Causal association of circulating cholesterol levels with dementia: a mendelian randomization meta-analysis

Prospective studies have shown that abnormally circulating cholesterol is associated with the risk of dementia. However, whether the association is causal or not remains unclear. We attempt to infer the causal association in a MR meta-analysis by using ApoE gene polymorphisms as instrument variables. Studies with dementia risk (27 studies) or circulating lipid levels (7 studies) were included, with totally 3136 dementia patients and 3103 healthy controls. The analyses showed that carriers of ε2 allele significantly were of decreased risk of AD (OR = 0.70; 95% CI: 0.58–0.84; P \u3c 0.01), whereas carriers of ε4 allele were of increased risk of AD (OR = 3.62; 95% CI: 3.03–4.32; P \u3c 0.05), compared to these of ε3 allele. Circulating TC was significantly reduced in carriers of ε2 allele (WMD = − 0.29 mmol/L; 95% CI: −0.54 to −0.03; P \u3c 0.05) and increased in carriers of ε4 allele (WMD = 0.42 mmol/l; 95% CI: 0.001–0.84; P \u3c 0.05). In addition, carriers of ε4 allele had reduction in circulating HDL-C (WMD = − 0.04 mmol/L; 95% CI: − 0.07 to −0.001; P \u3c 0.05). In comparing allele ε2 with ε3, the predicted OR of having AD for 1 mg/dL increment in circulating TC was 0.97 (95% CI: 0.86–0.98; P \u3c 0.05). Comparing allele ε4 with ε3, the predicted OR for a 1 mg/dL increment in TC was 1.08 (95% CI: 1.05–17.58; P \u3c 0.05), and reduction in HDL-C was 2.30 (95% CI: 1.51–43.99; P \u3c 0.05). Our findings demonstrate that high circulating TC and reduced HDL-C levels might be potential risk factors of the development of AD

Vascular endothelial growth factor and the risk of venous thromboembolism: A genetic correlation and two-sample Mendelian randomization study

Background: The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. Methods: Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran’s Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. Results: LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95 % confidence interval (CI), 1.009 – 1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (β = -0.021, 95 % CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. Conclusions: Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted

Investigation on the propagation characteristics of pressure wave during managed pressure drilling

The small difference between formation pressure and fracture pressure in offshore oil and gas reservoirs poses a huge challenge to drilling. Managed pressure drilling (MPD) technology, as a drilling technique that can accurately control bottomhole pressure, is an effective technique to solve this challenge. In MPD technology, the pressure wave propagation behavior and mechanism in the wellbore induced by wellhead backpressure are crucial for parameter design and efficient application. In this paper, pressure wave propagation characteristics and mechanism in gas-liquid flow were investigated with a new proposed pressure wave velocity model that considers inter-phase mass transfer effect. This new model and its solution algorithm were verified with experimental data in literature. The influence of gas invasion stage, drilling fluid type, drilling fluid density and backpressure on pressure wave propagation characteristics were investigated. Results show that the time for pressure wave induced by wellhead backpressure in the wellbore cannot be ignored in the design of the backpressure value during MPD. This propagation time increases with occurrence of gas invasion. Moreover, the propagation time in water-based drilling fluid is longer than that in oil-based drilling fluid, which is because the interphase mass transfer between invaded gas and oil-based drilling fluid. The influence mechanism of high drilling fluid density and wellhead backpressure on pressure wave propagation characteristics is due to the suppression of gas invasion process. These findings could be used as guides in parameters design and optimization in MPD

A transcription factor of the NAC family regulates nitrate-induced legume nodule senescence

