CIForm as a Transformer-based model for cell-type annotation of large-scale single-cell RNA-seq data.

Single-cell omics technologies have made it possible to analyze the individual cells within a biological sample, providing a more detailed understanding of biological systems. Accurately determining the cell type of each cell is a crucial goal in single-cell RNA-seq (scRNA-seq) analysis. Apart from overcoming the batch effects arising from various factors, single-cell annotation methods also face the challenge of effectively processing large-scale datasets. With the availability of an increase in the scRNA-seq datasets, integrating multiple datasets and addressing batch effects originating from diverse sources are also challenges in cell-type annotation. In this work, to overcome the challenges, we developed a supervised method called CIForm based on the Transformer for cell-type annotation of large-scale scRNA-seq data. To assess the effectiveness and robustness of CIForm, we have compared it with some leading tools on benchmark datasets. Through the systematic comparisons under various cell-type annotation scenarios, we exhibit that the effectiveness of CIForm is particularly pronounced in cell-type annotation. The source code and data are available at https://github.com/zhanglab-wbgcas/CIForm.

A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.

The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as an approximation for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays identified substitutions which conferred strong nirmatrelvir resistance and others that compromised activity. On the other hand, N142A and the P132H mutation, carried by the Omicron variant, caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.

STGRNS: an interpretable transformer-based method for inferring gene regulatory networks from single-cell transcriptomic data.

MOTIVATION: Single-cell RNA-sequencing (scRNA-seq) technologies provide an opportunity to infer cell-specific gene regulatory networks (GRNs), which is an important challenge in systems biology. Although numerous methods have been developed for inferring GRNs from scRNA-seq data, it is still a challenge to deal with cellular heterogeneity. RESULTS: To address this challenge, we developed an interpretable transformer-based method namely STGRNS for inferring GRNs from scRNA-seq data. In this algorithm, gene expression motif technique was proposed to convert gene pairs into contiguous sub-vectors, which can be used as input for the transformer encoder. By avoiding missing phase-specific regulations in a network, gene expression motif can improve the accuracy of GRN inference for different types of scRNA-seq data. To assess the performance of STGRNS, we implemented the comparative experiments with some popular methods on extensive benchmark datasets including 21 static and 27 time-series scRNA-seq dataset. All the results show that STGRNS is superior to other comparative methods. In addition, STGRNS was also proved to be more interpretable than "black box" deep learning methods, which are well-known for the difficulty to explain the predictions clearly. AVAILABILITY AND IMPLEMENTATION: The source code and data are available at https://github.com/zhanglab-wbgcas/STGRNS.

Associations of per- and polyfluoroalkyl substances (PFAS) and their mixture with risk of rheumatoid arthritis in the U.S. adult population.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are known environmental contaminants with immunosuppressive properties. Their connection to rheumatoid arthritis (RA), a condition influenced by the immune system, is not well studied. This research explores the association between PFAS exposure and RA prevalence. METHODS: This research utilized data from the NHANES, encompassing a sample of 10,496 adults from the 2003-2018 cycles, focusing on serum levels of several PFAS. The presence of RA was determined based on self-reports. This study used multivariable logistic regression to assess the relationship between individual PFAS and RA risk, adjusting for covariates to calculate odds ratios (ORs). The combined effects of PFAS mixtures were evaluated using BKMR, WQS regression, and quantile g-computation. Additionally, sex-specific associations were explored through stratified analysis. RESULTS: Higher serum PFOA (OR = 0.88, 95% CI: 0.79, 0.98), PFHxS (OR = 0.91, 95% CI: 0.83, 1.00), PFNA (OR = 0.87, 95% CI: 0.77, 0.98), and PFDA (OR = 0.89, 95% CI: 0.81, 0.99) concentration was related to lower odds of RA. Sex-specific analysis in single chemical models indicated the significant inverse associations were only evident in females. BKMR did not show an obvious pattern of RA estimates across PFAS mixture. The outcomes of sex-stratified quantile g-computation demonstrated that an increase in PFAS mixture was associated with a decreased odds of RA in females (OR: 0.76, 95% CI: 0.62, 0.92). We identified a significant interaction term of the WQS*sex in the 100 repeated hold out WQS analysis. Notably, a higher concentration of the PFAS mixture was significantly associated with reduced odds of RA in females (mean OR = 0.93, 95% CI: 0.88, 0.98). CONCLUSIONS: This study indicates potential sex-specific associations of exposure to various individual PFAS and their mixtures with RA. Notably, the observed inverse relationships were statistically significant in females but not in males. These findings contribute to the growing body of evidence indicating that PFAS may have immunosuppressive effects.

