Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy.

Aside from antibodies, peptides show great potential as immune checkpoint inhibitors (ICIs) due to several advantages, such as better tumor penetration and lower cost. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1 (FGL1). Here, we found that LAG-3 expression was higher than programmed cell death protein 1 (PD-1) in multiple human cancers by TCGA databases, and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning, which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II. Subsequently, d-amino acids were introduced to substitute the N- and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1, which restores T cell function in vitro and inhibits tumor growth in vivo. Further, a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1 blocking peptide OPBP-1(8-12), which activates T cell with enhanced proliferation and IFN-γ production. More importantly, LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response. In conclusion, we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function, and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

Alleviative Effect of Rutin on Zearalenone-Induced Reproductive Toxicity in Male Mice by Preventing Spermatogenic Cell Apoptosis and Modulating Gene Expression in the Hypothalamic-Pituitary-Gonadal Axis.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin found in many agricultural products and can cause reproductive disorders, mainly affecting spermatogenesis in male animals. Rutin (RUT) is a natural flavonoid compound recognized for its significant antioxidant, anti-inflammatory and estrogenic properties. The present study aimed to determine the protective role of RUT against ZEN-induced reproductive toxicity in male mice. Twenty-four adult Kunming male mice were divided into four groups: control, RUT (500 mg/kg RUT), ZEN (10 mg/kg ZEN), ZEN + RUT (500 mg/kg RUT + 10 mg/kg ZEN), with six replicates per treatment. The results indicated that RUT mitigated ZEN-induced disruption in spermatogenic cell arrangement, decreased spermatozoa count, and increased sperm mortality in the testes. RUT significantly restored ZEN-induced reduction in T, FSH, LH, and E2 serum levels. Moreover, RUT mitigated ZEN-induced apoptosis by increasing the mRNA expression level of bcl-2, decreasing the mRNA expression level of kiss1-r, and decreasing the protein expression level of caspase 8 in reproductive tissues. These findings indicate the protective role of RUT against ZEN-induced reproductive toxicity in male mice by regulating gonadotropin and testosterone secretions to maintain normal spermatogenesis via the HPG axis, which may provide a new application direction for RUT as a therapeutic agent to mitigate ZEN-induced reproductive toxicity.

Dual targeting of TIGIT and PD-1 with a novel small molecule for cancer immunotherapy.

Immune checkpoint inhibitors have unveiled promising clinical prospects in cancer treatment. Nonetheless, their effectiveness remains restricted, marked by consistently low response rates and affecting only a subset of patients. The co-blockade of TIGIT with PD-1 has exhibited substantial anti-tumor effects. Notably, there is a dearth of reports on small-molecule inhibitors concurrently targeting both TIGIT and PD-1. In this study, we employed Microscale Thermophoresis (MST) to screen our laboratory's existing repository of small molecules. Our findings illuminated Gln(TrT) 's affinity for both TIGIT and PD-1, affirming its potential to effectively inhibit TIGIT/PVR and PD-1/PD-L1 pathways. In vitro co-culture experiments substantiated Gln(TrT)'s proficiency in restoring Jurkat T-cell functionality by blocking both TIGIT/PVR and PD-1/PD-L1 interactions. In the MC38 murine tumor model, Gln(TrT) emerges as a pivotal modulator, promoting the intratumoral infiltration and functional competence of CD8+ T cells. Furthermore, whether used as a monotherapy or in conjunction with radiotherapy, Gln(TrT) substantially impedes MC38 tumor progression, significantly extending the survival of murine subjects.

'There is always good fortune in misfortune to encourage us in coping with difficulties'-The lived experiences of family caregivers of people with dementia during the COVID-19 outbreak in China: A phenomenological study.

