Substantial viral diversity in bats and rodents from East Africa: insights into evolution, recombination, and cocirculation.

BACKGROUND: Zoonotic viruses cause substantial public health and socioeconomic problems worldwide. Understanding how viruses evolve and spread within and among wildlife species is a critical step when aiming for proactive identification of viral threats to prevent future pandemics. Despite the many proposed factors influencing viral diversity, the genomic diversity and structure of viral communities in East Africa are largely unknown. RESULTS: Using 38.3 Tb of metatranscriptomic data obtained via ultradeep sequencing, we screened vertebrate-associated viromes from 844 bats and 250 rodents from Kenya and Uganda collected from the wild. The 251 vertebrate-associated viral genomes of bats (212) and rodents (39) revealed the vast diversity, host-related variability, and high geographic specificity of viruses in East Africa. Among the surveyed viral families, Coronaviridae and Circoviridae showed low host specificity, high conservation of replication-associated proteins, high divergence among viral entry proteins, and frequent recombination. Despite major dispersal limitations, recurrent mutations, cocirculation, and occasional gene flow contribute to the high local diversity of viral genomes. CONCLUSIONS: The present study not only shows the landscape of bat and rodent viromes in this zoonotic hotspot but also reveals genomic signatures driven by the evolution and dispersal of the viral community, laying solid groundwork for future proactive surveillance of emerging zoonotic pathogens in wildlife. Video Abstract.

The impact of Bayesian optimization on feature selection.

Feature selection is an indispensable step for the analysis of high-dimensional molecular data. Despite its importance, consensus is lacking on how to choose the most appropriate feature selection methods, especially when the performance of the feature selection methods itself depends on hyper-parameters. Bayesian optimization has demonstrated its advantages in automatically configuring the settings of hyper-parameters for various models. However, it remains unclear whether Bayesian optimization can benefit feature selection methods. In this research, we conducted extensive simulation studies to compare the performance of various feature selection methods, with a particular focus on the impact of Bayesian optimization on those where hyper-parameters tuning is needed. We further utilized the gene expression data obtained from the Alzheimer's Disease Neuroimaging Initiative to predict various brain imaging-related phenotypes, where various feature selection methods were employed to mine the data. We found through simulation studies that feature selection methods with hyper-parameters tuned using Bayesian optimization often yield better recall rates, and the analysis of transcriptomic data further revealed that Bayesian optimization-guided feature selection can improve the accuracy of disease risk prediction models. In conclusion, Bayesian optimization can facilitate feature selection methods when hyper-parameter tuning is needed and has the potential to substantially benefit downstream tasks.

Bayesian linear mixed model with multiple random effects for prediction analysis on high-dimensional multi-omics data.

MOTIVATION: Accurate disease risk prediction is an essential step in the modern quest for precision medicine. While high-dimensional multi-omics data have provided unprecedented data resources for prediction studies, their high-dimensionality and complex inter/intra-relationships have posed significant analytical challenges. RESULTS: We proposed a two-step Bayesian linear mixed model framework (TBLMM) for risk prediction analysis on multi-omics data. TBLMM models the predictive effects from multi-omics data using a hybrid of the sparsity regression and linear mixed model with multiple random effects. It can resemble the shape of the true effect size distributions and accounts for non-linear, including interaction effects, among multi-omics data via kernel fusion. It infers its parameters via a computationally efficient variational Bayes algorithm. Through extensive simulation studies and the prediction analyses on the positron emission tomography imaging outcomes using data obtained from the Alzheimer's Disease Neuroimaging Initiative, we have demonstrated that TBLMM can consistently outperform the existing method in predicting the risk of complex traits. AVAILABILITY AND IMPLEMENTATION: The corresponding R package is available on GitHub (https://github.com/YaluWen/TBLMM).

p53-regulated lncRNAs in cancers: from proliferation and metastasis to therapy.

Long non-coding RNAs (lncRNAs) have been identified as master gene regulators through various mechanisms such as transcription, translation, protein modification and RNA-protein complexes. LncRNA dysregulation is frequently associated with a variety of biological functions and human diseases including cancer. The p53 network is a key tumor-suppressive mechanism that transcriptionally activates target genes to suppress cellular proliferation in human malignancies. Recent research indicates that lncRNAs play an important role in the p53 signaling pathway. In this review, we summarize the current knowledge of lncRNAs in p53-relevant functions and provide an overview of how these altered lncRNAs contribute to tumor initiation and progression. We also discuss the association between lncRNA and up- or downstream genes of p53. These findings imply that lncRNAs can help identify cellular vulnerabilities that may prove to be promising potential biomarkers and therapeutic targets for cancer treatment.