Effectiveness and Safety of Early Versus Routine Switching from Low-Molecular-Weight Heparin to Maintenance Therapy of Rivaroxaban for Acute Iliofemoral Vein Thrombosis: A Retrospective Cohort Study.

BACKGROUND: The anticoagulation strategy of switching to rivaroxaban after 1 week of initial low-molecular-weight heparin (LMWH) therapy is recommended by a guideline for the treatment of acute iliofemoral deep vein thrombosis (DVT). However, the initial rivaroxaban dose in the switching strategy, as well as the effectiveness and safety of the early switching (less than 1 week) to rivaroxaban, remain inadequately substantiated. We aimed to evaluate the effectiveness and safety of early switching from LMWH to maintenance therapy of rivaroxaban (20 mg once daily) for acute iliofemoral DVT. METHODS: A retrospective cohort study was conducted using data from patients with acute iliofemoral DVT who received initial LMWH anticoagulation followed by rivaroxaban maintenance therapy. The clinical outcomes were compared between early (LMWH course ≤7 days) and routine (LMWH course >7 days) switching strategies within 3 months of initiating anticoagulation. RESULTS: 217 patients were included, 59 (27.2%) receiving early switching and 158 (72.8%) receiving routine switching. Compared with routine switching, patients with early switching had a significantly shorter hospital stay (7 days vs. 14 days, P < 0.001). The length of hospital stay was significantly positively correlated with the duration of LMWH (r = 0.762, P < 0.001). The incidences of recurrent venous thromboembolism (5.1% vs. 2.5%, P = 0.606), major bleeding (0% vs. 1.9%, P = 0.564), clinically relevant nonmajor bleeding (1.7% vs. 2.5%, P = 1.000) and all-cause mortality (6.8% vs. 2.5%, P = 0.283) were not statistically different between the 2 groups. CONCLUSIONS: Direct early switching from LMWH to maintenance therapy of rivaroxaban is effective and safe for acute iliofemoral DVT.

Genome-Wide Identification and Expression Analysis of Kiwifruit Leucine-Rich Repeat Receptor-Like Proteins Reveal Their Roles in Biotic and Abiotic Stress Responses.

Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we performed family identification, characterization, transcriptome data analysis, and differential gene expression analysis of kiwifruit LRR-RLPs. We identified totals of 101, 164, and 105 LRR-RLPs in Actinidia chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5', respectively. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Based on RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

Histone H2B lysine 122 and lysine 130, as the putative targets of Penicillium oxalicum LaeA, play important roles in asexual development, expression of secondary metabolite gene clusters, and extracellular glycoside hydrolase synthesis.