17 Pags.- 7 Figs. © 2023 The AuthorsLegumes establish symbioses with rhizobia by forming nitrogen-fixing nodules. Nitrate is amajor environmental factor that affects symbiotic functioning. However, the molecularmechanism of nitrate-induced nodule senescence is poorly understood. Comparative transcriptomic analysis reveals an NAC-type transcription factor inLotus japo-nicus, LjNAC094, that acts as a positive regulator in nitrate-induced nodule senescence.Stable overexpression and mutant lines ofNAC094were constructed and used for phenotypiccharacterization. DNA-affinity purification sequencing was performed to identify NAC094targeting genes and results were confirmed by electrophoretic mobility shift and transactiva-tion assays. Overexpression ofNAC094induces premature nodule senescence. Knocking outNAC094partially relieves nitrate-induced degradation of leghemoglobins and abolishes nodule expres-sion of senescence-associated genes (SAGs) that contain a conserved binding motif forNAC094. Nitrate-triggered metabolic changes in wild-type nodules are largely affected innac094mutant nodules. Induction ofNAC094and its targetingSAGswas almost blocked inthe nitrate-insensitivenlp1,nlp4, andnlp1 nlp4mutants. We conclude that NAC094 functions downstream of NLP1 and NLP4 by regulating nitrate-induced expression ofSAGs. Our study fills in a key gap between nitrate and the execution ofnodule senescence, and provides a potential strategy to improve nitrogen fixation and stresstolerance of legumes.This work was supported by the National Natural Science Foundation of China (32000192, 31870220), the Foundation of Hubei Hongshan Laboratory (2022hszd014), Fundamental Research Funds for the Central Universities (2662020SKPY007), and MCIN/AEI/10.13039/501100011033 (grant PID2020-113985GB-I00). We also thank the BaiChuan fellowship of College of Life Science and Technology, Huazhong Agricultural University, for funding support.Peer reviewe

Heme catabolism mediated by heme oxygenase in uninfected interstitial cells enables efficient symbiotic nitrogen fixation in Lotus japonicus nodules

18 Pags.- 8 Figs. © 2023 The Authors. New Phytologist.Legume nodules produce large quantities of heme required for the synthesis of leghemoglobin (Lb) and other hemoproteins. Despite the crucial function of Lb in nitrogen fixation and the toxicity of free heme, the mechanisms of heme homeostasis remain elusive. Biochemical, cellular, and genetic approaches were used to study the role of heme oxygenases (HOs) in heme degradation in the model legume Lotus japonicus. Heme and biliverdin were quantified and localized, HOs were characterized, and knockout LORE1 and CRISPR/Cas9 mutants for LjHO1 were generated and phenotyped. We show that LjHO1, but not the LjHO2 isoform, is responsible for heme catabolism in nodules and identify biliverdin as the in vivo product of the enzyme in senescing green nodules. Spatiotemporal expression analysis revealed that LjHO1 expression and biliverdin production are restricted to the plastids of uninfected interstitial cells. The nodules of ho1 mutants showed decreased nitrogen fixation, and the development of brown, rather than green, nodules during senescence. Increased superoxide production was observed in ho1 nodules, underscoring the importance of LjHO1 in antioxidant defense. We conclude that LjHO1 plays an essential role in degradation of Lb heme, uncovering a novel function of nodule plastids and uninfected interstitial cells in nitrogen fixation.This work was supported by the Ministry of Science and Technology of the People’s Republic of China (2021YFA0910800), National Natural Science Foundation of China (31870220), the Foundation of Hubei Hongshan Laboratory (2022hszd014), HZAU-AGIS Cooperation Fund (SZYJY2022005), and MCIN/AEI/10.13039/ 501100011033 of Spain (grant PID2020-113985GB-I00).Peer reviewe

Single cell-type transcriptome profiling reveals genes that promote nitrogen fixation in the infected and uninfected cells of legume nodules

2 Pags.- 1 Fig. © 2022 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use,distribution and reproduction in any medium, provided the original work is properly cited.Excessive application of nitrogen fertilizers has inevitably resultedin environmental problems. The symbiotic nitrogen fixation (SNF) that occurs in the root nodules of leguminous plants provides asustainable source of reduced nitrogen in agricultural ecosystems. More than 200 genes have been reported to regulate SNF, including rhizobial infection, nodule organogenesis and senescence (Royet al., 2020). Mature nodules consist mainly of twocell types: infected cells (IC) that contain nitrogen-fixing bac-teroids and uninfected cells (UC) that mediate active metabolismand nutrient transport. Although it is well known that SNFrequires functional specialization, the specific genes responsiblefor transcriptional regulation and carbon/nitrogen metabolismand transport in IC and UC remain largely unexplored.Single-cell transcriptomics has emerged as a powerful tech-nique for investigating spatiotemporal patterns of gene expression.This work was supported by the National Natural Science Foundation of China (31870220, 32000192), the China Post-doctoral Science Foundation (2020M680103), Fundamental Research Funds for the Central Universities 2662020SKPY007 and MCIN/AEI/10.13039/501100011033 (grant PID2020-113985GB-I00)Peer reviewe