AIM: To describe the lived experiences of family caregivers of individuals with dementia during the coronavirus disease (COVID-19) outbreak in China. DESIGN: This study used a descriptive phenomenological research method. METHODS: Between May and September 2021, semi-structured interviews were conducted with 22 family caregivers of people with dementia. Colaizzi's method was used for manual analysis. RESULTS: Qualitative data revealed an overarching experience of finding 'There is always good fortune in misfortune to encourage us in coping with difficulties'. Three themes emerged: family reactions to the COVID-19 outbreak, feeling supported by multiple resources performing respective functions and resilient adaptation to new situations. CONCLUSION: During the COVID-19 outbreak, family caregivers of people living with dementia in China looked for positive aspects among difficulties and experienced corresponding reactions, social support resources and resilient adapted coping styles. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Nurses in China and other countries facing similar pandemic characteristics, cultures or economic development levels, can guide family caregivers to look at family hardships from a positive perspective, develop interventions to rapidly respond to families' reactions after a disaster and help them identify social support resources and form adapted coping styles. IMPACT: We identified the resilience and the positive experiences of Chinese family caregivers of individuals with dementia during the COVID-19 outbreak. The results can inform countries with similar cultures and economic levels, offering measures to support their adaptation to pandemics. REPORTING METHOD: This study followed the COREQ guidelines. PATIENT OR PUBLIC CONTRIBUTION: Family caregivers of people with dementia who met the inclusion criteria and who were interested in sharing their understanding of their experiences, participated in the study.

A study evaluating liquid-based endometrial cytology test and transvaginal ultrasonography as a screening tool for endometrial cancer in 570 postmenopausal women.

OBJECTIVE: To evaluate the combination of transvaginal ultrasonography (TVS) and endometrial cytology test (ECT) as a potential diagnostic strategy for endometrial cancer and endometrial precancerous lesions in postmenopausal patients. METHODS: 570 postmenopausal patients admitted in our hospital due to abnormal bleeding or other symptoms and/or with endometrium thickness over 5 mm on ultrasound. The endometrial thickness was evaluated by TVS. Following obtainment with written consent, all patients underwent ECT, hysteroscopy and then dilatation and curettage (D&C). Cytological sampling was conducted by scratching the uterus cavity using SAP-1 and the samples were prepared as liquid-based smear using SurePath technology. The samples were stained using Papanicolaou method. The correlation between cytological diagnosis and TVS results with the D&C histological diagnosis was analyzed. The WHO classification was used for diagnosis. RESULTS: Sensitivity of ECT, TVS, ECT or TVS positive, ECT and TVS positive to diagnose atypical hyperplasia or worse were estimated at 80.7%, 86.8%, 97.4%, 70.2%, specificity at 94.7%, 20.4%, 17.5%, 88.4%, positive predictive value at 58.2%, 21.1%, 22.8%, 60.2%, negative predictive value at 94.4%, 86.1%, 96.4%, 92.2%, and accuracy at 84.6%, 33.7%, 33.5%, 84.7%, respectively. CONCLUSIONS: Transvaginal ultrasonography and Endometrial cytology test may be regarded as a effective first-line method in endometrial pathology detection in postmenopausal women.

Analysis of the microbiota composition in the genital tract of infertile patients with chronic endometritis or endometrial polyps.

Background: The previous researches show that infertile patients have a higher incidence of endometritis and endometrial polyps, and the occurrence of these two diseases is related to changes in the microbiota of the genital tract. We aim to determine the composition and changing characteristics of the microbiota in the genital tract (especially the endometrium) of infertile patients with chronic endometritis or endometrial polyps, and find the correlation between it and the occurrence of diseases. Methods: This is a prospective study. We collected genital tract biopsy samples from 134 asymptomatic infertile patients receiving assisted reproductive therapy before embryo transfer. Through pathological examination and 16S ribosomal RNA(16S rRNA) sequencing, we determined the distribution of chronic endometritis and endometrial polyps in these patients, as well as their distribution of reproductive tract microorganisms. Results: Compared with the normal control group, the microbial group of reproductive tract in patients with chronic endometritis and endometrial polyps is changed, and there are significant species differences and relative abundance differences in the vagina, cervix and uterine cavity. Lactobacillus, the dominant flora of female genital tract, showed a change in abundance in patients with endometrial diseases. Endometrial microbiota composed of Staphylococcus, Gardnerella, Atopobium, Streptococcus, Peptostreptococcus, Chlamydia, Fusobacterium, Acinetobacter, etc. are related to chronic endometritis and endometrial polyps. Conclusion: The results showed that, compared with the normal control group, the endometrial microbiota of infertile patients with chronic endometritis or endometrial polyps did have significant changes in the relative abundance distribution of species, suggesting that changes in local microecology may be an important factor in the occurrence of disease, or even adverse pregnancy outcomes. The further study of endometrial microecology may provide a new opportunity to further improve the diagnosis and treatment strategy of chronic endometritis.

