Structural insights into the functional divergence of WhiB-like proteins in Mycobacterium tuberculosis.

WhiB7 represents a distinct subclass of transcription factors in the WhiB-Like (Wbl) family, a unique group of iron-sulfur (4Fe-4S] cluster-containing proteins exclusive to the phylum of Actinobacteria. In Mycobacterium tuberculosis (Mtb), WhiB7 interacts with domain 4 of the primary sigma factor (σA4) in the RNA polymerase holoenzyme and activates genes involved in multiple drug resistance and redox homeostasis. Here, we report crystal structures of the WhiB7:σA4 complex alone and bound to its target promoter DNA at 1.55-Å and 2.6-Å resolution, respectively. These structures show how WhiB7 regulates gene expression by interacting with both σA4 and the AT-rich sequence upstream of the -35 promoter DNA via its C-terminal DNA-binding motif, the AT-hook. By combining comparative structural analysis of the two high-resolution σA4-bound Wbl structures with molecular and biochemical approaches, we identify the structural basis of the functional divergence between the two distinct subclasses of Wbl proteins in Mtb.

Structural basis of DNA binding by the WhiB-like transcription factor WhiB3 in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) WhiB3 is an iron-sulfur cluster-containing transcription factor belonging to a subclass of the WhiB-Like (Wbl) family that is widely distributed in the phylum Actinobacteria. WhiB3 plays a crucial role in the survival and pathogenesis of Mtb. It binds to the conserved region 4 of the principal sigma factor (σA4) in the RNA polymerase holoenzyme to regulate gene expression like other known Wbl proteins in Mtb. However, the structural basis of how WhiB3 coordinates with σA4 to bind DNA and regulate transcription is unclear. Here we determined crystal structures of the WhiB3:σA4 complex without and with DNA at 1.5 Å and 2.45 Å, respectively, to elucidate how WhiB3 interacts with DNA to regulate gene expression. These structures reveal that the WhiB3:σA4 complex shares a molecular interface similar to other structurally characterized Wbl proteins and also possesses a subclass-specific Arg-rich DNA-binding motif. We demonstrate that this newly defined Arg-rich motif is required for WhiB3 binding to DNA in vitro and transcriptional regulation in Mycobacterium smegmatis. Together, our study provides empirical evidence of how WhiB3 regulates gene expression in Mtb by partnering with σA4 and engaging with DNA via the subclass-specific structural motif, distinct from the modes of DNA interaction by WhiB1 and WhiB7.

On-Site Visualization Assay for Tumor-Associated miRNAs: Using Ru@TiO2 as a Peroxidase-like Nanozyme.

Accurate diagnosis of highly aggressive and deadly tumors is essential for effective treatment and improved patient outcomes, and microRNAs (miRNAs) have emerged as crucial biomarkers for their roles in tumor initiation, progression, and metastasis. Herein, we present an on-site visualization colorimetric assay for tumor-associated miRNAs using ruthenium nanoparticle decorated titanium dioxide nanoribbon (Ru@TiO2) as a peroxidase-like (POD) nanozyme. Remarkably, the Ru@TiO2 nanozyme can catalyze the oxidation of chromogenic substrates through its POD-like activity, which is effectively inhibited by pyrophosphate generated during the rolling circle amplification process, thereby enabling miRNA detection through a visible colorimetric readout. This approach provides a highly sensitive and specificity assay for miRNAs in diluted human serum with a detection limit of 100 pM. It shows great potential for clinical diagnostics and biological research, offering a promising tool for early cancer diagnosis and molecular diagnostics.

Bioinspired Heterogeneous Construction of Lignocellulose-Reinforced COF Membranes for Efficient Proton Conduction.

The exponential interest in covalent organic frameworks (COFs) arises from the direct correlation between their diverse and intriguing properties and the modular design principle. However, the insufficient interlamellar interaction among COF nanosheets greatly hinders the formation of defect-free membranes. Therefore, developing a methodology for the facile fabrication of these materials remains an enticing and highly desirable objective. Herein, ultrahigh proton conductivity and superior stability are achieved by taking advantage of COF composite membranes where 2D TB-COF nanosheets are linked by 1D lignocellulosic nanofibrils (LCNFs) through π-π and electrostatic interactions to form a robust and ordered structure. Notably, the high concentration of -SO3 H groups within the COF pores and the abundant proton transport paths at COFs-LCNFs interfaces impart composite membranes ultrahigh proton conductivity (0.348 S cm-1 at 80 °C and 100% RH). Moreover, the directional migration of protons along the stacked nanochannels of COFs is facilitated by oxygen atoms on the keto groups, as demonstrated by density functional theory (DFT) calculations. The simple design concept and reliable operation of the demonstrated mixed-dimensional composite membrane are expected to provide an ideal platform for next-generation conductive materials.

