Longitudinal Natural History Study of Visual Function in Bietti Crystalline Dystrophy: Implications for Early Intervention.

Purpose: To delineate the natural history of visual function parameters over time in individuals with Bietti crystalline dystrophy. Methods: This was a single-center retrospective longitudinal cohort study. Participants (n = 29) with a clinical diagnosis of Bietti crystalline dystrophy who harbored two alleles of disease-causing variants of the cytochrome P450 family 4 subfamily V member 2 gene (CYP4V2) were enrolled. Best-corrected visual acuity (BCVA), visual field (VF), and full-field ERG (ffERG) at baseline and their changes during the follow-up period were evaluated. Annual progression rates were calculated using three methods. Results: The mean age at the initial visit was 34.2 ± 7.5 years, with 5.9 ± 3.1 years follow-up. The annual progression rate from the longitudinal analysis using averaged individual progression rates was 0.079 logMAR units for BCVA, 1.14 dB for mean defect (MD) value of VF, and -18.06 µV and -5.45 µV for the b-wave amplitudes of scotopic 3.0 ERG and photopic 3.0 ERG, respectively. Mixed-model linear regression revealed annual progression rates of 0.068 logMAR units, 0.86 dB, -13.29 µV, and -3.75 µV, respectively. Cross-sectional progression rates from visual function versus age at baseline were 0.011 logMAR units, 0.47 dB, -1.85 µV, and -1.07 µV, respectively, which were significantly slower than those from the longitudinal data. Interocular symmetries for the MD values of VF and ffERG were good. Conclusions: Annual BCVA, VF, and ffERG progression rates were rapid, emphasizing the need for regular follow-up and early intervention. The progression rate cannot be inferred accurately from cross-sectional data from patients of different ages.

Optimization of TROSY- and anti-TROSY-based 15N CPMG relaxation dispersion experiments through phase cycling.

CPMG relaxation dispersion studies of biomolecular dynamics on the µs-ms timescale can provide detailed kinetic, thermodynamic, and structural insights into function. Frequently, the 15N spin serves as the probe of choice, as uniform incorporation of the 15N isotope is facile and cost-effective, and the interpretation of the resulting data is often relatively straightforward. In conventional CPMG relaxation dispersion experiments the application of CPMG pulses with constant radiofrequency (RF) phase can lead to artifactual dispersion profiles that result from off-resonance effects, RF field inhomogeneity, and pulse miscalibration. The development of CPMG experiments with the [0013]-phase cycle has significantly reduced the impact of pulse imperfections over a greater bandwidth of frequency offsets in comparison to constant phase experiments. Application of 15N-TROSY-based CPMG schemes to studies of the dynamics of large molecules is necessary for high sensitivity, yet the correct incorporation of the [0013]-phase cycle is non-trivial. Here we present TROSY- and anti-TROSY-based 15N CPMG experiments with the [0013]-phase cycling scheme and demonstrate, through comprehensive numerical simulations and experimental validation, enhanced resistance to pulse imperfections relative to traditional schemes utilizing constant phase CPMG pulses. Notably, exchange parameters derived from the new experiments are in good agreement with those obtained using other, more established, 15N-based CPMG approaches.

A Novel Risk Stratification-Based Immunomodulatory Treatment Strategy for Vogt-Koyanagi-Harada Disease.

