Drug repositioning with adaptive graph convolutional networks.

MOTIVATION: Drug repositioning is an effective strategy to identify new indications for existing drugs, providing the quickest possible transition from bench to bedside. With the rapid development of deep learning, graph convolutional networks (GCNs) have been widely adopted for drug repositioning tasks. However, prior GCNs based methods exist limitations in deeply integrating node features and topological structures, which may hinder the capability of GCNs. RESULTS: In this study, we propose an adaptive GCNs approach, termed AdaDR, for drug repositioning by deeply integrating node features and topological structures. Distinct from conventional graph convolution networks, AdaDR models interactive information between them with adaptive graph convolution operation, which enhances the expression of model. Concretely, AdaDR simultaneously extracts embeddings from node features and topological structures and then uses the attention mechanism to learn adaptive importance weights of the embeddings. Experimental results show that AdaDR achieves better performance than multiple baselines for drug repositioning. Moreover, in the case study, exploratory analyses are offered for finding novel drug-disease associations. AVAILABILITY AND IMPLEMENTATION: The soure code of AdaDR is available at: https://github.com/xinliangSun/AdaDR.

Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

Recent advances in the contribution of glucosinolates degradation products to cruciferous foods odor: factors that influence degradation pathways and odor attributes.

As one of the most important vegetables and oils consumed globally, cruciferous foods are appreciated for their high nutritional value. However, there is no comprehensive knowledge to sufficiently unravel the "flavor mystery" of cruciferous foods. The present review provides a comprehensive literature on the recent advances regarding the contribution of glucosinolates (GSL) degradation products to cruciferous foods odor, which focuses on key GSL degradation products contributing to distinct odor of cruciferous foods (Brassica oleracea, Brassica rapa, Brassica napus, Brassica juncea, Raphanus sativus), and key factors affecting GSL degradation pathways (i.e., enzyme-induced degradation, thermal-induced degradation, chemical-induced degradation, microwave-induced degradation) during different processing and cooking. A total of 93 volatile GSL degradation products (i.e., 36 nitriles, 33 isothiocyanates, 3 thiocyanates, 5 epithionitriles, and 16 sulfides) and 29 GSL (i.e., 20 aliphatic, 5 aromatic, and 4 indolic) were found in generalized cruciferous foods. Remarkably, cruciferous foods have a distinctive pungent, spicy, pickled, sulfur, and vegetable odor. In general, isothiocyanates are mostly present in enzyme-induced degradation of GSL and are therefore often enriched in fresh-cut or low-temperature, short-time cooked cruciferous foods. In contrast, nitriles are mainly derived from thermal-induced degradation of GSL, and are thus often enriched in high-temperature, long-time cooked cruciferous foods.

Processing and cooking can cause degradation of glucosinolates and formation of volatiles.Structure­odor relationship of glucosinolates degradation products is discussed.Nitriles, isothiocyanates, and sulfides play an important role in cruciferous foods odor.Both enzyme- and thermal-induced degradation of glucosinolates is strongly pH-dependent.

Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene.

BACKGROUND: Mutations in the SLC5A7 gene cause congenital myasthenia, a rare genetic disorder. Mutation points in the SLC5A7 gene differ among individuals and encompass various genetic variations; however, exon deletion variants have yet to be reported in related cases. This study aims to explore the clinical phenotype and genetic traits of a patient with congenital myasthenic syndrome due to SLC5A7 gene variation and those of their family members. CASE PRESENTATION: We describe a case of a Chinese male with congenital myasthenic syndrome presenting fluctuating limb weakness. Genetic testing revealed a heterozygous deletion mutation spanning exons 1-9 in the SLC5A7 gene. QPCR confirmed a deletion in exon 9 of the SLC5A7 gene in the patient's mother and brother. Clinical symptoms of myasthenia improved following treatment with pyridostigmine. CONCLUSION: Exons 1, 5, and 9 of the SLC5A7 gene encode the choline transporter's transmembrane region. Mutations in these exons can impact the stability and plasma membrane levels of the choline transporter. Thus, a heterozygous deletion in exons 1-9 of the SLC5A7 gene could be the pathogenic cause for this patient. In patients exhibiting fluctuating weakness, positive RNS, and seronegativity for myasthenia gravis antibodies, a detailed family history should be considered, and enhanced genetic testing is recommended to determine the cause.

