SMA1, a homolog of the splicing factor Prp28, has a multifaceted role in miRNA biogenesis in Arabidopsis

MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress gene expression. In plants, the RNase III enzyme Dicer-like (DCL1) processes primary miRNAs (pri-miRNAs) into miRNAs. Here, we show that SMALL1 (SMA1), a homolog of the DEADbox pre-mRNA splicing factor Prp28, plays essential roles in miRNA biogenesis in Arabidopsis. A hypomorphic sma1-1 mutation causes growth defects and reduces miRNA accumulation correlated with increased target transcript levels. SMA1 interacts with the DCL1 complex and positively influences primiRNA processing. Moreover, SMA1 binds the promoter region of genes encoding pri-miRNAs (MIRs) and is required for MIR transcription. Furthermore, SMA1 also enhances the abundance of the DCL1 protein levels through promoting the splicing of the DCL1 pre-mRNAs. Collectively, our data provide new insights into the function of SMA1/Prp28 in regulating miRNA abundance in plants

Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3βSer9, and Nrf2, and suppressed the activation of NF-κB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-κB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3βSer9, and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3β), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-κB signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3β-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis

Tryptophan in the mouse diet is essential for embryo implantation and decidualization

IntroductionNutritional deficiency occurs frequently during pregnancy and breastfeeding. Tryptophan (Trp), an essential amino acid which is critical for protein synthesis, serves as the precursor for serotonin, melatonin, and kynurenine (Kyn). The imbalance between serotonin and kynurenine pathways in Trp metabolism is closely related to inflammation and depression. This study assessed the effects of Trp deficiency on mouse early pregnancy.MethodsEmbryo implantation and decidualization were analyzed after female mice had been fed diets containing 0.2% Trp (for the control group), 0.062% Trp (for the low Trp group) and 0% Trp (for the Trp-free group) for two months. The uteri of the mice were collected on days 4, 5, and 8 of pregnancy for further analysis.ResultsOn day 8 of pregnancy, the number of implantation sites were found to be similar between the control and the low Trp groups. However, no implantation sites were detected in the Trp-free group. On day 5 of pregnancy, plane polarity- and decidualization-related molecules showed abnormal expression pattern in the Trp-free group. On day 4 of pregnancy, there was no significant difference in uterine receptivity molecules between the low-Trp group and the control group, but uterine receptivity was abnormal in the Trp-free group. At implantation sites of the Trp-free group, IDO and AHR levels were markedly elevated. This potentially increased levels of Kyn, 2-hydroxy estradiol, and 4-hydroxy estradiol to affect decidualization.ConclusionsTrp-free diet may impair decidualization via the IDO-KYN-AHR pathway

Decrease in seroprevalence of Hepatitis A after the implementation of nationwide disposable tableware use in Taiwan

<p>Abstract</p> <p>Background</p> <p>Taiwan is an endemic area of viral hepatitis, including hepatitis A, which is transmitted mainly from the fecal-oral route. In order to reduce the transmission through food intake, the government implemented a policy of nationwide disposal tableware use in public eating places in 1982. We conducted a study to estimate the seroprevalence of Hepatitis A in a group of workers in Taiwan in 2005, determine the risk factors, and compare seroprevalence to published estimates in Taiwan to evaluate changes in the seroprevalence after the implementation of the nationwide disposal tableware use.</p> <p>Methods</p> <p>We recruited workers of an industrial park during their annual health examinations in 2005 and measured their anti-hepatitis A virus IgG titer using microparticle enzyme immunoassay. We compared the seroprevalence across different birth cohorts within the study population and also analyzed data from previous studies.</p> <p>Results</p> <p>The overall sero-positive rate was 22.0% in the 11,777 participants. The rate was much lower among those who were covered by the program since birth (born after 1982) in comparison with those who were not (2.7% vs. 25.3%, p < 0.001). From the analyses of data from pervious studies, we found the age-specific rates were similar in cohorts born in or after 1982 across studies conducted in different time periods but decreased with the calendar year in cohorts born before 1982. In particular, the age-specific seroprevalence dropped to less than one third in a three-year period among those who were born around 1982.</p> <p>Conclusions</p> <p>Data from both the current and previous studies in different time periods supported the effectiveness of disposal tableware in preventing the transmission of hepatitis A.</p