PURPOSE: To develop a more tailored immunomodulatory treatment (IMT) strategy based on a novel 2-arm risk stratification system in Vogt-Koyanagi-Harada (VKH) patients. DESIGN: A retrospective clinical cohort study. METHODS: Seventy-nine VKH patients in the acute stage were stratified into low- (n = 58) and high-risk (n = 21) groups based on their exposure to risk factors. They were treated with oral glucocorticoids (GCs) plus as-needed (PRN) or first-line IMT. Best corrected visual acuity (BCVA), sunset glow fundus (SGF) occurrence, relapse rate, and systemic adverse events were evaluated during follow-up. RESULTS: Compared with the low-risk group, the high-risk group showed poorer BCVA at baseline (estimated difference 0.51, 95% CI 0.30-0.78; P < .001) and 6-month follow-up (estimated difference 0.08, 95% CI 0.00-0.08; P = .006), higher incidence of SGF at 12 months (52% vs 28%; RR 1.9, 95% CI 1.1-3.4; P = .040), and higher relapse rate at 6 months (24% vs 5%; RR 4.6, 95% CI 1.2-17.5; P = .028) and 12 months (52% vs 12%; RR 4.4, 95% CI 1.9-9.7; P < .001). In the low-risk cohort, no significant difference between the 2 IMT strategies was observed in primary outcomes. In the high-risk cohort, patients with the immediate IMT showed better BCVA (estimated difference -0.20, 95% CI -0.3 to -0.08; P = .007), lower incidence of SGF (27% vs 80%; RR 0.3, 95% CI 0.1-0.9; P = .030), and lower relapse rate (27% vs 80%; RR 0.3, 95% CI 0.1-0.9; P = .030) compared with the PRN regimen. Moreover, the immediate IMT regimen had a higher frequency of systemic adverse events than the PRN regimen (47% vs 7%; RR 7.1, 95% CI 2.5-20.4; P < .001). CONCLUSIONS: High-risk stratification at baseline was associated with poor prognosis. The immediate IMT regimen was only beneficial for high-risk VKH patients regarding visual outcome, SGF, and relapse rate. This study suggests a potential need for a customized IMT strategy for VKH patients.

AFB1 Triggers Lipid Metabolism Disorders through the PI3K/Akt Pathway and Mediates Apoptosis Leading to Hepatotoxicity.

As the most prevalent mycotoxin in agricultural products, aflatoxin B1 not only causes significant economic losses but also poses a substantial threat to human and animal health. AFB1 has been shown to increase the risk of hepatocellular carcinoma (HCC) but the underlying mechanism is not thoroughly researched. Here, we explored the toxicity mechanism of AFB1 on human hepatocytes following low-dose exposure based on transcriptomics and lipidomics. Apoptosis-related pathways were significantly upregulated after AFB1 exposure in all three hES-Hep, HepaRG, and HepG2 hepatogenic cell lines. By conducting a comparative analysis with the TCGA-LIHC database, four biomarkers (MTCH1, PPM1D, TP53I3, and UBC) shared by AFB1 and HCC were identified (hazard ratio > 1), which can be used to monitor the degree of AFB1-induced hepatotoxicity. Simultaneously, AFB1 induced abnormal metabolism of glycerolipids, sphingolipids, and glycerophospholipids in HepG2 cells (FDR < 0.05, impact > 0.1). Furthermore, combined analysis revealed strong regulatory effects between PIK3R1 and sphingolipids (correlation coefficient > 0.9), suggesting potential mediation by the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (AKT) signaling pathway within mitochondria. This study revealed the dysregulation of lipid metabolism induced by AFB1 and found novel target genes associated with AFB-induced HCC development, providing reliable evidence for elucidating the hepatotoxicity of AFB as well as assessing food safety risks.

Extraordinary preservation of gene collinearity over three hundred million years revealed in homosporous lycophytes.

Homosporous lycophytes (Lycopodiaceae) are a deeply diverged lineage in the plant tree of life, having split from heterosporous lycophytes (Selaginella and Isoetes) ~400 Mya. Compared to the heterosporous lineage, Lycopodiaceae has markedly larger genome sizes and remains the last major plant clade for which no chromosome-level assembly has been available. Here, we present chromosomal genome assemblies for two homosporous lycophyte species, the allotetraploid Huperzia asiatica and the diploid Diphasiastrum complanatum. Remarkably, despite that the two species diverged ~350 Mya, around 30% of the genes are still in syntenic blocks. Furthermore, both genomes had undergone independent whole genome duplications, and the resulting intragenomic syntenies have likewise been preserved relatively well. Such slow genome evolution over deep time is in stark contrast to heterosporous lycophytes and is correlated with a decelerated rate of nucleotide substitution. Together, the genomes of H. asiatica and D. complanatum not only fill a crucial gap in the plant genomic landscape but also highlight a potentially meaningful genomic contrast between homosporous and heterosporous species.

Clinical and genetic characterization of a large cohort of Chinese patients with Bietti crystalline retinopathy.