Salidroside Inhibits α-Amanitin-Induced AML-12 Cell Apoptosis via the Regulation of PINK1/Parkin-Mediated Mitophagy and Mitochondrial Function.

Poisoning caused by the mushroom Amanita phalloides, due to the toxin α-amanitin, accounts for approximately 90% of food poisoning deaths in China with no specific antidotes. To investigate the role of salidroside (Sal) in α-amanitin (α-AMA)-induced mitophagy, mouse liver cells AML-12 were exposed to α-AMA in the presence of Sal or not. Intracellular reactive oxygen species (ROS) levels were measured using a ROS detection kit, mitochondrial activity was evaluated using a mitochondrial red fluorescent probe kit or JC-1 dye, and protein expression levels of PINK1, Parkin, LC3 II, P62, Bax, Bcl-2, Caspase 3, Cleaved-Caspase 3, PARP I, and Cleaved-PARP I were detected through Western blot. Results demonstrated that α-AMA led to increased intracellular ROS levels, cell apoptosis, and decreased mitochondrial membrane potential. Notably, expression levels of mitophagy-related proteins PINK1, Parkin, and LC3 increased significantly while the P62 protein expression decreased remarkably. Furthermore, Sal reversed the α-AMA-induced decrease in cell viability and mitochondrial membrane potential and increase in intracellular ROS level. In addition, Sal promoted expression levels of PINK1, Parkin, and LC3 II while suppressing the Bax/Bcl-2 ratio, Cleaved-Caspase 3, and Cleaved-PARP I as well as P62. The results above proved that salidroside alleviates α-AMA-induced mouse liver cells damage via promoting PINK1/Parkin-mediated mitophagy and reducing cell apoptosis.

Fulvic Acid Enhances Nitrogen Fixation and Retention in Paddy Soils through Microbial-Coupled Carbon and Nitrogen Cycling.

Fulvic acid, the most soluble and active humic substance, is widely used as an agent to remediate contaminated soils and improve soil fertility. However, the influence of fulvic acid (FA), as a microbial carbon source, on carbon and nitrogen cycles in paddy soils remains elusive. Therefore, to investigate it, an incubation experiment was conducted. Gas analyses indicated that the carbon dioxide and methane emissions were enhanced in FA treatment, which increased up to 94.08-fold and 5.06-fold, respectively. 15N-labeling experiments revealed that nitrogen fixation capability was promoted (1.2-fold) to reduce the carbon and nitrogen imbalance due to fulvic acid amendment. Metagenomic analysis further revealed that gene abundances of degradation of lignin-like compounds, gallate degradation, methanogenesis, nitrogen fixation, and urea hydrolysis increased, while the bacterial ammonia oxidation and anaerobic ammonium oxidation decreased, caused by FA application. Metabolic reconstruction of metagenome-assembled genomes revealed that Azospirillaceae, Methanosarcinaceae, and Bathyarchaeota, with higher abundance in FA treatment, were the key microorganisms to maintain the carbon and nitrogen balance. The metabolic pathways of fulvic acid degradation and coupled nitrogen fixation and retention were constructed. Collectively, our results provided novel insights into the theoretical basis of the use of humic substances for reducing nitrogen fertilization and climate change.

Labile Carbon from Artificial Roots Alters the Patterns of N2O and N2 Production in Agricultural Soils.

Labile carbon (C) continuously delivered from the rhizosphere profoundly affects terrestrial nitrogen (N) cycling. However, nitrous oxide (N2O) and dinitrogen (N2) production in agricultural soils in the presence of continuous root C exudation with applied N remains poorly understood. We conducted an incubation experiment using artificial roots to continuously deliver small-dose labile C combined with 15N tracers to investigate N2O and N2 emissions in agricultural soils with pH and organic C (SOC) gradients. A significantly negative exponential relationship existed between N2O and N2 emissions under continuous C exudation. Increasing soil pH significantly promoted N2 emissions while reducing N2O emissions. Higher SOC further promoted N2 emissions in alkaline soils. Native soil-N (versus fertilizer-N) was the main source of N2O (average 67%) and N2 (average 80%) emissions across all tested soils. Our study revealed the overlooked high N2 emissions, mainly derived from native soil-N and strengthened by increasing soil pH, under relatively real-world conditions with continuous root C exudation. This highlights the important role of N2O and N2 production from native soil-N in terrestrial N cycling when there is a continuous C supply (e.g., plant-root exudate) and helps mitigate emissions and constrain global budgets of the two concerned nitrogenous gases.