Core histones in the nucleosome are subject to a wide variety of posttranslational modifications (PTMs), such as methylation, phosphorylation, ubiquitylation, and acetylation, all of which are crucial in shaping the structure of the chromatin and the expression of the target genes. A putative histone methyltransferase LaeA/Lae1, which is conserved in numerous filamentous fungi, functions as a global regulator of fungal growth, virulence, secondary metabolite formation, and the production of extracellular glycoside hydrolases (GHs). LaeA's direct histone targets, however, were not yet recognized. Previous research has shown that LaeA interacts with core histone H2B. Using S-adenosyl-L-methionine (SAM) as a methyl group donor and recombinant human histone H2B as the substrate, it was found that Penicillium oxalicum LaeA can transfer the methyl groups to the C-terminal lysine (K) 108 and K116 residues in vitro. The H2BK108 and H2BK116 sites on recombinant histone correspond to P. oxalicum H2BK122 and H2BK130, respectively. H2BK122A and H2BK130A, two mutants with histone H2B K122 or K130 mutation to alanine (A), were constructed in P. oxalicum. The mutants H2BK122A and H2BK130A demonstrated altered asexual development and decreased extracellular GH production, consistent with the findings of the laeA gene deletion strain (ΔlaeA). The transcriptome data showed that when compared to wild-type (WT) of P. oxalicum, 38 of the 47 differentially expressed (fold change ≥ 2, FDR ≤ 0.05) genes that encode extracellular GHs showed the same expression pattern in the three mutants ΔlaeA, H2BK122A, and H2BK130A. The four secondary metabolic gene clusters that considerably decreased expression in ΔlaeA also significantly decreased in H2BK122A or H2BK130A. The chromatin of promotor regions of the key cellulolytic genes cel7A/cbh1 and cel7B/eg1 compacted in the ΔlaeA, H2BK122A, and H2BK130A mutants, according to the results of chromatin accessibility real-time PCR (CHART-PCR). The chromatin accessibility index dropped. The histone binding pocket of the LaeA-methyltransf_23 domain is compatible with particular histone H2B peptides, providing appropriate electrostatic and steric compatibility to stabilize these peptides, according to molecular docking. The findings of the study demonstrate that H2BK122 and H2BK130, which are histone targets of P. oxalicum LaeA in vitro, are crucial for fungal conidiation, the expression of gene clusters encoding secondary metabolites, and the production of extracellular GHs.

Inhibition of Hypoxia-Inducible Transcription Factor (HIF-1α) Signaling with Sulfonyl-γ-AApeptide Helices.

The development of inhibitors that selectively block protein-protein interactions (PPIs) is crucial for chemical biology, medicinal chemistry, and biomedical sciences. Herein, we reported the design, synthesis, and investigation of sulfonyl-γ-AApeptide as an alternative strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible factor 1α (HIF-1α) and p300 PPI by mimicking the helical domain of HIF-1α involved in the binding to p300. The designed molecules recognized the p300 protein with high affinity and potently inhibited the hypoxia-inducible signaling pathway. Gene expression profiling supported the idea that the lead molecules selectively inhibited hypoxia-inducible genes involved in the signaling cascade. Our studies also demonstrated that both helical faces consisting of either chiral side chains or achiral sulfonyl side chains of sulfonyl-γ-AApeptides could be adopted for mimicry of the α-helix engaging in PPIs. Furthermore, these sulfonyl-γ-AApeptides were cell-permeable and exhibited favorable stability and pharmacokinetic profiles. Our results could inspire the design of helical sulfonyl-γ-AApeptides as a general strategy to mimic the protein helical domain and modulate many other PPIs.

The complex Tup1-Cyc8 bridges transcription factor ClrB and putative histone methyltransferase LaeA to activate the expression of cellulolytic genes.

The degradation of lignocellulosic biomass by cellulolytic enzymes is involved in the global carbon cycle. The hydrolysis of lignocellulosic biomass into fermentable sugars is potential as an excellent industrial resource to produce a variety of chemical products. The production of cellulolytic enzymes is regulated mainly at the transcriptional level in filamentous fungi. Transcription factor ClrB and the putative histone methyltransferase LaeA, are both necessary for the expression of cellulolytic genes. However, the mechanism by which transcription factors and methyltransferase coordinately regulate cellulolytic genes is still unknown. Here, we reveal a transcriptional regulatory mechanism involving Penicillium oxalicum transcription factor ClrB (PoClrB), complex Tup1-Cyc8, and putative histone methyltransferase LaeA (PoLaeA). As the transcription factor, PoClrB binds the targeted promoters of cellulolytic genes, recruits PoTup1-Cyc8 complex via direct interaction with PoTup1. PoTup1 interacts with PoCyc8 to form the coactivator complex PoTup1-Cyc8. Then, PoTup1 recruits putative histone methyltransferase PoLaeA to modify the chromatin structure of the upstream region of cellulolytic genes, thereby facilitating the binding of transcription machinery to activating the corresponding cellulolytic gene expression. Our results contribute to a better understanding of complex transcriptional regulation mechanisms of cellulolytic genes and will be valuable for lignocellulosic biorefining.