PURPOSE: To investigate the clinical and genetic characteristics for a large cohort of Chinese patients with Bietti crystalline retinopathy (BCR). METHODS: A total of 208 Chinese BCR patients from 175 families were recruited. Comprehensive clinical evaluations and genetic analysis were performed. Genotype-phenotype correlations were evaluated through statistical analysis. RESULTS: The patients' median age was 37 years (range, 20-76 years). The median best corrected visual acuity (BCVA) was 0.8 LogMAR unit (range, 2.8 to -0.12). A significant decline of BCVA was revealed in patients over 40 years old (P<0.001). Two clinical types were observed: peripheral type (type P) and central type (type C). Significantly more type C patients had a worse central visual acuity, but a more preserved retinal function (P<0.05). Molecular screening detected biallelic CYP4V2 pathogenic variants in 98.3% (172/175) of the families, including 19 novel ones. The most frequent pathogenic variant was c.802-8_810del17insGC, with the allele frequency of 55.7% (195/350), followed by c.992A>C (28/350, 8%) and c.1091-2A>G (23/350, 6.6%). BCR patients with one c.802-8_810del17insGC and one truncating variant (IVS6-8/Tru) had BCVA>1.3 LogMAR unit (Snellen equivalent<20/400) at a younger age than those with homozygous c.802-8_810del17insGC variants (homo IVS6-8) (P=0.031). CONCLUSIONS: BCR patients preserved relatively good vision before 40 years old. Two distinct clinical types of BCR were observed. BCR patients with IVS6-8/Tru had an earlier decline in visual acuity than those with homo IVS6-8. Our findings enhance the knowledge of BCR and will be helpful in patient selection for gene therapy.

A simplified machine learning model utilizing platelet-related genes for predicting poor prognosis in sepsis.

Background: Thrombocytopenia is a known prognostic factor in sepsis, yet the relationship between platelet-related genes and sepsis outcomes remains elusive. We developed a machine learning (ML) model based on platelet-related genes to predict poor prognosis in sepsis. The model underwent rigorous evaluation on six diverse platforms, ensuring reliable and versatile findings. Methods: A retrospective analysis of platelet data from 365 sepsis patients confirmed the predictive role of platelet count in prognosis. We employed COX analysis, Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) techniques to identify platelet-related genes from the GSE65682 dataset. Subsequently, these genes were trained and validated on six distinct platforms comprising 719 patients, and compared against the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ-Failure Assessment (SOFA) score. Results: A PLT count <100×109/L independently increased the risk of death in sepsis patients (OR = 2.523; 95% CI: 1.084-5.872). The ML model, based on five platelet-related genes, demonstrated impressive area under the curve (AUC) values ranging from 0.5 to 0.795 across various validation platforms. On the GPL6947 platform, our ML model outperformed the APACHE II score with an AUC of 0.795 compared to 0.761. Additionally, by incorporating age, the model's performance was further improved to an AUC of 0.812. On the GPL4133 platform, the initial AUC of the machine learning model based on five platelet-related genes was 0.5. However, after including age, the AUC increased to 0.583. In comparison, the AUC of the APACHE II score was 0.604, and the AUC of the SOFA score was 0.542. Conclusion: Our findings highlight the broad applicability of this ML model, based on platelet-related genes, in facilitating early treatment decisions for sepsis patients with poor outcomes. Our study paves the way for advancements in personalized medicine and improved patient care.

Inhibitory receptor CD47 binding to plasma TSP1 suppresses NK-cell IFN-γ production via activating the JAK/STAT3 pathway during HIV infection.

BACKGROUND: Natural killer (NK) cells play an important first-line role against tumour and viral infections and are regulated by inhibitory receptor expression. Among these inhibitory receptors, the expression, function, and mechanism of cluster of differentiation 47 (CD47) on NK cells during human immunodeficiency virus (HIV) infection remain unclear. METHODS: Fresh peripheral blood mononuclear cells (PBMCs) were collected from people living with HIV (PLWH) and HIV negative controls (NC) subjects. Soluble ligand expression levels of CD47 were measured using ELISA. HIV viral proteins or Toll-like receptor 7/8 (TLR7/8) agonist was used to investigate the mechanisms underlying the upregulation of CD47 expression. The effect of CD47 on NK cell activation, proliferation, and function were evaluated by flow cytometry. RNA-seq was used to identify downstream pathways for CD47 and its ligand interactions. A small molecule inhibitor was used to restore the inhibition of NK cell function by CD47 signalling. RESULTS: CD47 expression was highly upregulated on the NK cells from PLWH, which could be due to activation of the Toll-like receptor 7/8 (TLR7/8) pathway. Compared with NC subjects, PLWH subjects exhibited elevated levels of CD47 ligands, thrombospondin-1 (TSP1), and counter ligand signal regulatory protein-α (SIRPα). The TSP1-CD47 axis drives the suppression of interferon gamma (IFN-γ) production and the activation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway in NK cells. After treatment with a STAT3 inhibitor, the NK cells from PLWH showed significantly improved IFN-γ production. CONCLUSIONS: The current data indicate that the binding of the inhibitory receptor CD47 to plasma TSP1 suppresses NK cell IFN-γ production by activating the JAK/STAT3 pathway during HIV infection. Our results suggest that CD47 and its related signalling pathways could be targets for improving NK cell function in people living with HIV.