Fossil and Nonfossil Sources of Winter Organic Aerosols in the Regional Background Atmosphere of China.

Carbonaceous aerosols (CA) from anthropogenic emissions have been significantly reduced in urban China in recent years. However, the relative contributions of fossil and nonfossil sources to CA in rural and background regions of China remain unclear. In this study, the sources of different carbonaceous fractions in fine aerosols (PM2.5) from five background sites of the China Meteorological Administration Atmosphere Watch Network during the winter of 2019 and 2020 were quantified using radiocarbon (14C) and organic markers. The results showed that nonfossil sources contributed 44-69% to total carbon at these five background sites. Fossil fuel combustion was the predominant source of elemental carbon at all sites (73 ± 12%). Nonfossil sources dominated organic carbon (OC) in these background regions (61 ± 13%), with biomass burning or biogenic-derived secondary organic carbon (SOC) as the most important contributors. However, the relative fossil fuel source to OC in China (39 ± 13%) still exceeds those at other regional/background sites in Asia, Europe, and the USA. SOC dominated the fossil fuel-derived OC, highlighting the impact of regional transport from anthropogenic sources on background aerosol levels. It is therefore imperative to develop and implement aerosol reduction policies and technologies tailored to both the anthropogenic and biogenic emissions to mitigate the environmental and health risks of aerosol pollution across China.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Identification of AURKA as a Biomarker Associated with Cuproptosis and Ferroptosis in HNSCC.

Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.

The Effect of Salvianolic Acid A on Tumor-Associated Macrophage Polarization and Its Mechanisms in the Tumor Microenvironment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with a high degree of malignancy and poor prognosis. Tumor-associated macrophages (TAMs) have been identified as significant contributors to the growth and metastasis of TNBC through the secretion of various growth factors and chemokines. Salvianolic acid A (SAA) has been shown to have anti-cancer activities. However, the potential activity of SAA on re-polarized TAMs remains unclear. As there is a correlation between the TAMs and TNBC, this study investigates the effect of SAA on TAMs in the TNBC microenvironment. For that purpose, M2 TAM polarization was induced by two kinds of TNBC-conditioned medium (TNBC-TCM) in the absence or presence of SAA. The gene and protein expression of TAM markers were analyzed by qPCR, FCM, IF, ELISA, and Western blot. The protein expression levels of ERK and p-ERK in M2-like TAMs were analyzed by Western blot. The migration and invasion properties of M2-like TAMs were analyzed by Transwell assays. Here, we demonstrated that SAA increased the expression levels of CD86, IL-1ß, and iNOS in M2-like TAMs and, conversely, decreased the expression levels of Arg-1 and CD206. Moreover, SAA inhibited the migration and invasion properties of M2-like TAMs effectively and decreased the protein expression of TGF-ß1 and p-ERK in a concentration-dependent manner, as well as TGF-ß1 gene expression and secretion. Our current findings for the first time demonstrated that SAA inhibits macrophage polarization to M2-like TAMs by inhibiting the ERK pathway and promotes M2-like TAM re-polarization to the M1 TAMs, which may exert its anti-tumor effect by regulating M1/M2 TAM polarization. These findings highlight SAA as a potential regulator of M2 TAMs and the possibility of utilizing SAA to reprogram M2 TAMs offers promising insights for the clinical management of TNBC.

Effects of irradiation on the aging and sensory quality of navel orange distilled spirits.

BACKGROUND: 60 Co-γ irradiation can simulate the effects of aging and enhance the flavor of distilled spirits. The present study aimed to investigate the effects of 0, 2, 4, 6, 8 and 10 kGy 60 Co-γ irradiation doses on the key aroma components in newly produced navel orange distilled spirits and thus determine the mechanism of their aging distilled spirits. RESULTS: The identification of aroma compounds demonstrated that ethyl hexanoate, d-limonene, ethyl octanoate, 3-methyl-1-butanol and linalool are the key aroma compounds in navel orange distilled spirits, which were increased except for linalool with irradiation doses of 2-6 kGy. Irradiation treatment simulated the effects of the aging of navel orange distilled spirits by promoting the content of total acids, total esters and aldehydes. Irradiation doses of 2-6 kGy increased the aroma intensity of navel orange distilled spirits, reaching an optimum at 6 kGy. However, irradiation doses as high as 8 and 10 kGy decreased the content of esters in navel orange distilled spirits, which led to a deterioration of the spirit flavor. CONCLUSION: Low doses of 60 Co-γ irradiation can simulate the effects of the aging by increasing the content of key aromatic compounds in navel orange distilled spirits. © 2023 Society of Chemical Industry.