Major-effect quantitative trait locus qLKR4.1 encodes a phospholipase Dδ protein associated with low-K+ stress tolerance by promoting root length.

KEY MESSAGE: qLKR4.1, controlling low K+ resistance in tomato, was fine-mapped to an interval of 67.5 kb on chromosome A04, and one gene encoding phospholipase Dδ was identified as a candidate gene. In plants, changes in root length are an important morphological response to low K+ (LK) stress; however, the underlying genetics in tomato remain unclear. Here, we combined bulked segregant analysis-based whole-genome sequencing, single-nucleotide polymorphism haplotyping, and fine genetic mapping to identify a candidate gene as a major-effect quantitative trait loci (QTL), i.e., qLKR4.1, which was associated with LK tolerance due to increased root elongation in the tomato line JZ34. Through multiple analyses, we found that Solyc04g082000 is the most likely candidate for qLKR4.1, which encodes phospholipase Dδ (PLDδ). Increased root elongation under LK in JZ34 may be attributed to a non-synonymous single-nucleotide polymorphism in the Ca2+-binding domain region of this gene. Solyc04g082000 increases root length through its PLDδ activity. Silencing of Solyc04g082000Arg in JZ34 led to a significant decrease in root length compared with silencing of Solyc04g082000His allele in JZ18 under LK conditions. Mutation of a Solyc04g082000 homologue in Arabidopsis, pldδ, resulted in decreased primary root lengths under LK conditions, compared to the wild type. Transgenic tomato expressing the qLKR4.1Arg allele from JZ34 exhibited a significant increase in root length compared with the wild type expressing the allele from JZ18 under LK conditions. Taken together, our results confirm that the PLDδ gene Solyc04g082000 exerts important functions in increasing tomato root length and LK tolerance.

Electroacupuncture and human iPSC-derived small extracellular vesicles regulate the gut microbiota in ischemic stroke via the brain-gut axis.

Electroacupuncture (EA) and induced pluripotent stem cell (iPSC)-derived small extracellular vesicles (iPSC-EVs) have substantial beneficial effects on ischemic stroke. However, the detailed mechanisms remain unclear. Here, we explored the mechanisms underlying the regulation of EA and iPSC-EVs in the microbiome-gut-brain axis (MGBA) after ischemic stroke. Ischemic stroke mice (C57BL/6) were subjected to middle cerebral artery occlusion (MCAO) or Sham surgery. EA and iPSC-EVs treatments significantly improved neurological function and neuronal and intestinal tract injury, downregulated the levels of IL-17 expression and upregulated IL-10 levels in brain and colon tissue after cerebral ischemia-reperfusion. EA and iPSC-EVs treatments also modulated the microbiota composition and diversity as well as the differential distribution of species in the intestines of the mice after cerebral ischemia-reperfusion. Our results demonstrated that EA and iPSC-EVs treatments regulated intestinal immunity through MGBA regulation of intestinal microbes, reducing brain and colon damage following cerebral ischemia and positively impacting the outcomes of ischemic stroke. Our findings provide new insights into the application of EA combined with iPSC-EVs as a treatment for ischemic stroke.

Abbreviated Versus Full-Protocol MRI for Breast Cancer Neoadjuvant Chemotherapy Response Assessment: Diagnostic Performance by General and Breast Radiologists.