Weak SARS-CoV-2-specific responses of TIGIT-expressing CD8 + T cells in people living with HIV after a third dose of a SARS-CoV-2 inactivated vaccine.

BACKGROUND: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), an inhibitory receptor expressed on T cells, plays a dysfunctional role in antiviral infection and antitumor activity. However, it is unknown whether TIGIT expression on T cells influences the immunological effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated vaccines. METHODS: Forty-five people living with HIV (PLWH) on antiretroviral therapy (ART) for more than two years and 31 healthy controls (HCs), all received a third dose of a SARS-CoV-2 inactivated vaccine, were enrolled in this study. The amounts, activation, proportion of cell subsets, and magnitude of the SARS-CoV-2-specific immune response of TIGIT + CD4 + and TIGIT + CD8 + T cells were investigated before the third dose but 6 months after the second vaccine dose (0W), 4 weeks (4W) and 12 weeks (12W) after the third dose. RESULTS: Compared to that in HCs, the frequency of TIGIT + CD8 + T cells in the peripheral blood of PLWH increased at 12W after the third dose of the inactivated vaccine, and the immune activation of TIGIT + CD8 + T cells also increased. A decrease in the ratio of both T naïve (T N ) and central memory (T CM ) cells among TIGIT + CD8 + T cells and an increase in the ratio of the effector memory (T EM ) subpopulation were observed at 12W in PLWH. Interestingly, particularly at 12W, a higher proportion of TIGIT + CD8 + T cells expressing CD137 and CD69 simultaneously was observed in HCs than in PLWH based on the activation-induced marker assay. Compared with 0W, SARS-CoV-2-specific TIGIT + CD8 + T-cell responses in PLWH were not enhanced at 12W but were enhanced in HCs. Additionally, at all time points, the SARS-CoV-2-specific responses of TIGIT + CD8 + T cells in PLWH were significantly weaker than those of TIGIT - CD8 + T cells. However, in HCs, the difference in the SARS-CoV-2-specific responses induced between TIGIT + CD8 + T cells and TIGIT - CD8 + T cells was insignificant at 4W and 12W, except at 0W. CONCLUSIONS: TIGIT expression on CD8 + T cells may hinder the T-cell immune response to a booster dose of an inactivated SARS-CoV-2 vaccine, suggesting weakened resistance to SARS-CoV-2 infection, especially in PLWH. Furthermore, TIGIT may be used as a potential target to increase the production of SARS-CoV-2-specific CD8 + T cells, thereby enhancing the effectiveness of vaccination.

The effects of the tumor suppressor gene PTEN on the proliferation and apoptosis of breast cancer cells via AKT phosphorylation.