Altered Brain Function in Treatment-Resistant and Non-treatment-resistant Depression Patients: A Resting-State Functional Magnetic Resonance Imaging Study

ObjectiveIn this study, we used amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) to observe differences in local brain functional activity and its characteristics in patients with treatment-resistant depression (TRD) and non-treatment-resistant depression (nTRD), and to explore the correlation between areas of abnormal brain functional activity and clinical symptoms.MethodThirty-seven patients with TRD, 36 patients with nTRD, and 35 healthy controls (HCs) were included in resting-state fMRI scans. ALFF and ReHo were used for image analysis and further correlation between abnormal brain regions and clinical symptoms were analyzed.ResultsANOVA revealed that the significantly different brain regions of ALFF and ReHo among the three groups were mainly concentrated in the frontal and temporal lobes. Compared with the nTRD group, the TRD group had decreased ALFF in the left/right inferior frontal triangular gyrus, left middle temporal gyrus, left cuneus and bilateral posterior lobes of the cerebellum, and increased ALFF in the left middle frontal gyrus and right superior temporal gyrus, and the TRD group had decreased ReHo in the left/right inferior frontal triangular gyrus, left middle temporal gyrus, and increased ReHo in the right superior frontal gyrus. Compared with the HC group, the TRD group had decreased ALFF/ReHo in both the right inferior frontal triangular gyrus and the left middle temporal gyrus. Pearson correlation analysis showed that both ALFF and ReHo values in these abnormal brain regions were positively correlated with HAMD-17 scores (P < 0.05).ConclusionAlthough the clinical symptoms were similar in the TRD and nTRD groups, abnormal neurological functional activity were present in some of the same brain regions. Compared with the nTRD group, ALFF and ReHo showed a wider range of brain area alterations and more complex neuropathological mechanisms in the TRD group, especially in the inferior frontal triangular gyrus of the frontal lobe and the middle temporal gyrus of the temporal lobe

A Full Stage Data Augmentation Method in Deep Convolutional Neural Network for Natural Image Classification

Nowadays, deep learning has achieved remarkable results in many computer vision related tasks, among which the support of big data is essential. In this paper, we propose a full stage data augmentation framework to improve the accuracy of deep convolutional neural networks, which can also play the role of implicit model ensemble without introducing additional model training costs. Simultaneous data augmentation during training and testing stages can ensure network optimization and enhance its generalization ability. Augmentation in two stages needs to be consistent to ensure the accurate transfer of specific domain information. Furthermore, this framework is universal for any network architecture and data augmentation strategy and therefore can be applied to a variety of deep learning based tasks. Finally, experimental results about image classification on the coarse-grained dataset CIFAR-10 (93.41%) and fine-grained dataset CIFAR-100 (70.22%) demonstrate the effectiveness of the framework by comparing with state-of-the-art results

A Malus crabapple chalcone synthase gene, McCHS, regulates red petal color and flavonoid biosynthesis.

Chalcone synthase is a key and often rate-limiting enzyme in the biosynthesis of anthocyanin pigments that accumulate in plant organs such as flowers and fruits, but the relationship between CHS expression and the petal coloration level in different cultivars is still unclear. In this study, three typical crabapple cultivars were chosen based on different petal colors and coloration patterns. The two extreme color cultivars, 'Royalty' and 'Flame', have dark red and white petals respectively, while the intermediate cultivar 'Radiant' has pink petals. We detected the flavoniods accumulation and the expression levels of McCHS during petals expansion process in different cultivars. The results showed McCHS have their special expression patterns in each tested cultivars, and is responsible for the red coloration and color variation in crabapple petals, especially for color fade process in 'Radiant'. Furthermore, tobacco plants constitutively expressing McCHS displayed a higher anthocyanins accumulation and a deeper red petal color compared with control untransformed lines. Moreover, the expression levels of several anthocyanin biosynthetic genes were higher in the transgenic McCHS overexpressing tobacco lines than in the control plants. A close relationship was observed between the expression of McCHS and the transcription factors McMYB4 and McMYB5 during petals development in different crabapple cultivars, suggesting that the expression of McCHS was regulated by these transcription factors. We conclude that the endogenous McCHS gene is a critical factor in the regulation of anthocyanin biosynthesis during petal coloration in Malus crabapple