BACKGROUND. Abbreviated protocols could allow wider adoption of MRI in patients undergoing breast cancer neoadjuvant chemotherapy (NAC). However, abbreviated MRI has been explored primarily in screening settings. OBJECTIVE. The purpose of this article was to compare diagnostic performance of abbreviated MRI and full-protocol MRI for evaluation of breast cancer NAC response, stratifying by radiologists' breast imaging expertise. METHODS. This retrospective study included 203 patients with breast cancer (mean age, 52.1 ± 11.2 [SD] years) from two hospitals who underwent MRI before NAC initiation and after NAC completion before surgical resection from March 2017 to April 2021. Abbreviated MRI was extracted from full-protocol MRI and included the axial T2-weighted sequence and precontrast and single early postcontrast T1-weighted sequences. Three general radiologists and three breast radiologists independently interpreted abbreviated and full-protocol MRI in separate sessions, identifying enhancing lesions to indicate residual tumor and measuring lesion size. The reference standard was presence and size of residual tumor on pathologic assessment of post-NAC surgical specimens. RESULTS. A total of 50 of 203 patients had pathologic complete response (pCR). Intraobserver and interobserver agreement for abbreviated and full-protocol MRI for general and breast radiologists ranged from substantial to nearly perfect (κ = 0.70-0.81). Abbreviated MRI compared with full-protocol MRI showed no significant difference for general radiologists in sensitivity (54.7% vs 57.3%, p > .99), specificity (92.8% vs 95.6%, p = .29), or accuracy (83.4% vs 86.2%, p = .30), nor for breast radiologists in sensitivity (60.0% vs 61.3%, p > .99), specificity (94.6% vs 97.4%, p = .22), or accuracy (86.0% vs 88.5%, p = .30). Sensitivity, specificity, and accuracy were not significantly different between protocols for any reader individually (p > .05). Mean difference in residual tumor size on MRI relative to pathology for abbreviated protocol ranged for general radiologists from -0.19 to 0.03 mm and for breast radiologists from -0.15 to -0.05 mm, and for full protocol ranged for general radiologists from 0.57 to 0.65 mm and for breast radiologists from 0.66 to 0.79 mm. CONCLUSION. Abbreviated compared with full-protocol MRI showed similar intraobserver and interobserver agreement and no significant difference in diagnostic performance. Full-protocol MRI but not abbreviated MRI slightly overestimated pathologic tumor sizes. CLINICAL IMPACT. Abbreviated protocols may facilitate use of MRI for post-NAC response assessment by general and breast radiologists.

Propofol decreases cisplatin resistance of non-small cell lung cancer by inducing GPX4-mediated ferroptosis through the miR-744-5p/miR-615-3p axis.

Non-small cell lung cancer (NSCLC) is associated with high morbidity and mortality. Propofol functions as a tumor-inhibitor drug by regulating microRNAs (miRNAs). The primary objective of this study is to explore the functional mechanism of propofol in cisplatin (Cis) resistance of NSCLC cells by regulating the miR-744-5p/miR-615-3p axis. Cis-resistant NSCLC cell lines were cultured and chemotherapy-resistance (CR) to Cis of NSCLC cells to Cis was confirmed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, flow cytometry, and colony formation assay. Ferroptosis was evaluated by measurement of iron content, ferroptosis-related proteins (GPX4/ ACSL4/SLC7A11) and lipid peroxidation (SOD/GSH/MDA) through Western blot analysis and assay kits. After the dual-luciferase reporter assay to testify gene interactions, the functional rescue experiments and nude mouse tumor formation assay were performed. Based on results, propofol reduced IC50 value and CR of NSCLC cells to Cis and induced ferroptosis. Propofol upregulated miR-744-5p/miR-615-3p to inhibit GPX4 transcription. Upregulation of GPX4 or downregulation of miR-744-5p/miR-615-3p attenuated the inhibitory effect of propofol on CR to Cis. In vivo, propofol inhibited tumor growth and CR to Cis by upregulating miR-744-5p/miR-615-3p and inhibiting GPX4 to induce ferroptosis. In summary, propofol inhibited GPX4-mediated ferroptosis and reduces CR of NSCLC cells to Cis through the miR-744-5p/miR-615-3p axis. SIGNIFICANCE: To study the effect of propofol on chemoresistance of non-small cell lung cancer (NSCLC), and to provide a new theoretical basis for the treatment of NSCLC.