Purification and characterization of limonin D-ring lactone hydrolase from sweet orange (Citrus sinensis (L.) Osbeck) seeds.

BACKGROUND: Citrus products often suffer from delayed bitterness, which is generated from the conversion of non-bitter precursors (limonoate A-ring lactone, LARL) to limonin under the catalysis of limonin D-ring lactone hydrolase (LDLH). In this study, LDLH was isolated and purified from sweet orange seeds, and a rapid and accurate high-performance liquid chromatography method to quantify LARL was developed and applied to analyze the activity and enzymatic properties of purified LDLH. RESULTS: Purified LDLH (25.22 U mg-1) showed bands of 245 kDa and 17.5 kDa molecular weights in native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate PAGE analysis respectively. After a 24 h incubation under strongly acidic (pH 3) or strongly alkaline (pH 9) conditions, LDLH still retained approximately 100% activity. Moreover, LDLH activity was not impaired by thermal treatment at 50 °C for 120 min. Enzyme inhibition assays showed that LDLH was inactivated only after ethylenediaminetetraacetic acid treatment, and other enzyme inhibitors showed no significant effect on its activity. In addition, the LDLH activity of calcium ion (Ca2+) intervention was 108% of that in the blank group, and that of zinc ion (Zn2+) intervention was 71%. CONCLUSION: LDLH purified in this study was a multimer containing 17.5 kDa monomer with a wide pH tolerance range (pH 3-9) and excellent thermal stability. Moreover, LDLH might be a metallopeptidase, and its activity was stimulated by Ca2+ and significantly inhibited by Zn2+. These findings improve our understanding of LDLH and provide some important implications for reducing the bitterness in citrus products in the future. © 2024 Society of Chemical Industry.

[Applicability of H2FPEF and HFA-PEFF Scores in Chinese Patients Suffering From Heart Failure With Preserved Ejection Fraction and Heart Failure With Preserved Ejection Fraction Complicated With Atrial Fibrillation].

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction (HFpEF) and HFpEF complicated with atrial fibrillation (HFpEF-AF) in Chinese patients and explore the related factors. Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from 2009 to 2020 were selected and assigned to a HFpEF-AF group (n=267) and a HFpEF group (n=568) according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic (ROC) curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated. Results There was no difference in the HFA-PEFF score between the two groups (P=0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group (P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high performance in diagnosing all HFpEF patients,with the area under the curve (AUC) of 0.892 and 0.922 and the optimal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in diagnosing HFpEF-AF (AUC of approximately 1.000) and low performance in diagnosing HFpEF (AUC of 0.885). Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

[Protective effect of Albizia chinensis saponin on ethanol-induced gastric mucosal injury in rats focus on mucus and mucosal barriers].