Comparative network analysis reveals the dynamics of organic acid diversity during fruit ripening in peach (Prunus persica L. Batsch).

BACKGROUND: Organic acids are important components that determine the fruit flavor of peach (Prunus persica L. Batsch). However, the dynamics of organic acid diversity during fruit ripening and the key genes that modulate the organic acids metabolism remain largely unknown in this kind of fruit tree which yield ranks sixth in the world. RESULTS: In this study, we used 3D transcriptome data containing three dimensions of information, namely time, phenotype and gene expression, from 5 different varieties of peach to construct gene co-expression networks throughout fruit ripening of peach. With the network inferred, the time-ordered network comparative analysis was performed to select high-acid specific gene co-expression network and then clarify the regulatory factors controlling organic acid accumulation. As a result, network modules related to organic acid synthesis and metabolism under high-acid and low-acid comparison conditions were identified for our following research. In addition, we obtained 20 candidate genes as regulatory factors related to organic acid metabolism in peach. CONCLUSIONS: The study provides new insights into the dynamics of organic acid accumulation during fruit ripening, complements the results of classical co-expression network analysis and establishes a foundation for key genes discovery from time-series multiple species transcriptome data.

Midterm Results of Drug-Coated Balloon and Bare Metal Stent in the Treatment of TASCII C/D Femoropopliteal Artery Occlusive Disease: A Retrospective Multicenter Study.

PURPOSE: This study aimed to compare midterm efficacy between drug-coated balloon (DCB) and bare metal stent (BMS) in the treatment of TASCII C/D femoropopliteal artery lesions. METHODS: The clinical data of patients with TASCII C/D femoropopliteal artery disease admitted to 3 vascular surgery centers from January 2018 to January 2021 were retrospectively analyzed. Patients were divided into DCB group and BMS group. The DCB group was further subdivided into DCB alone subgroup and DCB+BMS subgroup. Study primary outcomes were freedom from clinical-driven target lesion reintervention (FCD-TLR) at 24 months postprocedure. Secondary outcomes included ankle brachial index (ABI), Rutherford classification, major amputation rate, and mortality. RESULTS: A total of 410 consecutive patients were enrolled. At 24 months follow-up, in DCB group (114 patients) relative to BMS group (296 patients), FCD-TLR (86.00% vs 71.91%, p=0.039), and ABI (0.53±0.11 vs 0.47±0.19, p=0.007) were higher; mean Rutherford class was lower (1.57±0.68 vs 3.31±1.39, p=0.000); and major amputation rate (0.87% vs 4.05%, p>0.05) and all-cause mortality (8.92% vs 6.41%, p>0.05) were statistically similar. In DCB alone, subgroup relative to DCB+BMS subgroup, FCD-TLR (90.00% vs 85.00%, p>0.05), major amputation rate (0 vs 1.08%, p>0.05), and all-cause mortality rate (9.09% vs 8.69%, p>0.05) were statistically similar, while FCD-TLR was higher in the DCB+BMS subgroup (90.00% vs 71.91%, p=0.045). CONCLUSION: At midterm follow-up of patients treated for TASCII C/D femoropopliteal artery disease, use of DCB or of DCB combined with rescue BMS appeared similarly efficacious, and yielded more favorable outcomes than use of BMS. CLINICAL IMPACT: The efficacy of drug-coated balloons relative to that of bare metal stents for the treatment of complex femoropopliteal artery lesions, particularly TASCII grade D lesions, remains uncertain. There is a scarcity of multicenter comparative studies, and in this multicenter retrospective study with up to 24-month follow-up, use of drug-coated balloon alone or combined with rescue bare metal stent appeared similarly efficacious while yielding more favorable outcomes than use of bare metal stent alone in the treatment of TASCII grade C/D femoropopliteal artery lesions. Randomized studies are warranted.