Characteristics and potential diagnostic ability of vaginal microflora in patients with aerobic vaginitis using 16S Ribosomal RNA sequencing.

PURPOSE: We aimed to explore the possible function of guiding dominant microflora for aerobic vaginitis (AV) women patients in China to know its diagnostic ability for the further clinical application. METHOD: The characteristics and community compositions of AV vaginal microbiota was evaluated by high-throughput 16S ribosomal RNA (16S rRNA) sequencing after the vaginal microecology evaluations. RESULTS: The increased colonization of Streptococcus agalactiae and Streptococcus anginosus and the absence of Lactobacillus are typical manifestations of AV patients. In addition, Lactobacillus were the major correlated bacteria with control groups of Modified Donders' Score under 3. Most of the significant KEGG pathways were classified into metabolism pathway, where the two bacteria behaved their own metabolism characteristics. CONCLUSION: The increased colonizations of Streptococcus agalactiae and Streptococcus anginosus and the absences of Lactobacillus are the typical manifestations of AV.

Nomogram for the prediction of triple-negative breast cancer histological heterogeneity based on multiparameter MRI features: A preliminary study including metaplastic carcinoma and non- metaplastic carcinoma.

Objectives: Triple-negative breast cancer (TNBC) is a heterogeneous disease, and different histological subtypes of TNBC have different clinicopathological features and prognoses. Therefore, this study aimed to establish a nomogram model to predict the histological heterogeneity of TNBC: including Metaplastic Carcinoma (MC) and Non-Metaplastic Carcinoma (NMC). Methods: We evaluated 117 patients who had pathologically confirmed TNBC between November 2016 and December 2020 and collected preoperative multiparameter MRI and clinicopathological data. The patients were randomly assigned to a training set and a validation set at a ratio of 3:1. Based on logistic regression analysis, we established a nomogram model to predict the histopathological subtype of TNBC. Nomogram performance was assessed with the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve. According to the follow-up information, disease-free survival (DFS) survival curve was estimated using the Kaplan-Meier product-limit method. Results: Of the 117 TNBC patients, 29 patients had TNBC-MC (age range, 29-65 years; median age, 48.0 years), and 88 had TNBC-NMC (age range, 28-88 years; median age, 44.5 years). Multivariate logistic regression analysis demonstrated that lesion type (p = 0.001) and internal enhancement pattern (p = 0.001) were significantly predictive of TNBC subtypes in the training set. The nomogram incorporating these variables showed excellent discrimination power with an AUC of 0.849 (95% CI: 0.750-0.949) in the training set and 0.819 (95% CI: 0.693-0.946) in the validation set. Up to the cutoff date for this analysis, a total of 66 patients were enrolled in the prognostic analysis. Six of 14 TNBC-MC patients experienced recurrence, while 7 of 52 TNBC-NMC patients experienced recurrence. The DFS of the two subtypes was significantly different (p=0.035). Conclusions: In conclusion, we developed a nomogram consisting of lesion type and internal enhancement pattern, which showed good discrimination ability in predicting TNBC-MC and TNBC-NMC.

Accurate 16S Absolute Quantification Sequencing Revealed Vaginal Microecological Composition and Dynamics During Mixed Vaginitis Treatment With Fufang FuRong Effervescent Suppository.

