool underlies pathogenesis in androgenetic alopecia (AGA). Reactivation of quiescent HFSCs is considered an efficient treatment strategy for hair loss. The retinoic acid (RA) is critical to ensure stem cell homeostasis and function. However, little is known about whether RA regulates HFSC homeostasis. We aimed to investigate the impact of RA on HFSC homeostasis and the underlying mechanisms, in order to provide new potential targets for medical therapies of AGA. METHODS: Microdissected hair follicles from the occipital and frontal scalp in AGA were obtained for RNA sequencing analysis and test. The C57BL/6 mice model in telogen was established to investigate the effect of exogenous RA. Miniaturized hair follicles from frontal scalp were incubated with or without RA in hair follicle organ culture to test the effects on hair shaft elongation, hair cycling and HFSC activities. A strategy to characterize the effect of RA on HFSC in primary culture was developed to identify novel mechanisms that control HFSC activation. A clinical study was performed to test the efficacy of RA treatment in AGA patients. RESULTS: RA signalling was inhibited in the course of AGA pathogenesis along with HFSC dysfunction. Hair regeneration was retarded in AGA miniaturized hair follicles with RA deficiency, but they tended to recover after treatment with RA. In addition, RA treatment during the telogen phase facilitated HFSC anagen entry and accelerated hair growth. Mechanistically, RA promoted hair growth by stimulating stem cells via Wnt/ß-catenin signalling and accelerating the transition from a dormant to an activated state. Furthermore, a clinical study suggested that RA has obvious advantages in the early intervention of AGA by reactivating HFSCs. CONCLUSIONS: Our study provides insights into the reactivation of HFSCs in AGA and provides potential targets for medical therapies.