Analysis of spiritual well-being status and influencing factors in patients with esophageal cancer: a cross-sectional study.

OBJECTIVE: To understand the status of spiritual well-being in patients with esophageal cancer and analyze its influencing factors. METHODS: A total of 187 patients with esophageal cancer (EC) from two grade A hospitals in Chengdu were selected and investigated by general data questionnaire, chronic disease function evaluation-spirituality scale 12 (FACIT-SP-12), general well-being scale (GWB), and Anderson symptom assessment scale gastrointestinal tract (MDASI-GI). RESULTS: The spiritual well-being score of patients with esophageal cancer was (25.13 ± 9.63). Spiritual well-being was positively correlated with general well-being and negatively correlated with symptom burden (P < 0.01). The results of multiple stepwise linear regression analysis showed that hobbies, disease stage, general well-being, and symptom burden were the main influencing factors for the spiritual well-being of esophageal cancer patients (P < 0.05), explaining 49.0% of the total variation. CONCLUSIONS: The spiritual well-being of patients with esophageal cancer is lower than the middle level, In addition, whether there is a hobby in life, disease stage, subjective well-being, and symptom burden are the main factors affecting the spiritual well-being of patients with EC. It is suggested that medical staff should take targeted care measures according to the influencing factors, so as to improve the spiritual well-being level of patients and improve the quality of life of patients.

Solamargine Induces Hepatocellular Carcinoma Cell Apoptosis and Ferroptosis via Regulating STAT1/MTCH1 Axis.

BACKGROUND: Solamargine (SM) has been shown to play anti-tumor role in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of SM in HCC progression deserve further exploration. METHODS: HCC cell proliferation and apoptosis were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Ferroptosis was evaluated by detecting the levels of Fe2+, iron, MDA, ROS and GSH in HCC cells. In addition, mitochondrial carrier 1 (MTCH1) mRNA level was detected by quantitative real-time PCR. Western blot was used to test MTCH1 and signal transduction and activation of transcription 1 (STAT1) protein levels. Dual-luciferase reporter assay was employed to analyze the interaction between STAT1 and MTCH1. A mouse xenograft model was also constructed to explore the role of SM in vivo. RESULTS: SM could potentially suppress HCC cell growth by inducing ferroptosis. MTCH1 was highly expressed in HCC tissues and cells, and its silencing inhibited HCC cell proliferation, promoted apoptosis and ferroptosis. MTCH1 expression was reduced by SM, and its overexpression reversed SM-induced HCC cell apoptosis and ferroptosis. Furthermore, STAT1 facilitated MTCH1 transcription and promoted its expression. Besides, STAT1 expression could be reduced by SM, and its overexpression abolished the decreasing effect of SM on MTCH1 expression. In vivo, SM suppressed HCC tumor growth by reducing MTCH1 expression. CONCLUSION: SM promoted HCC cell apoptosis and ferroptosis via the STAT1/MTCH1 axis.

Differences in preimplantation blastocyst chromosomal aberrations between polycystic ovary syndrome women and controls: a multi-center retrospective cohort study.