Perfluoroalkyl and polyfluoroalkyl substances and hypertensive disorders of pregnancy: A systematic review and meta-analysis.

Hypertensive disorders of pregnancy (HDP), including gestational hypertension (GH) and preeclampsia (PE), cause significant morbidity and mortality among pregnant women. Several environmental toxins, particularly those that affect the normal function of the placenta and the endothelium, are emerging as potential risk factors for HDP. Among them, per- and polyfluoroalkyl substances (PFAS), widely used in a variety of commercial products, have been related to a variety of adverse health effects including HDP. This study was conducted by searching three databases for observational studies reporting associations between PFAS and HDP, all of which were published before December 2022. We used random-effects meta-analysis to calculate pooled risk estimates, and assessing each combination of exposure and outcome for quality and level of evidence. In total, 15 studies were included in the systematic review and meta-analysis. The results from meta-analyses showed that risk of PE was increased with exposure to PFOA (perfluorooctanoic acid) (RR = 1.39, 95% CI = 1.05, 1.85; N = 6 studies; exposure = 1 ln-unit increment; low certainty), PFOS (perfluorooctane sulfonate) (RR = 1.51, 95% CI = 1.23, 1.86; N = 6 studies; exposure = 1 ln-unit increment; moderate certainty), and PFHxS (perfluorohexane sulfonate) (RR = 1.39, 95% CI = 1.10, 1.76; N = 6 studies; exposure = 1 ln-unit increment; low certainty). PFOS was also associated with an increased risk of HDP (RR = 1.39, 95% CI = 1.10, 1.76; exposure = 1 ln-unit increment; low certainty). Exposure to legacy PFAS (PFOA, PFOS, PFHxS) is associated with an increased risk of PE, and PFOS is further associated with HDP. In view of the limitations of meta-analysis and quality of evidence, these findings should be interpreted with caution. Further research is required that assesses exposure to multiple PFAS in diverse and well-powered cohorts.

Joint effects of prenatal exposure to air pollution and pregnancy-related anxiety on birth weight: A prospective birth cohort study in Ma'anshan, China.

BACKGROUND: A growing number of studies have shown that prenatal exposure to chemical and non-chemical stressors has effects on fetal growth. The co-exposure of both better reflects real-life exposure patterns. However, no studies have included air pollutants and pregnancy-related anxiety (PrA) as mixtures in the analysis. METHOD: Using the birth cohort study method, 576 mother-child pairs were included in the Ma'anshan Maternal and Child Health Hospital. Evaluate the exposure levels of six air pollutants during pregnancy using inverse distance weighting (IDW) based on the pregnant woman's residential address and air pollution data from monitoring stations. Prenatal anxiety levels were assessed using the PrA Questionnaire. Generalized linear regression (GLR), quantile g-computation (QgC) and bayesian kernel machine regression (BKMR) were used to assess the independent or combined effects of air pollutants and PrA on birth weight for gestational age z-score (BWz). RESULT: The results of GLR indicate that the correlation between the six air pollutants and PrA with BWz varies depending on the different stages of pregnancy and pollutants. The QgC shows that during trimester 1, when air pollutants and PrA are considered as a whole exposure, an increase of one quartile is significantly negatively correlated with BWz. The BKMR similarly indicates that during trimester 1, the combined exposure of air pollutants and PrA is moderately correlated with a decrease in BWz. CONCLUSION: Using the method of analyzing mixed exposures, we found that during pregnancy, the combined exposure of air pollutants and PrA, particularly during trimester 1, is associated with BWz decrease. This supports the view that prenatal exposure to chemical and non-chemical stressors has an impact on fetal growth.