Background: The proliferation and apoptosis of cancer cells play important roles in breast carcinomas. However, to date, there have been few reports on the correlation between the expression of PTEN and AKT phosphorylation in breast cancer. This present study investigated the effects of the phosphatase and tensin homology deleted from chromosome 10 (PTEN) gene on the proliferation and apoptosis of breast cancer cells through protein kinase B (AKT) phosphorylation. Methods: Human breast cancer MDA-MB-231 cells were transfected with the pcDNA3.0 control vector or the pcDNA3.0-PTEN vector for 48 hours. The Cell Counting Kit 8 (CCK-8) was used to detect cell survival rates, double staining was performed to detect apoptosis, and Western blot (WB) analysis was conducted to detect protein expression. The effects of PTEN expression on the cell cycle and apoptosis of human breast cancer cell line MDA-MB-231, and on the levels of phosphorylated AKT protein were further analyzed. Moreover, the relationship between the PTEN gene and clinical features were also analyzed. Results: The cell survival rate of cells transfected with pcDNA3.0-PTEN was significantly lower than that of cells transfected with the control pcDNA3.0 vector (55.65%±12.18% vs. 97.32%±12.45%, P=0.004). Compared with the pcDNA3.0 group, the apoptosis rate of the pcDNA3.0-PTEN group was significantly increased (20.65±2.18 vs. 2.32±0.45, P=0.001). The expression of PTEN protein in pcDNA3.0-PTEN group was higher than that in the pcDNA3.0 group, and the expression of the AKT and mTOR proteins was significantly lower than that in pcDNA3.0 group (P<0.05). The expression of PTEN in the lymph node metastasis positive group was significantly higher than that in the lymph node metastasis negative group (P<0.05). The expression of the AKT protein in breast cancer was higher than that in normal breast tissue, and the difference was statistically significant (P<0.01). Conclusions: Overexpression of the PTEN gene can promote AKT phosphorylation, increase the apoptotic index of breast cancer cells, and reduce the proliferative activity of breast cancer cells. This provided a new direction for the next treatment of breast cancer, but further clinical research is needed.

Multiomics comparison among populations of three plant sources of Amomi Fructus.

Amomi Fructus (Sharen, AF) is a traditional Chinese medicine (TCM) from three source species (or varieties), including Wurfbainia villosa var. villosa (WVV), W. villosa var. xanthioides (WVX), or W. longiligularis (WL). Among them, WVV has been transplanted from its top-geoherb region, Guangdong, to its current main production area, Yunnan, for >50 years in China. However, the genetic and transcriptomic differentiation among multiple AF source species (or varieties) and between the origin and transplanted populations of WVV is unknown. In our study, the observed overall higher expression of terpenoid biosynthesis genes in WVV than in WVX provided possible evidence for the better pharmacological effect of WVV. We also screened six candidate borneol dehydrogenases (BDHs) that potentially catalyzed borneol into camphor in WVV and functionally verified them. Highly expressed genes at the P2 stage of WVV, Wv05G1424 and Wv05G1438, were capable of catalyzing the formation of camphor from (+)-borneol, (-)-borneol and DL-isoborneol. Moreover, the BDH genes may experience independent evolution after acquiring the ancestral copies, and the following tandem duplications might account for the abundant camphor content in WVV. Furthermore, four populations of WVV, WVX, and WL are genetically differentiated, and the gene flow from WVX to WVV in Yunnan contributed to the greater genetic diversity in the introduced population (WVV-JH) than in its top-geoherb region (WVV-YC), which showed the lowest genetic diversity and might undergo genetic degradation. In addition, terpene synthesis (TPS) and BDH genes were selected among populations of multiple AF source species (or varieties) and between the top- and non-top-geoherb regions, which might explain the difference in metabolites between these populations. Our findings provide important guidance for the conservation, genetic improvement, and industrial development of the three source species (or varieties) and for identifying top-geoherbalism with molecular markers, and proper clinical application of AF.

Safety and Immunogenicity of the Inactivated COVID-19 Vaccine Booster in People Living with HIV in China.

Current knowledge regarding the long-term humoral response of people infected with human immunodeficiency virus to the third dose of inactivated coronavirus disease (COVID-19) vaccine is incomplete. As a result, concerns remain about the safety and efficacy of the vaccination. To improve our understanding of the safety and immunogenicity of the COVID-19 inactivated vaccine booster in people living with HIV (PLWH), a prospective study was conducted on participants who had not yet received a third dose of the COVID-19 inactivated vaccine, had no history of SARS-CoV-2 infection, and had received a second dose of the vaccine more than six months prior. The primary safety outcomes included the incidence of adverse reactions, changes in CD4+ T-cell count, viral load, blood routine examination, liver and kidney function examination, blood sugar, and blood lipid examination. The pseudovirus-neutralizing antibody responses to the D614G variant, Delta variant, and Omicron variants BA.5 and BF.7 were evaluated before vaccination, 14 days, 28 days, 3 months, and 6 months after vaccination to evaluate the immune response of PLWH to the injection of inactivated vaccine booster and the safety of the vaccine. In conclusion, COVID-19 vaccine booster shots were effective in PLWH, resulting in an increase in the number of CD4+ T-cells, neutralizing antibodies that lasted up to six months, and higher levels of neutralizing antibodies lasting approximately 3 months. However, the vaccine protection against the two variants of BA.5 and BF.7 was significantly lower than that of D614G and Delta.