PURPOSE: Comprehensive chromosomal status of blastocyst from women with polycystic ovary syndrome (PCOS) was limited. This study aimed to identify possible differences in the preimplantation blastocyst chromosome aberrations between PCOS women and controls receiving preimplantation genetic testing (PGT). METHODS: This was a multi-center retrospective cohort study including a total of 707 blastocysts from 147 PCOS women and 3006 blastocysts from 821 control women receiving PGT between 2015 and 2021. Embryonic chromosomal aberration spectrums were compared between PCOS and controls. Mixed effects generalized linear model was conducted to explore possible influence of PCOS-related endocrinological disorders on embryonic chromosomal abnormalities. RESULTS: Blastocysts from PCOS demonstrated significantly lower aneuploidy rate (15.2% vs. 25.2% per women, P < 0.001; 14.7% vs. 25.4% per blastocyst, P < 0.001) but greater mosaicism rate (12.5% vs. 8.0% per women, P = 0.007; 16.5% vs. 8.7% per blastocyst, P < 0.001). Mixed effects generalized linear model identified PCOS as an independent protective factor against embryonic aneuploidy (adjusted odds ratio = 0.68, 95% confidence interval, 0.50-0.93, P = 0.014) but a risk factor for embryonic mosaicism (adjusted odds ratio = 1.52, 95% confidence interval 1.11-2.10, P = 0.009). Further model analysis suggested that insulin resistance could be responsible for the increased risk of embryonic mosaicism among PCOS women (adjusted odds ratio = 2.17, 95% confidence interval, 1.10-4.31, P = 0.026). CONCLUSION: PCOS is associated with a lower aneuploidy risk but an increased mosaicism risk in preimplantation blastocysts, and insulin resistance should be investigated as a potential cause.

Occurrence of antimicrobial resistance and class 1 integrons in Staphylococcus aureus isolated from bovine mastitis in China.

Integrons are important genetic elements that allow easy acquisition and dissemination of antimicrobial resistance genes. Studies reporting occurrence of integrons in Staphylococcus aureus (S. aureus) isolated from bovine mastitis in large dairy farms across China are scarce. The aim of this study was to investigate the occurrence of class 1 integrons (intI1), antimicrobial resistance (AMR) and associated genes in S. aureus isolated from bovine mastitis and their associations. Minimum inhibitory concentrations (MICs) were determined to evaluate the AMR phenotypes, whereas PCR was carried out to assess the occurrence of AMR genes and intI1. In addition, index cluster analysis was used to estimate associations between AMR phenotype, genotype and intI1 in 103 isolates. Overall, 83% of S. aureus were intI1-positive and 5 types of gene cassettes were detected. Susceptibility against single antimicrobial agents ranged from 0% (erythromycin), 12% (ampicillin) and 16% (penicillin G) to 96% (gentamicin). Most isolates (64%) were intermediate-resistant against erythromycin, whereas resistance against ceftriaxone (22%), clindamycin (4%), cefotaxime (2%), tetracycline (1%) and ciprofloxacin (1%) were relatively uncommon. The predominant resistant gene was blaZ gene (n = 88, 85%) followed by tetD gene (n = 85, 83%). With an estimated prevalence of 12% of the mecA gene, methicillin-resistant S. aureus isolates had higher MIC50 and MIC90 for majority of antimicrobials than methicillin-susceptible S. aureus isolates. Presence of the ermC gene was associated with erythromycin resistance. Ampicillin, erythromycin and penicillin G resistance were associated with intI1. The data presented in our study indicated that class 1 integron-mediated resistance possibly plays an important role in dissemination of AMR in S. aureus isolated from bovine mastitis.

A Nomogram Prediction Model for Persistent Pulmonary Hypertension of the Newborn in Neonates Hospitalized for the First Time After Birth.

OBJECTIVE: Persistent pulmonary hypertension of the newborn (PPHN) is one of the critical neonatal diseases associated with high morbidity and mortality. This study attempted to conduct a nomogram prediction model for performing early identification of PPHN and providing effective information for clinical practice. METHODS: A total of 456 newborns who first admitted to the hospital after birth were included in the analysis, including 138 newborns with PPHN and 318 newborns without PPHN (as controls). The optimal predictive variables selection was performed based on LASSO (least absolute shrinkage and selection operator) regression and multivariate logistic regression. Using the selected variables, a nomogram prediction model was developed. To validate the model, the model was assessed using the receiver operating characteristic curve, calibration plot, and clinical impact curve. RESULTS: Six predictors, namely, gestational age, neonatal respiratory distress syndrome, the levels of hemoglobin and creatine kinase-MB, gestational thyroid dysfunction, and Pa o2 , were identified by LASSO and multivariate logistic regression analysis from the original 30 variables studied. The constructed model, using these predictors, exhibited favorable predictive ability for PPHN, with an area under the receiver operating characteristic of 0.897 (sensitivity = 0.876, specificity = 0.785) in the training set and 0.871 (sensitivity = 0.902, specificity = 0.695) in the validation set, and was well calibrated, as indicated by the PHosmer-Lemeshow test values of 0.233 and 0.876 for the training and validation sets, respectively. CONCLUSIONS: The model included gestational age, neonatal respiratory distress syndrome, the levels of hemoglobin and creatine kinase-MB, gestational thyroid dysfunction, and Pa o2 had good prediction performance for predicting PPHN among newborns first admitted to the hospital after birth.