Background: The diagnosis and treatment of mixed vaginitis are more complicated than single pathogenic infections, and there may be adverse reactions and several contraindications to conventional antibiotic therapy. Therefore, this study aimed to evaluate the preliminary effects of Fufang Furong Effervescent Suppository for the management of aerobic vaginitis (AV) mixed with bacterial vaginosis (BV) using Accurate 16S absolute quantification sequencing (Accu16S). Methods: In the present randomized, blind, multi-center clinical trial, women (20 to 55 years) who had received a diagnosis of AV+BV were randomly assigned into clindamycin positive control (n = 41) and Fufang Furong Effervescent Suppository (n = 39) groups. The follow-up occurred in three time periods (V1: -2~0 days; V2: 15-17 days; V3: 40 ± 3 days). At each visit, two vaginal swabs, one for clinical evaluation and one for laboratory examination, were taken from each patient. The Nugent score, Donders' score, drug-related complications, recurrence rates, and microecological changes of vaginal swabs were assessed in the time three periods. Results: At baseline, the two groups were similar in frequency of presentation with vaginal burning, odor, abnormal discharge, and itching. No meaningful differences in Nugent and Donders' scores were detected between the two groups at stage V2 (Nugent: p = 0.67; Donders': p = 0.85) and V3 (Nugent: p = 0.97; Donders: p = 0.55). The Furong group presented fewer complications compared to the Clindamycin group. However, this difference was not statistically significant (p = 0.15). Additionally, Accu16S indicated that the total abundance of bacteria in both groups sharply decreased in stage V2, but slightly increased in V3. In stage V3, the absolute abundance of Lactobacillus in the Furong group was considerably higher compared to untreated samples (p < 0.05). On the other hand, no momentous increase was detected in the Clindamycin group (p > 0.05). Conclusion: Fufang Furong Effervescent Suppository can be as effective as clindamycin cream in the management of AV+BV while may restore the vagina microecosystem better.

Evaluation of the Effects of Anti-PD-1 Therapy on Triple-Negative Breast Cancer in Mice by Diffusion Kurtosis Imaging and Dynamic Contrast-Enhanced Imaging.

BACKGROUND: The monitoring of immunotherapies is still based on changes in the tumor size in imaging, with a long evaluation period and low sensitivity. PURPOSE: To investigate the effectiveness of diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the therapeutic efficacy of anti-programmed death-1 (PD-1) therapy in a mouse triple negative breast cancer (TNBC) model. STUDY TYPE: Prospective. ANIMAL MODEL: A total of 54 BALB/c mouse subcutaneous 4 T1 transplantation models of TNBC. FIELD STRENGTH/SEQUENCE: A 3.0-T; turbo spin echo (TSE) T2-weighted imaging, DKI with seven b values (0, 500, 1000, 1500, 2000, 2500, and 3000 sec/mm2 ) and T1-twist DCE acquisition series. ASSESSMENT: DKI and DCE-MRI parameters were evaluated by two radiologists independently. Regions of interest (ROIs) were drawn manually on the maximum cross-sectional area of the lesion; care was taken to avoid necrotic areas. The tumor cell density, the CD45 and CD31 levels were analyzed by two pathologists. STATISTICAL TESTS: The two-tailed unpaired t-test, Mann-Whitney U test, Fisher's exact test and Pearson correlation coefficient were performed. A P < 0.05 was considered statistically significant. RESULTS: The apparent diffusion coefficient (ADC), mean diffusivity (MD), Ktrans and Kep values were significantly different between the two groups at each time point after treatment. There were significant differences in the mean kurtosis (MK) and Ve values between the two groups at 5 and 10 days after treatment but no significant differences at 15 days (P = 0.317 and 0.183, respectively). The ADC and MD values were significantly correlated with tumor cell density (ADC, r = -0.833; MD, r = 0.890) and the CD45 level (ADC, r = 0.720; MD, r = 0.718). The Ktrans and Kep values were significantly correlated with the CD31 level (Ktrans , r = 0.820; Kep , r = 0.683). DATA CONCLUSION: DKI and DCE-MRI could reflect the changes in tumor microstructure and tumor tissue vasculature after anti-PD-1 therapy, respectively. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 4.