This study aims to explore the protective effect of Albizia chinensis saponin on ethanol-induced acute gastric ulcer in rats and elucidate its mechanisms. SD rats were deprived of water for 24 hours before the experiment. The control group and model group were administered water by gavage, and the positive drug group received rabeprazole sodium solution(40 mg·kg~(-1)) by gavage. The experimental groups were given different doses of Albizia chinensis saponin solution(3, 10, and 30 mg·kg~(-1)). After 30 minutes, the control group received 1.5 mL of water by gavage, while the other groups were administered an equal volume of 95% ethanol for modeling. After six hours, the rats were killed by cervical dislocation, and the stomachs were collected. The ulcer area was measured, and the ulcer index was calculated. Hematoxylin-eosin(HE) staining was performed to assess histopathological changes in gastric tissue. Periodic acid-Schiff(PAS) staining was used to evaluate the distribution of gastric mucosal surface mucus. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of phospholipids and aminohexose in the gastric mucosa. Western blot was performed to determine the expression levels of the bicarbonate transporter, matrix metalloproteinase, and tight junction-associated proteins in gastric tissue. Immunohistochemistry(IHC) staining was conducted to quantify the number of positive cells for secreted mucin and tight junction-associated proteins. The results showed that the gastric tissue surface of rats in the control group was smooth without ulceration, and the gastric ulcer index of rats in the model group was 35±11. Albizia chinensis saponin at doses of 3, 10, and 30 mg·kg~(-1) resulted in inhibition rates of gastric ulcer of 46%(P<0.01), 85%(P<0.001), and 100%(P<0.001), respectively. Severe disruption of gastric mucosal structure and absence of the mucus layer were observed in the model group. Compared with the model group, the Albizia chinensis saponin group showed intact gastric mucosal surface mucus layer, significantly increased levels of phospholipids and aminohexose in the mucus, increased number of MUC5AC positive cells, and upregulated expression levels of the bicarbonate transporter SLC26A3 and CFTR. It also showed decreased phosphorylation of JNK and c-Jun, reduced expression levels of MMP-8, elevated expression of TIMP-1, and increased expression levels of Occludin and ZO-1. In conclusion, Albizia chinensis saponin enhances the function of the mucus-bicarbonate barrier by upregulating the content of MUC5AC, phospholipids, and aminohexose and increasing the expression levels of the bicarbonate transporter SLC26A3 and CFTR. Moreover, Albizia chinensis saponin exerts its protective effects on gastric ulcers by inhibiting the JNK signaling pathway to prevent excessive activation of MMP-8, thereby reducing the degradation of Occludin and ZO-1 and enhancing the mucosal barrier function. In summary, Albizia chinensis saponin exerts its anti-gastric ulcer effects by simultaneously enhancing the mucus barrier and the mucosal barrier.

[Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate]. / è‹¯ä¸é ¸ç”˜æ²¹é ¯æ²»ç–—å„¿ç«¥é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡1例.

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

Regulatory effect of NK homeobox 1 (NKX2.1) on melanocortin 4 receptor (Mc4r) promoter in Mandarin fish.

The melanocortin 4 receptor (MC4R) is a G protein-coupled transporter that mediates the regulation of thyroid hormones and leptin on energy balance and food intake. However, the mechanisms of transcriptional regulation of Mc4r by thyroid hormone and leptin in fish have been rarely reported. The messenger RNA expression of Mc4r gene was significantly higher in brain than those in other tissues of mandarin fish. We analyzed the structure and function of a 2029 bp sequence of Mc4r promoter. Meanwhile, overexpression of NKX2.1 and incubation with leptin significantly increased Mc4r promoter activity, but triiodothyronine showed the opposite effect. In addition, mutations in the NKX2.1 binding site abolished not only the activation of Mc4r promoter activity by leptin but also the inhibitory effect of thyroid hormones on Mc4r promoter activity. In summary, these results suggested that thyroid hormones and leptin might regulate the transcriptional expression of Mc4r through NKX2.1.

Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Differential regulation of hippocampal transcriptome by circulating estrogen.

Estrogen (E2) modulates the synaptic structure and plasticity in the hippocampus. Previous studies showed that E2 fluctuations during various phases of the menstrual cycle produce subtle neurosynaptic changes that impact women's behavior, emotion, and cognitive functions. In this study, we explored the transcriptome of the hippocampus via RNA-seq (RNA-sequencing) between proestrus (PE) and diestrus (DE) stages in young female rats to determine the effect of E2 of PE and DE stages on hippocampal gene expression. We identified 238 genes (at 1.5-fold-change selection criteria, FDR adjusted p-value < 0.05) as differentially expressed genes (DEGs) that responded to E2 between PE and DE stages. Functional analysis based on Gene Ontology (GO) revealed that a higher E2 level corresponded to an increase in gene transcription among most of the DEGs, suggesting biological mechanisms operating differentially in the hippocampus of female rats between PE and DE stages in the estrus cycle; while analysis with Kyoto Encyclopedia of Genes and Genomes database (KEGG) found that the DEGs involving neuroactive ligand-receptor interaction, antigen processing, cell adhesion molecules, and presentation were upregulated in PE stage, whereas DEGs in pathways relating to bile secretion, coagulation cascades, osteoclast differentiation, cysteine and methionine metabolism were upregulated in DE stage of the estrus cycle. The high-fold expression of DEGs was confirmed by a follow-up quantitative real-time PCR. Our findings in this current study have provided fundamental information for further dissection of neuro-molecular mechanisms in the hippocampus in response to E2 fluctuation and its relationship with disorders.