The associations of gestational weight gain and midpregnancy lipid levels with placental size and placental-to-birth weight ratio: findings from a chinese birth cohort study.

BACKGROUND: The placenta serves as the sole maternal organ responsible for transmitting nutrients to the fetus, playing a crucial role in supporting standard fetal growth and development. To date, only a small number of studies have investigated the impact of maternal gestational weight gain and lipid concentrations on placental development. This study aimed to explore the influence of weight gain during pregnancy and lipid levels in the second trimester on placental weight, volume, and the placental weight ratio. METHODS: This birth cohort study encompassed 1,358 mother-child pairs. Placental data for each participant was gathered immediately post-delivery, and the study incorporated data on gestational weight gain throughout pregnancy and lipid profiles from the mid-trimester. A linear regression model was employed to assess the correlations between gestational weight gain, mid-trimester lipid levels, and metrics such as placental weight, placental volume, and the placental-to-birth weight ratio (PFR). RESULTS: In the study groups of pre-pregnancy underweight, normal weight, and overweight, the placental weight increased by 4.93 g (95% CI: 1.04-8.81), 2.52 g (95% CI: 1.04-3.99), and 3.30 g (95% CI: 0.38-6.22) per 1 kg of gestational weight gain, respectively. Within the pre-pregnancy underweight and normal weight groups, the placental volume increased by 6.79 cm^3 (95% CI: 3.43-10.15) and 2.85 cm^3 (95% CI: 1.31-4.39) per 1 kg of gestational weight gain, respectively. Additionally, placental weight exhibited a positive correlation with triglyceride (TG) levels (ß = 9.81, 95% CI: 3.28-16.34) and a negative correlation with high-density lipoprotein (HDL-C) levels (ß = - 46.30, 95% CI: - 69.49 to - 23.11). Placental volume also showed a positive association with TG levels (ß = 14.54, 95% CI: 7.69-21.39). Conversely, PFR demonstrated a negative correlation with increasing HDL-C levels (ß = - 0.89, 95% CI: - 1.50 to - 0.27). CONCLUSIONS: Gestational weight gain was significantly correlated with both placental weight and volume. This association was especially pronounced in women who, prior to pregnancy, were underweight or of normal weight. Additionally, TG and HDL-C levels during the mid-trimester were linked to placental development.

Inhibition of VDAC1 Rescues Aß 1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/ß-Catenin Pathways.

Beta-amyloid (Aß) accumulation in the brains of Alzheimer's disease (AD) patients leads to mitochondrial dysfunction and ferroptosis in neurons. Voltage-dependent anion channel 1 (VDAC1) is a major protein in the mitochondrial outer membrane. It has been reported that VDAC1 associated with mitochondrial dysfunction and ferroptosis. However, the mechanism by which VDAC1 regulates mitochondrial dysfunction and ferroptosis of neurons in AD remains unclear. This study is aimed at investigating the mechanism of action of VDAC1 in mitochondrial dysfunction and ferroptosis in neurons of the AD model. In this study, we determined cell viability after treatment with Aß 1-42 via the MTT assay. The SOD, MDA, ROS, and MMP production was measured via the SOD kit, MDA kit, DCFDA staining, and JC-1 staining. The memory abilities of mice were detected via the Morris water maze test. The expression of AMPK/mTOR, Wnt/ß-catenin, and GPX4 regulated by VDAC1 was detected via western blotting. Our present study showed that PC12 cells had decreased cell viability, increased LDH release, and decreased GPX4 expression after Aß 1-42 treatment. Meanwhile, Aß 1-42 induced MMP and SOD downregulation and increased MDA and ROS generation in PC12 cells. In addition, the expression of VDAC1 is increased in the brain tissue of AD mice and Aß 1-42-treated PC12 cells. Further investigation of the role of VDAC1 in regulating AD found that all effects induced by Aß 1-42 were reversed by inhibition of VDAC1. Additionally, inhibition of VDAC1 activates the AMPK/mTOR and Wnt/ß-catenin pathways. Taken together, these findings demonstrate that inhibition of VDAC1 alleviates mitochondrial dysfunction and ferroptosis in AD neurons by activating AMPK/mTOR and Wnt/ß-catenin.