Morphological Signatures of Neurogenesis and Neuronal Migration in Hypothalamic Vasopressinergic Magnocellular Nuclei of the Adult Rat.

The arginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker (Ionized calcium binding adaptor molecule 1, Iba1), and 5'-bromo-2'-deoxyuridine (BrdU), we report morphological evidence that low-rate neurogenesis and migration occur in adult AVPMNS in the rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the supraaoptic (SON) and paraventricular (PVN) nuclei. These findings raise new questions about AVPMNS's potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.

Chicken Interferon-Alpha and -Lambda Exhibit Antiviral Effects against Fowl Adenovirus Serotype 4 in Leghorn Male Hepatocellular Cells.

Hydropericardium hepatitis syndrome (HHS) is primarily caused by fowl adenovirus serotype 4 (FAdV-4), causing high mortality in chickens. Although vaccination strategies against FAdV-4 have been adopted, HHS still occurs sporadically. Furthermore, no effective drugs are available for controlling FAdV-4 infection. However, type I and III interferon (IFN) are crucial therapeutic agents against viral infection. The following experiments were conducted to investigate the inhibitory effect of chicken IFN against FadV-4. We expressed recombinant chicken type I IFN-α (ChIFN-α) and type III IFN-λ (ChIFN-λ) in Escherichia coli and systemically investigated their antiviral activity against FAdV-4 infection in Leghorn male hepatocellular (LMH) cells. ChIFN-α and ChIFN-λ dose dependently inhibited FAdV-4 replication in LMH cells. Compared with ChIFN-λ, ChIFN-α more significantly inhibited viral genome transcription but less significantly suppressed FAdV-4 release. ChIFN-α- and ChIFN-λ-induced IFN-stimulated gene (ISG) expression, such as PKR, ZAP, IRF7, MX1, Viperin, IFIT5, OASL, and IFI6, in LMH cells; however, ChIFN-α induced a stronger expression level than ChIFN-λ. Thus, our data revealed that ChIFN-α and ChIFN-λ might trigger different ISG expression levels, inhibiting FAdV-4 replication via different steps of the FAdV-4 lifecycle, which furthers the potential applications of IFN antiviral drugs in chickens.

AOB Nitrosospira cluster 3a.2 (D11) dominates N2O emissions in fertilised agricultural soils.

Ammonia-oxidation process directly contribute to soil nitrous oxide (N2O) emissions in agricultural soils. However, taxonomy of the key nitrifiers (within ammonia oxidising bacteria (AOB), archaea (AOA) and complete ammonia oxidisers (comammox Nitrospira)) responsible for substantial N2O emissions in agricultural soils is unknown, as is their regulation by soil biotic and abiotic factors. In this study, cumulative N2O emissions, nitrification rates, abundance and community structure of nitrifiers were investigated in 16 agricultural soils from major crop production regions of China using microcosm experiments with amended nitrogen (N) supplemented or not with a nitrification inhibitor (nitrapyrin). Key nitrifier groups involved in N2O emissions were identified by comparative analyses of the different treatments, combining sequencing and random forest analyses. Soil cumulative N2O emissions significantly increased with soil pH in all agricultural soils. However, they decreased with soil organic carbon (SOC) in alkaline soils. Nitrapyrin significantly inhibited soil cumulative N2O emissions and AOB growth, with a significant inhibition of the AOB Nitrosospira cluster 3a.2 (D11) abundance. One Nitrosospira multiformis-like OTU phylotype (OTU34), which was classified within the AOB Nitrosospira cluster 3a.2 (D11), had the greatest importance on cumulative N2O emissions and its growth significantly depended on soil pH and SOC contents, with higher growth at high pH and low SOC conditions. Collectively, our results demonstrate that alkaline soils with low SOC contents have high N2O emissions, which were mainly driven by AOB Nitrosospira cluster 3a.2 (D11). Nitrapyrin can efficiently reduce nitrification-related N2O emissions by inhibiting the activity of AOB Nitrosospira cluster 3a.2 (D11). This study advances our understanding of key nitrifiers responsible for high N2O emissions in agricultural soils and their controlling factors, and provides vital knowledge for N2O emission mitigation in agricultural ecosystems.

