Paternal Smoking and Risk of Childhood Acute Lymphoblastic Leukemia: Systematic Review and Meta-Analysis

Objective. To investigate the association between paternal smoking and childhood acute lymphoblastic leukemia (ALL). Method. We identified 18 published epidemiologic studies that reported data on both paternal smoking and childhood ALL risk. We performed a meta-analysis and analyzed dose-response relationships on ALL risk for smoking during preconception, during pregnancy, after birth, and ever smoking. Results. The summary odds ratio (OR) of childhood ALL associated with paternal smoking was 1.11 (95% Confidence Interval (CI): 1.05–1.18, I2 = 18%) during any time period, 1.25 (95% CI: 1.08–1.46, I2 = 53%) preconception; 1.24 (95% CI: 1.07–1.43, I2 = 54%) during pregnancy, and 1.24 (95% CI: 0.96–1.60, I2 = 64%) after birth, with a dose-response relationship between childhood ALL and paternal smoking preconception or after birth. Conclusion. The evidence supports a positive association between childhood ALL and paternal ever smoking and at each exposure time period examined. Future epidemiologic studies should assess paternal smoking during well-defined exposure windows and should include biomarkers to assess smoking exposure and toxicological mechanisms

Elongated Physiological Structure Segmentation via Spatial and Scale Uncertainty-aware Network

Robust and accurate segmentation for elongated physiological structures is challenging, especially in the ambiguous region, such as the corneal endothelium microscope image with uneven illumination or the fundus image with disease interference. In this paper, we present a spatial and scale uncertainty-aware network (SSU-Net) that fully uses both spatial and scale uncertainty to highlight ambiguous regions and integrate hierarchical structure contexts. First, we estimate epistemic and aleatoric spatial uncertainty maps using Monte Carlo dropout to approximate Bayesian networks. Based on these spatial uncertainty maps, we propose the gated soft uncertainty-aware (GSUA) module to guide the model to focus on ambiguous regions. Second, we extract the uncertainty under different scales and propose the multi-scale uncertainty-aware (MSUA) fusion module to integrate structure contexts from hierarchical predictions, strengthening the final prediction. Finally, we visualize the uncertainty map of final prediction, providing interpretability for segmentation results. Experiment results show that the SSU-Net performs best on cornea endothelial cell and retinal vessel segmentation tasks. Moreover, compared with counterpart uncertainty-based methods, SSU-Net is more accurate and robust

CKS Proteins Promote Checkpoint Recovery by Stimulating Phosphorylation of Treslin

CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro. Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication

Expression Analysis and Interaction Protein Screening of CRY1 in Strawberry

Cryptochrome 1 (CRY1), a main blue light receptor protein, plays a significant role in several biological processes. However, the expression patterns and function of CRY1 in strawberry have not been identified. Here, the expression profile of CRY1 in different tissues and developmental stages of strawberry fruit, and expression patterns response to abiotic stresses (low temperature, salt and drought) were analyzed. Its subcellular localization, interaction proteins and heterologous overexpression in tobacco were also investigated. The results showed that CRY1 was mainly expressed in leaves and fruits with an expression peak at the initial red stage in strawberry fruit. Abiotic stresses could significantly induce the expression of CRY1. The CRY1 protein was located in both nucleus and cytoplasm. Five proteins (CSN5a-like, JAZ5, eIF3G. NF-YC9, and NDUFB9) interacting with CRY1 were discovered. Genes related flowering times, such as HY5 and CO, in three overexpressed FaCRY1 tobacco lines, were significantly upregulated. Taken together, our results suggested CRY1 have a broad role in biological processes in strawberry