The effects of gestational diabetes mellitus on fetal growth: is it different for low-risk and medium-high-risk pregnant women?

BACKGROUND: It has been suggested that gestational diabetes mellitus (GDM) alters the growth trajectory of a fetus and increases the risk of abnormal birth weight. In spite of this, there is still a significant debate regarding the mode and optimal timing of diagnosing this condition. Our aim was to determine fetal growth velocity and birth biometry in pregnant women with GDM at varying risk levels. METHODS: We conducted a cohort study involving 1023 pregnant women at a maternity hospital in Ma'anshan, China. All women completed an oral glucose tolerance test at 24-28 weeks' gestation. We measured fetal head circumference (HC), femoral length (FL), abdominal circumference (AC), biparietal diameter (BPD), and estimate fetal weight (EFW) by ultrasound at 17, 24, 31, and 35 weeks' gestation, respectively. RESULTS: Overall, 5115 ultrasound scans were performed. Among both low-risk and medium-high-risk pregnant women at 17-24 weeks' gestation, GDM exposure was associated with an increase in fetal growth velocity. Neonates born to women with GDM at medium-high risk had significantly larger birth weights than those born to women without GDM, while this was not observed in women at low risk. CONCLUSION: In medium-high-risk pregnant women, exposure to GDM has a greater effect on the fetus, leading to abnormal fetal growth velocity that lasts beyond week 24. It is evident from our results that the effects of GDM on fetal growth differ between medium-high-risk pregnant women and low-risk pregnant women, and therefore a different screening program based on the risk factor for GDM is warranted.

A Genome-Wide Analysis of the Pentatricopeptide Repeat Protein Gene Family in Two Kiwifruit Species with an Emphasis on the Role of RNA Editing in Pathogen Stress.

Kiwifruit is a perennial fruit tree with high nutritional and economic value; however, various pathogen stresses have resulted in reductions in its yield and quality. Pentatricopeptide repeat proteins (PPRs), characterized by tandem repetitions of 35 amino acid motifs, play roles in RNA editing, mRNA stability, and splicing. They may also regulate plant development and growth. Nevertheless, the roles of PPRs in plant development and disease resistance remain unclear. In this study, we focused on the roles of PPRs in the fruit development and pathogen stress of kiwifruit and conducted a series of analyses of the PPR gene family in two representative kiwifruit species (Actinidia chinensis (Ach) and Actinidia eriantha (Ace)) with markedly different degrees of disease resistance. A total of 497 and 499 PPRs were identified in Ach and Ace, respectively. All the kiwifruit PPRs could be phylogenetically divided into four subfamilies. There were about 40.68% PPRs predicted to be localized to mitochondria or chloroplasts. A synteny analysis showed that the expansion of the kiwifruit PPRs mainly originated from segmental duplication. Based on RNA-seq data from the fruit over 12 periods of development and maturity, a weighted correlation network analysis suggested that two PPRs, Actinidia20495.t1 and Actinidia15159.t1, may be involved in fruit development and maturation. In addition, we observed different responses with respect to the expression of PPRs and RNA editing between resistant and susceptible kiwifruits following infection with pathogenic bacteria, indicating the regulatory role of PPRs in the stress response via the modulation of RNA editing. The differentially expressed upstream transcription factors of the PPRs were further identified; they may regulate resistance adaption by modulating the expression of the PPRs. Collectively, these results suggest that PPRs play roles in the development and disease resistance of kiwifruit and provide candidate genes for further clarifying the resistance mechanisms in kiwifruits.