Three Strategies in Engineering Nanomedicines for Tumor Microenvironment-Enabled Phototherapy.

Canonical phototherapeutics have several limitations, including a lack of tumor selectivity, nondiscriminatory phototoxicity, and tumor hypoxia aggravation. The tumor microenvironment (TME) is characterized by hypoxia, acidic pH, and high levels of H2 O2 , GSH, and proteases. To overcome the shortcomings of canonical phototherapy and achieve optimal theranostic effects with minimal side effects, unique TME characteristics are employed in the development of phototherapeutic nanomedicines. In this review, the effectiveness of three strategies for developing advanced phototherapeutics based on various TME characteristics is examined. The first strategy involves targeted delivery of phototherapeutics to tumors with the assistance of TME-induced nanoparticle disassembly or surface modification. The second strategy involves near-infrared absorption increase-induced phototherapy activation triggered by TME factors. The third strategy involves enhancing therapeutic efficacy by ameliorating TME. The functionalities, working principles, and significance of the three strategies for various applications are highlighted. Finally, possible challenges and future perspectives for further development are discussed.

Autoimmunity in Anti-Glomerular Basement Membrane Disease: A Review of Mechanisms and Prospects for Immunotherapy.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against the glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and severe alveolar hemorrhage. The noncollagenous domain of the α3 chain of type IV collagen, α3(IV)NC1, contains the main target autoantigen in this disease. Epitope mapping studies of α3(IV)NC1 have identified several nephritogenic epitopes and critical residues that bind to autoantibodies and trigger anti-GBM disease. The discovery of novel target antigens has revealed the heterogeneous nature of this disease. In addition, both epitope spreading and mimicry have been implicated in the pathogenesis of anti-GBM disease. Epitope spreading refers to the development of autoimmunity to new autoepitopes, thus worsening disease progression, whereas epitope mimicry, which occurs via sharing of critical residues with microbial peptides, can initiate autoimmunity. An understanding of these autoimmune responses may open opportunities to explore potential new therapeutic approaches for this disease. We review how current advances in epitope mapping, identification of novel autoantigens, and the phenomena of epitope spreading and mimicry have heightened the understanding of autoimmunity in the pathogenesis of anti-GBM disease, and we discuss prospects for immunotherapy.

Modeling of a multireflector terahertz imaging system using a geometrical optics model based on angular spectrum theory.

We propose a simulation method for a multireflector terahertz imaging system. The description and verification of the method are based on an existing active bifocal terahertz imaging system at 0.22 THz. Using the phase conversion factor and angular spectrum propagation, the computation of the incident and received fields requires only a simple matrix operation. The phase angle is used to calculate the ray tracking direction, and the total optical path is used to calculate the scattering field of defective foams. Compared with the measurements and simulations of aluminum disks and defective foams, the validity of the simulation method is confirmed in the field of view of 50 cm × 90 cm at 8 m. This work aims to develop better imaging systems by predicting their imaging behavior for different targets before manufacturing.

Image distortion by ambiguous multiple-photon detections in a superconducting nanowire single-photon imager and the correction method.

Scaling up superconducting nanowire single-photon detectors (SNSPDs) into a large array for imaging applications is the current pursuit. Although various readout architectures have been proposed, they cannot resolve multiple-photon detections (MPDs) currently, which limits the operation of the SNSPD arrays at high photon flux. In this study, we focused on the readout ambiguity of a superconducting nanowire single-photon imager applying time-of-flight multiplexing readout. The results showed that image distortion depended on both the incident photon flux and the imaging object. By extracting multiple-photon detections on idle pixels, which were virtual because of the incorrect mapping from the ambiguous readout, a correction method was proposed. An improvement factor of 1.3~9.3 at a photon flux of µ = 5 photon/pulse was obtained, which indicated that joint development of the pixel design and restoration algorithm could compensate for the readout ambiguity and increase the dynamic range.