Serum metabolomics analysis in patients with alcohol dependence

ObjectiveAlcohol dependence (AD) is a chronic recurrent mental disease caused by long-term drinking. It is one of the most prevalent public health problems. However, AD diagnosis lacks objective biomarkers. This study was aimed to shed some light on potential biomarkers of AD patients by investigating the serum metabolomics profiles of AD patients and the controls.MethodsLiquid chromatography-mass spectrometry (LC–MS) was used to detect the serum metabolites of 29 AD patients (AD) and 28 controls. Six samples were set aside as the validation set (Control: n = 3; AD group: n = 3), and the remaining were used as the training set (Control: n = 26; AD group: n = 25). Principal component analysis (PCA) and partial least squares discriminant analysis (PCA-DA) were performed to analyze the training set samples. The metabolic pathways were analyzed using the MetPA database. The signal pathways with pathway impact >0.2, value of p <0.05, and FDR < 0.05 were selected. From the screened pathways, the metabolites whose levels changed by at least 3-fold were screened. The metabolites with no numerical overlap in their concentrations in the AD and the control groups were screened out and verified with the validation set.ResultsThe serum metabolomic profiles of the control and the AD groups were significantly different. We identified six significantly altered metabolic signal pathways, including protein digestion and absorption; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; linoleic acid metabolism; butanoate metabolism; and GABAergic synapse. In these six signal pathways, the levels of 28 metabolites were found to be significantly altered. Of these, the alterations of 11 metabolites changed by at least 3-fold compared to the control group. Of these 11 metabolites, those with no numerical overlap in their concentrations between the AD and the control groups were GABA, 4-hydroxybutanoic acid, L-glutamic acid, citric acid and L-glutamine.ConclusionThe metabolite profile of the AD group was significantly different from that of the control group. GABA, 4-hydroxybutanoic acid, L-glutamic acid, citric acid, and L-glutamine could be used as potential diagnostic markers for AD

Melatonin-Mediated Sugar Accumulation and Growth Inhibition in Apple Plants Involves Down-Regulation of Fructokinase 2 Expression and Activity

Melatonin has been reported to play roles in regulating carbohydrate levels and plant growth. However, little is known about the exact mechanism by which melatonin regulates sugar levels and growth in plants. In this study, it was found that high levels of melatonin inhibited the growth of wild-type (WT) apple plants and induced significant accumulations of fructose, glucose, and sucrose in apple leaves, while MdFRK2 expression was significantly downregulated. MdFRK2 promoter transiently expressed in tobacco leaves further supported that the expression of MdFRK2 could be inhibited by exogenous melatonin. After applying exogenous melatonin, the suppression of MdFRK2 expression was significantly rescued in transgenic apples overexpressing MdFRK2 via the 35S promoter. Fructose, glucose, and sucrose concentrations increased less as compared to WT apple plants. Wild-type plants showed a stunted phenotype 21 days after melatonin treatment, while MdFRK2-overexpressing plants exhibited slightly inhibited growth, indicating that the downregulated MdFRK2 expression in response to melatonin was involved in melatonin-mediated growth inhibition. Taken together, these results demonstrate the involvement of MdFRK2 in melatonin-induced sugar accumulation and growth inhibition. Our findings shed light on the roles played by MdFRK2 in connecting melatonin action and plant growth

The modulation of acute methamphetamine on the neuronal network oscillations in rat hippocampal CA3 area.

Gamma frequency oscillations (γ, 30–100 Hz) have been suggested to underlie various cognitive and motor functions. The psychotomimetic drug methamphetamine (MA) enhances brain γ oscillations associated with changes in psychomotor state. Little is known about the cellular mechanisms of MA modulation on γ oscillations. We explored the effects of multiple intracellular kinases on MA modulation of γ induced by kainate in area CA3 of rat ventral hippocampal slices. We found that dopamine receptor type 1 and 2 (DR1 and DR2) antagonists, the serine/threonine kinase PKB/Akt inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonists prevented the enhancing effect of MA on γ oscillations, whereas none of them affected baseline γ strength. Protein kinase A, phosphoinositide 3-kinase and extracellular signal-related kinases inhibitors had no effect on MA. We propose that the DR1/DR2-Akt-NMDAR pathway plays a critical role for the MA enhancement of γ oscillations. Our study provides an new insight into the mechanisms of acute MA on MA-induced psychosis