Therapeutic Potential of a Combination of Electroacupuncture and Human iPSC-Derived Small Extracellular Vesicles for Ischemic Stroke.

This paper aimed to explore the roles of the combination of electroacupuncture (EA) and induced pluripotent stem cell-derived small extracellular vesicles (iPSC-EVs) on mice with ischemic stroke and the underlying mechanisms. A focal cerebral ischemia model was established in C57BL/6 mice through middle cerebral artery occlusion (MCAO). After 3 days, neurological impairment and motor function were examined by performing behavioral tests. The infarct volume and neuronal apoptosis were examined using TTC staining and TUNEL assays. Flow cytometry was performed to assess the proliferation of T lymphocytes. The changes in the interleukin (IL)-33/ST2 axis were evaluated by immunofluorescence and Western blotting. The combination of EA and iPSC-EVs treatment ameliorated neurological impairments and reduced the infarct volume and neuronal apoptosis in MCAO mice. EA plus iPSC-EVs suppressed T helper (Th1) and Th17 responses and promoted the regulatory T cell (Treg) response. In addition, EA plus iPSC-EVs exerted neuroprotective effects by regulating the IL-33/ST2 axis and inhibiting the microglia and astrocyte activation. Taken together, the study shows that EA and iPSC-EVs exerted a synergistic neuroprotective effect in MCAO mice, and this treatment may represent a novel potent therapy for ischemic stroke and damage to other tissues.

The role of upper and lower genital tract microbiota alterations in term chorionamnionitis: A prospective study.

Objective: This study aimed to compare the dynamics of lower and upper genital tract microbiota in normal term pregnancy, histological chorioamnionitis (HCA), and clinical chorioamnionitis (CCA) patients to provide a reference for the diagnosis and treatment of chorioamnionitis (CAM) patients. Methods: We prospectively collected vaginal and cervical secretions, as well as placenta tissues, fetal membranes, and amniotic fluid from normal-term pregnant women, HCA and CCA patients. Then, we performed genomic DNA extraction and PCR amplification for all samples. The eligible samples were analyzed by 16S ribosomal RNA (16S rRNA) sequencing. Additionally, all placenta tissues were histopathologically examined, and neonatal pharyngeal swabs and placenta tissues from the HCA and CCA groups were subjected to microbial culture. Results: A total of 85 term pregnant women were enrolled in this study, including 34 in the normal group (N), 37 in the HCA group, and 14 in the CCA group. A total of 171 qualified samples were analyzed by 16S rRNA sequencing. The results suggested that the cervical microbiota was highly similar to the vaginal microbiota in normal term parturients, with Lactobacillus as the dominant bacterium. Moreover, there was no difference in the alpha and beta diversity of vaginal microbiota between the N, HCA, and CCA groups at the genus level. Besides, no significant differences were detected in cervical microbiome among the three groups. Regarding intrauterine microorganisms, the N and HCA groups had similar microbial composition but were different from the CCA group. No microbe was detected in the placental tissue of normal term parturients, while some microorganisms were found in the intrauterine amniotic fluid and fetal membrane samples. Regardless of cultivation or 16S rRNA sequencing, an extremely low microbial positive rate was detected in HCA and CCA intrauterine samples. Compared to the normal group, Lactobacillus was significantly reduced in the CCA group intrauterine, and Ureaplasma and Enterococcus increased with no statistically significant. Conclusion: The N, HCA and CCA groups had similar composition of vaginal and cervical microflora. Some normal-term pregnant women can harbor non-pathogenic microbiota in the uterine cavity. Sterile inflammation is more frequent than microbial-associated inflammation in term HCA and CCA parturients.

Portable Pulsed Coherent Lidar for Noncooperation Targets at the Few-Photon Level.