Unsupervised contrastive graph learning for resting-state functional MRI analysis and brain disorder detection.

Resting-state functional magnetic resonance imaging (rs-fMRI) helps characterize regional interactions that occur in the human brain at a resting state. Existing research often attempts to explore fMRI biomarkers that best predict brain disease progression using machine/deep learning techniques. Previous fMRI studies have shown that learning-based methods usually require a large amount of labeled training data, limiting their utility in clinical practice where annotating data is often time-consuming and labor-intensive. To this end, we propose an unsupervised contrastive graph learning (UCGL) framework for fMRI-based brain disease analysis, in which a pretext model is designed to generate informative fMRI representations using unlabeled training data, followed by model fine-tuning to perform downstream disease identification tasks. Specifically, in the pretext model, we first design a bi-level fMRI augmentation strategy to increase the sample size by augmenting blood-oxygen-level-dependent (BOLD) signals, and then employ two parallel graph convolutional networks for fMRI feature extraction in an unsupervised contrastive learning manner. This pretext model can be optimized on large-scale fMRI datasets, without requiring labeled training data. This model is further fine-tuned on to-be-analyzed fMRI data for downstream disease detection in a task-oriented learning manner. We evaluate the proposed method on three rs-fMRI datasets for cross-site and cross-dataset learning tasks. Experimental results suggest that the UCGL outperforms several state-of-the-art approaches in automated diagnosis of three brain diseases (i.e., major depressive disorder, autism spectrum disorder, and Alzheimer's disease) with rs-fMRI data.

Predicting risk of blastocyst aneuploidy among women with previous aneuploid pregnancy loss: a multicenter-data-based multivariable model.

STUDY QUESTION: Can blastocyst aneuploidy be predicted for patients with previous aneuploid pregnancy loss (PAPL) and receiving preimplantation genetic testing for aneuploidy (PGT-A)? SUMMARY ANSWER: Multivariable logistic regression models were established to predict high risk of blastocyst aneuploidy using four identified factors, presenting good predictive performance. WHAT IS KNOWN ALREADY: Aneuploidy is the most common embryonic chromosomal abnormality leading to pregnancy loss. Several studies have demonstrated a higher embryo aneuploidy rate in patients with PAPL, which has suggested that PGT-A should have benefits in PAPL patients intending to improve their pregnancy outcomes. However, recent studies have failed to demonstrate the efficacy of PGT-A for PAPL patients. One possible way to improve the efficacy is to predict the risk of blastocyst aneuploidy risk in order to identify the specific PAPL population who may benefit from PGT-A. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter retrospective cohort study based on data analysis of 1119 patients receiving PGT-A in three reproductive medical centers of university affiliated teaching hospitals during January 2014 to June 2020. A cohort of 550 patients who had one to three PAPL(s) were included in the PAPL group. In addition, 569 patients with monogenic diseases without pregnancy loss were taken as the non-PAPL group. PARTICIPANTS/MATERIALS, SETTING, METHODS: PGT-A was conducted using single nucleotide polymorphism microarrays and next-generation sequencing. Aneuploidy rates in Day 5 blastocysts of each patient were calculated and high-risk aneuploidy was defined as a rate of ≥50%. Candidate risk factors for high-risk aneuploidy were selected using the Akaike information criterion and were subsequently included in multivariable logistic regression models. Overall predictive accuracy was assessed using the confusion matrix, discrimination by area under the receiver operating characteristic curve (AUC), and calibration by plotting the predicted probabilities versus the observed probabilities. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Blastocyst aneuploidy rates were 30 ± 25% and 21 ± 19% for PAPL and non-PAPL groups, respectively. Maternal age (odds ratio (OR) = 1.31, 95% CI 1.24-1.39, P < 0.001), number of PAPLs (OR = 1.40, 95% CI 1.05-1.86, P = 0.02), estradiol level on the ovulation trigger day (OR = 0.47, 95% CI 0.30-0.73, P < 0.001), and blastocyst formation rate (OR = 0.13, 95% CI 0.03-0.50, P = 0.003) were associated with high-risk of blastocyst aneuploidy. The predictive model based on the above four variables yielded AUCs of 0.80 using the training dataset and 0.83 using the test dataset, with average and maximal discrepancies of 2.89% and 12.76% for the training dataset, and 0.98% and 5.49% for the test dataset, respectively. LIMITATIONS, REASONS FOR CAUTION: Our conclusions might not be compatible with those having fewer than four biopsied blastocysts and diminished ovarian reserves, since all of the included patients had four or more biopsied blastocysts and had exhibited good ovarian reserves. WIDER IMPLICATIONS OF THE FINDINGS: The developed predictive model is critical for counseling PAPL patients before PGT-A by considering maternal age, number of PAPLs, estradiol levels on the ovulation trigger day, and the blastocyst formation rate. This prediction model achieves good risk stratification and so may be useful for identifying PAPL patients who may have higher risk of blastocyst aneuploidy and can therefore acquire better pregnancy outcomes by PGT-A. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China under Grant (81871159). No competing interest existed in the study. TRIAL REGISTRATION NUMBER: N/A.