Development and validation of explainable machine-learning models for carotid atherosclerosis early screening.

BACKGROUND: Carotid atherosclerosis (CAS), an important factor in the development of stroke, is a major public health concern. The aim of this study was to establish and validate machine learning (ML) models for early screening of CAS using routine health check-up indicators in northeast China. METHODS: A total of 69,601 health check-up records from the health examination center of the First Hospital of China Medical University (Shenyang, China) were collected between 2018 and 2019. For the 2019 records, 80% were assigned to the training set and 20% to the testing set. The 2018 records were used as the external validation dataset. Ten ML algorithms, including decision tree (DT), K-nearest neighbors (KNN), logistic regression (LR), naive Bayes (NB), random forest (RF), multiplayer perceptron (MLP), extreme gradient boosting machine (XGB), gradient boosting decision tree (GBDT), linear support vector machine (SVM-linear), and non-linear support vector machine (SVM-nonlinear), were used to construct CAS screening models. The area under the receiver operating characteristic curve (auROC) and precision-recall curve (auPR) were used as measures of model performance. The SHapley Additive exPlanations (SHAP) method was used to demonstrate the interpretability of the optimal model. RESULTS: A total of 6315 records of patients undergoing carotid ultrasonography were collected; of these, 1632, 407, and 1141 patients were diagnosed with CAS in the training, internal validation, and external validation datasets, respectively. The GBDT model achieved the highest performance metrics with auROC of 0.860 (95% CI 0.839-0.880) in the internal validation dataset and 0.851 (95% CI 0.837-0.863) in the external validation dataset. Individuals with diabetes or those over 65 years of age showed low negative predictive value. In the interpretability analysis, age was the most important factor influencing the performance of the GBDT model, followed by sex and non-high-density lipoprotein cholesterol. CONCLUSIONS: The ML models developed could provide good performance for CAS identification using routine health check-up indicators and could hopefully be applied in scenarios without ethnic and geographic heterogeneity for CAS prevention.

Diel dynamics of multi-omics in elkhorn fern provide new insights into weak CAM photosynthesis.

Crassulacean acid metabolism (CAM) has high water-use efficiency (WUE) and is widely recognized to have evolved from C3 photosynthesis. Different plant lineages have convergently evolved CAM, but the molecular mechanism that underlies C3-to-CAM evolution remains to be clarified. Platycerium bifurcatum (elkhorn fern) provides an opportunity to study the molecular changes underlying the transition from C3 to CAM photosynthesis because both modes of photosynthesis occur in this species, with sporotrophophyll leaves (SLs) and cover leaves (CLs) performing C3 and weak CAM photosynthesis, respectively. Here, we report that the physiological and biochemical attributes of CAM in weak CAM-performing CLs differed from those in strong CAM species. We investigated the diel dynamics of the metabolome, proteome, and transcriptome in these dimorphic leaves within the same genetic background and under identical environmental conditions. We found that multi-omic diel dynamics in P. bifurcatum exhibit both tissue and diel effects. Our analysis revealed temporal rewiring of biochemistry relevant to the energy-producing pathway (TCA cycle), CAM pathway, and stomatal movement in CLs compared with SLs. We also confirmed that PHOSPHOENOLPYRUVATE CARBOXYLASE KINASE (PPCK) exhibits convergence in gene expression among highly divergent CAM lineages. Gene regulatory network analysis identified candidate transcription factors regulating the CAM pathway and stomatal movement. Taken together, our results provide new insights into weak CAM photosynthesis and new avenues for CAM bioengineering.

Effective Extraction of Bisphenol Compounds from Milk with Stable Zr(IV)-Based Metal-Organic Framework Particles.