The modification of meteorological factors on the relationship between air pollution and periodontal diseases: an exploration based on different interaction strategies.

We aimed to characterize the association between air pollutants exposure and periodontal diseases outpatient visits and to explore the interactions between ambient air pollutants and meteorological factors. The outpatient visits data of several large stomatological and general hospitals in Hefei during 2015-2020 were collected to explore the relationship between daily air pollutants exposure and periodontal diseases by combining Poisson's generalized linear model (GLMs) and distributed lag nonlinear model (DLNMs). Subgroup analysis was performed to identify the vulnerability of different populations to air pollutants exposure. The interaction between air pollutants and meteorological factors was verified in both multiplicative and additive interaction models. An interquartile range (IQR) increased in nitrogen dioxide (NO2) concentration was associated with the greatest lag-specific relative risk (RR) of gingivitis at lag 3 days (RR = 1.087, 95% CI 1.008-1.173). Fine particulate matter (PM2.5) exposure also increased the risk of periodontitis at the day of exposure (RR = 1.049, 95% CI 1.004-1.096). Elderly patients with gingivitis and periodontitis were both vulnerable to PM2.5 exposure. The interaction analyses showed that exposure to high levels of NO2 at low temperatures was related to an increased risk of gingivitis, while exposure to high levels of NO2 and PM2.5 may also increase the risk of gingivitis and periodontitis in the high-humidity environment, respectively. This study supported that NO2 and PM2.5 exposure increased the risk of gingivitis and periodontitis outpatient visits, respectively. Besides, the adverse effects of air pollutants exposure on periodontal diseases may vary depending on ambient temperature and humidity.

RSNET: inferring gene regulatory networks by a redundancy silencing and network enhancement technique.

BACKGROUND: Current gene regulatory network (GRN) inference methods are notorious for a great number of indirect interactions hidden in the predictions. Filtering out the indirect interactions from direct ones remains an important challenge in the reconstruction of GRNs. To address this issue, we developed a redundancy silencing and network enhancement technique (RSNET) for inferring GRNs. RESULTS: To assess the performance of RSNET method, we implemented the experiments on several gold-standard networks by using simulation study, DREAM challenge dataset and Escherichia coli network. The results show that RSNET method performed better than the compared methods in sensitivity and accuracy. As a case of study, we used RSNET to construct functional GRN for apple fruit ripening from gene expression data. CONCLUSIONS: In the proposed method, the redundant interactions including weak and indirect connections are silenced by recursive optimization adaptively, and the highly dependent nodes are constrained in the model to keep the real interactions. This study provides a useful tool for inferring clean networks.

Structural Insights into Molecular Recognition by Human Chemokine CCL19.

The human chemokines CCL19 and CCL21 bind to the G protein-coupled receptor (GPCR) CCR7 and play an important role in the trafficking of immune cells as well as cancer metastasis. Conserved binding sites for sulfotyrosine residues on the receptor contribute significantly to the chemokine/GPCR interaction and have been shown to provide promising targets for new drug-discovery efforts to disrupt the chemokine/GPCR interaction and, consequently, tumor metastasis. Here, we report the first X-ray crystal structure of a truncated CCL19 (residues 7-70) at 2.50 Å resolution, revealing molecular details crucial for protein-protein interactions. Although the overall structure is similar to the previously determined NMR model, there are important variations, particularly near the N terminus and the so-called 30's and 40's loops. Computational analysis using the FTMap server indicates the potential importance of these areas in ligand binding and the differences in binding hotspots compared to CCL21. NMR titration experiments using a CCR7-derived peptide (residues 5-11, TDDYIGD) further demonstrate potential receptor recognition sites, such as those near the C terminus and 40's loop, which consist of both positively charged and hydrophobic residues that may be important for receptor binding. Taken together, the X-ray, NMR, and computational analysis herein provide insights into the overall structure and molecular features of CCL19 and enables investigation into this chemokine's function and inhibitor development.