Crosstalk Between Autophagy and Inflammation in Chronic Cerebral Ischaemia.

Chronic cerebral ischaemia (CCI) is a high-incidence cardiovascular and cerebrovascular disease that is very common in clinical practice. Although many pathogenic mechanisms have been explored, there is still great controversy among neuroscientists regarding the pathogenesis of CCI. Therefore, it is important to elucidate the mechanisms of CCI occurrence and progression for the prevention and treatment of ischaemic cerebrovascular disorders. Autophagy and inflammation play vital roles in CCI, but the relationship between these two processes in this disease remains unknown. Here, we review the progression and discuss the functions, actions and pathways of autophagy and inflammation in CCI, including a comprehensive view of the transition from acute disease to CCI through ischaemic repair mechanisms. This review may provide a reference for future research and treatment of CCI. Schematic diagram of the interplay between autophagy and inflammation in CCI. CCI lead to serious, life-threatening complications. This review summarizes two factors in CCI, including autophagy and inflammation, which have been focused for the mechanisms of CCI. In short, the possible points of intersection are shown in the illustration. CCI, Chronic cerebral ischaemia; ER stress, Endoplasmic reticulum stress; ROS, Reactive oxygen species.

Prognostic value of the nutritional risk index in patients with newly diagnosed multiple myeloma.

The nutritional risk index (NRI), which is based on weight and albumin levels, is closely associated with the prognosis of many cancers. However, its prognostic value has not been investigated in patients with newly diagnosed multiple myeloma (NDMM). We aimed to assess the association between the NRI and survival outcomes in patients with NDMM. We retrospectively collected and analyzed clinical and laboratory data from patients with NDMM between 2005 and 2019 at our center. Patients were stratified into the high NRI (> 89) and low NRI (≤ 89) groups for prognostic analysis. The NRI and other variables were also explored to evaluate their prognostic value for overall survival (OS). A total of 638 patients diagnosed with NDMM were retrospectively included. Patients in the high NRI group had a significantly better median OS than those in the low NRI group (64 months vs 43 months, p < 0.001). In the multivariate analysis, a high NRI was shown to be an independent prognostic factor for OS (hazard ratio, 0.758; 95% confidence interval, 0.587-0.977; p = 0.033). Age, performance status, transplant status, and lactate dehydrogenase level were also independent prognostic factors for OS. In conclusion, our study demonstrates that the NRI is a simple and useful predictor of survival outcomes in patients with NDMM.

Rational Design of Noncentrosymmetric Organic-Inorganic Hybrids with a π-Conjugated Pyridium-Type Cation for High Nonlinear-Optical Performance.

Organic-inorganic hybrid materials have attracted increasing attention due to their unique superiority by combining the features of organic parts with inorganic parts. Herein, two organic-inorganic hybrid nonlinear-optical crystals, [C5H6O2N3]2[IO3]2 (I) and [C5H6O2N3][HSO4]·H2O (II), were successfully synthesized in aqueous solution by selecting 2-amino-3-nitropyridine as the cation and different anions of [IO3]- and [HSO4]-. The two compounds crystallized in the noncentrosymmetric space groups of P21 and P212121, respectively. I displays second-harmonic-generation (SHG) effects of 2.4 × KDP (KH2PO4) and a large birefringence (Δncal ∼ 0.22). Moreover, II exhibits a stronger SHG response of 5.2 × KDP, an enhanced band gap (2.81 eV), as well as a large birefringence (Δncal ∼ 0.25). This work points out a new feasible path for the rational design of high-performance organic-inorganic hybrid materials.