The decoherence in coherent lidar becomes serious with the increase in distance. A small laser spot can suppress the decoherence of the echo light from noncooperation targets. However, it is very difficult to keep a small light spot over a long distance. In this paper, a pulsed coherent lidar with high sensitivity at the few-photon level was demonstrated. A phase plate was used to modulate the wavefront of the laser to achieve 100 m focusing which reduced the decoherence effect. Based on coherent detection and time-of-flight (TOF) measurements, long-distance laser ranging and imaging on all days was realized. A signal classification and superposition method was used to extract the echo signal submerged in noise. The system was experimentally demonstrated by ranging different noncooperation targets within 105.0 m. The measurement rate was 10 k/s, and the measurement uncertainty was 1.48 cm. In addition, laser imaging was realized at ~50.0 m. The system was simple and portable as well as eye safe, and it may offer new application possibilities in automated vehicle lidar.

Deep Neural Networks Offer Morphologic Classification and Diagnosis of Bacterial Vaginosis.

Bacterial vaginosis (BV) is caused by the excessive and imbalanced growth of bacteria in vagina, affecting 30 to 50% of women. Gram staining followed by Nugent scoring based on bacterial morphotypes under the microscope is considered the gold standard for BV diagnosis; this method is often labor-intensive and time-consuming, and results vary from person to person. We developed and optimized a convolutional neural network (CNN) model and evaluated its ability to automatically identify and classify three categories of Nugent scores from microscope images. The CNN model was first established with a panel of microscopic images with Nugent scores determined by experts. The model was trained by minimizing the cross-entropy loss function and optimized by using a momentum optimizer. The separate test sets of images collected from three hospitals were evaluated by the CNN model. The CNN model consisted of 25 convolutional layers, 2 pooling layers, and a fully connected layer. The model obtained 82.4% sensitivity and 96.6% specificity with the 5,815 validation images when altered vaginal flora and BV were considered the positive samples, which was better than the rates achieved by top-level technologists and obstetricians in China. The capability of our model for generalization was so strong that it exhibited 75.1% accuracy in three categories of Nugent scores on the independent test set of 1,082 images, which was 6.6% higher than the average of three technologists, who are hold bachelor's degrees in medicine and are qualified to make diagnostic decisions. When three technologists ran one specimen in triplicate, the precision of three categories of Nugent scores was 54.0%. One hundred three samples diagnosed by two technologists on different days showed a repeatability of 90.3%. The CNN model outperformed human health care practitioners in terms of accuracy and stability for three categories of Nugent score diagnosis. The deep learning model may offer translational applications in automating diagnosis of bacterial vaginosis with proper supporting hardware.

Prebiotic Maltose Gel Can Promote the Vaginal Microbiota From BV-Related Bacteria Dominant to Lactobacillus in Rhesus Macaque.

The high incidence of bacterial vaginosis recurrence is common after treatment with an antibiotic agent and suggests the need for new treatments to prevent this. We conducted a randomized trial to evaluate the ability of maltose gel to treat bacterial vaginosis. Eighteen female rhesus macaques were randomly assigned, in a 2:1 ratio, to receive maltose gel or placebo gel by syringe to the fornix of the vagina for five consecutive days. We used 16S rRNA sequencing data from 70 swab samples of vaginal secretions in two groups in total on days 0, 3, and 5 after medication initiation and days 3 and 5 after medication withdrawal for the study of microbiome composition. We found that, in the placebo control group, there was no significant change in the composition and abundance of vaginal microbiota during the follow-up period. In the maltose gel test group, the abundance of Lactobacillus in the vagina microbiota increased gradually with the prolongation of the treatment time on Days 3 and 5 (ANOVA p = 6.99e-5 < 0.01) but began to decrease after the withdrawal of maltose gel, which was different from that of the control group. Correspondingly, the diversity and abundance of BV-related bacteria, Fusobacterium, Parvimonas, Mobiluncus, Campylobacter, Prevotella, and Sneathia, decreased on Day 0 to Day 5 of medication and increased after drug withdrawal in the maltose gel test group. The study confirms that maltose gel can facilitate the proliferation of Lactobacillus and promote the transition of the vaginal microbiota from BV-related bacteria dominant to Lactobacillus dominant in the rhesus macaque.