Bisphenol compounds (BPs) have recently been the subject of growing interest due to their wide use in industrial and consumer products. Besides their adverse effects on human endocrine system, effective extraction of BPs and their elimination from complex sample matrix are still significant challenges in food analysis. Herein, a novel Zr(IV)-based metal-organic framework (MOF), named BUT-16, has been synthesized and utilized for the extraction and enrichment of BPs in milk samples. Bisphenol A (BPA), one of the highest production volume BPs, is used as a model molecule. The uptake capacity for BPA can reach up to 48 mg/g, and the adsorption rate is rapid (∼10 min), because of the larger surface area and cooperation of multiple functionalities of BUT-16. Employing BUT-16 in solid-phase extraction, coupled with ultra-performance liquid chromatography-tandem mass spectrometry detection, we generated a rapid, facile, and robust method for the enrichment and detection of trace BPA and its 12 substitutes in milk samples. After optimization, the limits of detection and quantification for BPs can be achieved as low as 0.05 and 0.2 ng/mL, respectively. Without the correction of the isotopic internal standard, the average recoveries of BPs at the different spiked concentrations varied from 63.8 to 120.6%, with a satisfactory precision (RSD ≤ 8.2%). Furthermore, the proposed method was successfully applied to the detection of BPs in real milk samples, and the results were in accordance with those of methods reported previously.

Molecular Network Analysis Discloses the Limited Contribution to HIV Transmission for Patients with Late HIV Diagnosis in Northeast China.

In the "treat all" era, the high rate of late HIV diagnosis (LHD) worldwide remains an impediment to ending the HIV epidemic. In this study, we analyzed LHD in newly diagnosed people living with HIV (PLWH) and its impact on HIV transmission in Northeast China. Sociodemographic information, baseline clinical data, and plasma samples obtained from all newly diagnosed PLWH in Shenyang, the largest city in Northeast China, between 2016 and 2019 were evaluated. Multivariate logistic regression analysis was performed to identify risk factors associated with LHD. A molecular network based on the HIV pol gene was constructed to assess the risk of HIV transmission with LHD. A total of 2882 PLWH, including 882 (30.6%) patients with LHD and 1390 (48.2%) patients with non-LHD, were enrolled. The risk factors for LHD were older age (≥ 30 years: p < .01) and diagnosis in the general population through physical examination (p < .0001). Moreover, the molecular network analysis revealed that the clustering rate (p < .0001), the fraction of individuals with ≥ 4 links (p = .0847), and the fraction of individuals linked to recent HIV infection (p < .0001) for LHD were significantly or marginally significantly lower than those recorded for non-LHD. Our study indicates the major risk factors associated with LHD in Shenyang and their limited contribution to HIV transmission, revealing that the peak of HIV transmission of LHD at diagnosis may have been missed. Early detection, diagnosis, and timely intervention for LHD may prevent HIV transmission.

Clinical and Molecular Features of a Chinese Cohort With Syndromic and Nonsyndromic Retinal Dystrophies Related to the CEP290 Gene.

PURPOSE: To reveal the clinical and genetic features of 54 Chinese pedigrees with syndromic or nonsyndromic retinal dystrophies related to CEP290 and to explore the genotype-phenotype correlation. DESIGN: Retrospective cohort study. METHODS: Patients diagnosed with nonsyndromic inherited retinal dystrophy (IRD) or syndromic ciliopathy (SCP) were enrolled. We identified 61 patients from 54 families carrying biallelic pathogenic CEP290 variants using next-generation sequencing, Sanger sequencing, and co-segregation validation. Genotype-phenotype correlation was evaluated. RESULTS: This study included 37 IRD patients from 32 families and 24 patients with SCP from 22 pedigrees. Four retinal dystrophy phenotypes were confirmed: Leber congenital amaurosis (LCA, 46/61), early-onset severe retinal dystrophy (EOSRD, 4/61), retinitis pigmentosa (RP, 10/61), and cone-rod dystrophy (CORD, 1/61). The SCP phenotypes included Joubert syndrome (JS) (23/24) and Bardet-Biedl syndrome (BBS) (1/24). We detected 73 different CEP290 variants, of which 33 (45.2%) were not previously reported. Two novel copy number variations (CNVs) and 1 novel pathogenic synonymous change were identified. The most recurrent alterations in the IRD and SCP were p.Q123* (6/64, 9.4%) and p.I556Ffs*17 (10/44, 22.7%), respectively. IRD patients carried more stop-gain alleles (25/64, 39.1%), whereas SCP patients carried more frameshift alleles (23/44, 52.3%). CONCLUSIONS: LCA was the most common retinal dystrophy phenotype, and JS was the most prevalent syndrome in CEP290 patients; RP/CORD and BBS may be present in early adulthood. The hot spot variants and distribution of genotypes were distinct between IRD and SCP. Our study expands the CEP290 variant spectrum and enhances the current knowledge of CEP290 heterogeneity.