Virchow: A Million-Slide Digital Pathology Foundation Model

Computational pathology uses artificial intelligence to enable precision medicine and decision support systems through the analysis of whole slide images. It has the potential to revolutionize the diagnosis and treatment of cancer. However, a major challenge to this objective is that for many specific computational pathology tasks the amount of data is inadequate for development. To address this challenge, we created Virchow, a 632 million parameter deep neural network foundation model for computational pathology. Using self-supervised learning, Virchow is trained on 1.5 million hematoxylin and eosin stained whole slide images from diverse tissue groups, which is orders of magnitude more data than previous works. When evaluated on downstream tasks including tile-level pan-cancer detection and subtyping and slide-level biomarker prediction, Virchow outperforms state-of-the-art systems both on internal datasets drawn from the same population as the pretraining data as well as external public datasets. Virchow achieves 93% balanced accuracy for pancancer tile classification, and AUCs of 0.983 for colon microsatellite instability status prediction and 0.967 for breast CDH1 status prediction. The gains in performance highlight the importance of pretraining on massive pathology image datasets, suggesting pretraining on even larger datasets could continue improving performance for many high-impact applications where limited amounts of training data are available, such as drug outcome prediction

Properties of Graphene: A Theoretical Perspective

In this review, we provide an in-depth description of the physics of monolayer and bilayer graphene from a theorist's perspective. We discuss the physical properties of graphene in an external magnetic field, reflecting the chiral nature of the quasiparticles near the Dirac point with a Landau level at zero energy. We address the unique integer quantum Hall effects, the role of electron correlations, and the recent observation of the fractional quantum Hall effect in the monolayer graphene. The quantum Hall effect in bilayer graphene is fundamentally different from that of a monolayer, reflecting the unique band structure of this system. The theory of transport in the absence of an external magnetic field is discussed in detail, along with the role of disorder studied in various theoretical models. We highlight the differences and similarities between monolayer and bilayer graphene, and focus on thermodynamic properties such as the compressibility, the plasmon spectra, the weak localization correction, quantum Hall effect, and optical properties. Confinement of electrons in graphene is nontrivial due to Klein tunneling. We review various theoretical and experimental studies of quantum confined structures made from graphene. The band structure of graphene nanoribbons and the role of the sublattice symmetry, edge geometry and the size of the nanoribbon on the electronic and magnetic properties are very active areas of research, and a detailed review of these topics is presented. Also, the effects of substrate interactions, adsorbed atoms, lattice defects and doping on the band structure of finite-sized graphene systems are discussed. We also include a brief description of graphane -- gapped material obtained from graphene by attaching hydrogen atoms to each carbon atom in the lattice.Comment: 189 pages. submitted in Advances in Physic

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region

Both Conifer II and Gnetales are characterized by a high frequency of ancient mitochondrial gene transfer to the nuclear genome

Background Mitochondrial gene transfer/loss is common in land plants, and therefore the fate of missing mitochondrial genes has attracted more and more attention. The gene content of gymnosperm mitochondria varies greatly, supplying a system for studying the evolutionary fate of missing mitochondrial genes. Results Here, we studied the tempo and pattern of mitochondrial gene transfer/loss in gymnosperms represented by all 13 families, using high-throughput sequencing of both DNA and cDNA. All 41 mitochondrial protein-coding genes were found in cycads, Ginkgo and Pinaceae, whereas multiple mitochondrial genes were absent in Conifer II and Gnetales. In Conifer II, gene transfer from mitochondria to the nucleus followed by loss of the mitochondrial copy was common, but complete loss of a gene in both mitochondrial and nuclear genomes was rare. In contrast, both gene transfer and loss were commonly found in Gnetales. Notably, in Conifer II and Gnetales, the same five mitochondrial genes were transferred to the nuclear genome, and these gene transfer events occurred, respectively, in ancestors of the two lineages. A two-step transfer mechanism (retroprocessing and subsequent DNA-mediated gene transfer) may be responsible for mitochondrial gene transfer in Conifer II and Gnetales. Moreover, the mitochondrial gene content variation is correlated with gene length, GC content, hydrophobicity, and nucleotide substitution rates in land plants. Conclusions This study reveals a complete evolutionary scenario for variations of mitochondrial gene transferring in gymnosperms, and the factors responsible for mitochondrial gene content variation in land plants