Recurrent vitreous opacity caused by intraocular Toxocara larva: a case report and literature review.

BACKGROUND: Toxocara larva entity has seldom been reported on the surface of the retina. We report on an unusual case of recurrent vitreous opacity caused by intraocular Toxocara larva after vitrectomy. CASE PRESENTATION: A 34-year-old male was referred to our clinic with a 6-month history of decreased visual acuity in the right eye characterized as red, painless, and progressive. Optos fundus photograph showed optic disc elevation with granuloma, and proliferative membrane starting from the optic disc and running towards the superior temporal retina due to the movement of a Toxocara larva, which was covered by the proliferative membrane in the superior temporal retina. Since it adhered closely to the retina, the lesion in the superior temporal retina was not removed to avoid induction of an iatrogenic retinal break and the larva was not found during the first diagnostic pars plana vitrectomy. Intraocular Anti-Toxocara IgG was 45.53U (< 3, enzyme-linked immunosorbent assay (ELISA)), and the Goldmann-Witmer coefficient was 8.55, confirming the diagnosis of ocular toxocariasis. After this operation, visual acuity improved to 20/200. However, vitreous opacity worsened again, and the proliferative membrane expanded around the Toxocara larva three weeks after the operation. Toxocara larva was found and removed in the superior temporal region during the second operation. His visual acuity improved to 20/100, vitreous opacity disappeared, and the retina was stable two months after the second operation. CONCLUSION: It is advisable to remove suspected Toxocara larva to prevent the reoccurrence of ocular toxocariasis.

Development of precocious puberty in children: Surmised medicinal plant treatment.

Precocious puberty in children is one of the common endocrine diseases in paediatrics. Epidemiological surveys have shown that the number of children with precocious puberty has significantly increased globally. Precocious puberty negatively affects the physical and mental health of children and may increase the risk of hypertension, diabetes, obesity and infertility in adulthood. Therefore, the initiating factors of adolescence have become core issues in the study of sexual development in children. Owing to developments in molecular genetics, many studies have been able to show that precocious puberty is mostly resulted in autosomal inheritance. For instance, makorin ring finger protein 3 gene (MKRN3) may be implicated in familial CPP. Gonadotropin-releasing hormone agonist (GnRHa) is the gold standard for treatment, but its safety still requires long-term evaluation and management. Traditional medicinal plants have been used in clinical treatments and in exploring novel treatment methods. From the collected datas, in Asia, traditional Chinese medicine treatment is based on the principles of nourishing Yin, lowering fire and draining fire from the liver to help precocious children and alleviate or delay the onset of precocious puberty by medicinal plants such as Anemarrhena asphodeloides Bge., Phellodendron amurense Rupr., Rehmannia glutinosa and Poria cocos Wolf. They play an important role in exploring the pharmacological mechanisms of precocious puberty treatment effects and drug development. Therefore, by elucidating the occurrence and development of precocious puberty, this review provides novel and valuable insights of paediatric endocrine therapy accessing the published researches on the effectiveness of traditional herbal medicine in the treatment of precocious puberty and its therapeutic mechanisms.

CD38+CD39+ NK cells associate with HIV disease progression and negatively regulate T cell proliferation.

The ectonucleotidases CD38 and CD39 have a critical regulatory effect on tumors and viral infections via the adenosine axis. Natural killer (NK) cells produce cytokines, induce cytotoxic responses against viral infection, and acquire immunoregulatory properties. However, the roles of CD38 and CD39 expressed NK cells in HIV disease require elucidation. Our study showed that the proportions of CD38+CD39+ NK cells in HIV-infected individuals were positively associated with HIV viral loads and negatively associated with the CD4+ T cell count. Furthermore, CD38+CD39+ NK cells expressed additional inhibitory receptors, TIM-3 and LAG-3, and produced more TGF-ß. Moreover, autologous NK cells suppressed the proliferation of CD8+ T and CD4+ T cells of HIV-infected individuals, and inhibiting CD38 and CD39 on NK cells restored CD8+ T and CD4+ T cell proliferation in vitro. In conclusion, these data support a critical role for CD38 and CD39 on NK cells in HIV infection and targeting CD38 and CD39 on NK cells may be a potential therapeutic strategy against HIV infection.