Long non-coding RNA HIF1A-As2 and MYC form a double-positive feedback loop to promote cell proliferation and metastasis in KRAS-driven non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.

A graphitic-C3N4 derivative containing heptazines merged with phenyls: synthesis, purification and application as a high-efficiency metal-free quasi-green phosphor for white LEDs.

Because rare-earth elements are scarce, expensive, and unsustainable, it is of great significance to develop rare-earth-free (even metal-free) luminescent materials as phosphors for LEDs. Here, a graphitic-C3N4 (g-C3N4) derivative containing some heptazines merged with phenyls has been synthesized via thermal polymerization of melamine and quinazoline-2,4(1H,3H)-dione at an optimal mole ratio of 18 : 1. In comparison with g-C3N4 synthesized from melamine only, the photoluminescent (PL) emission colour changed from blue to green, the maximum emission wavelength (λ em,max) changed from 467 nm to 508 nm, and the PL quantum yield (PLQY) increased from 8.0% to 24.0%. It was further purified via vacuum sublimation, and a product with yellowish green emission (λ em,max = 517 nm) and PLQY up to 45.5% was obtained. This sublimated product had high thermal stability and low thermal quenching; its thermal decomposition temperature was as high as 527 °C, and its relative PL emission intensity at 100 °C was 90.8% of that at 20 °C. Excited by blue light chips (λ em,max ≈ 460 nm), cold, neutral and warm white LEDs can be fabricated using the sublimated product and orange-emitting (Sr,Ba)3SiO5:Eu2+ as phosphors. The good performances of these white LEDs (for example, the CIE coordinates, color rendering index and correlated color temperature were (0.31, 0.33), 84.4 and 6577 K, respectively) suggest that the low-efficiency blue-emitting g-C3N4 had been successfully converted into a high-efficiency metal-free quasi-green phosphor.

Copper Ion Mediates Yeast-to-Hypha Transition in Yarrowia lipolytica.

Copper is an essential element that maintains yeast physiological function at low concentrations, but is toxic in excess. This study reported that Cu(II) significantly promoted the yeast-to-hypha transition of Yarrowia lipolytica in dose-dependent manner. Strikingly, the intracellular Cu(II) accumulation was drastically reduced upon hyphae formation. Moreover, we investigated the effect of Cu(II) on the physiological function of Y. lipolytica during the dimorphic transition and found that cellular viability and thermomyces lanuginosus lipase (TLL) were both influenced by the Cu(II)-induced yeast-to-hypha transition. Overall, hyphal cells survived better than yeast-form cells with copper ions. Furthermore, transcriptional analysis of the Cu(II)-induced Y. lipolytica before and after hyphae formation revealed a transition state between them. The results showed multiple differentially expressed genes (DEGs) were turned over between the yeast-to-transition and the transition-to-hyphae processes. Furthermore, gene set enrichment analysis (GSEA) identified that multiple KEGG pathways, including signaling, ion transport, carbon and lipid metabolism, ribosomal, and other biological processes, were highly involved in the dimorphic transition. Importantly, overexpression screening of more than thirty DEGs further found four novel genes, which are encoded by YALI1_B07500g, YALI1_C12900g, YALI1_E04033g, and YALI1_F29317g, were essential regulators in Cu-induced dimorphic transition. Overexpression of each of them will turn on the yeast-to-hypha transition without Cu(II) induction. Taken together, these results provide new insight to explore further the regulatory mechanism of dimorphic transition in Y. lipolytica.

Controlled gold-palladium cores in ceria hollow spheres as nanoreactor for plasmon-enhanced catalysis under visible light irradiation.

Visible-light-driven organic transformations boosting by localized surface plasmon resonance (LSPR) have been attracting considerable interests. Gold-palladium (Au-Pd) bimetallic nanoparticles (NPs) are considered as ideal plasmonic catalysts realizing efficient light-driven catalysis. Nevertheless, stability and adjustability of plasmonic Au-Pd NPs remain to be a challenging task. Herein, we designed the controlled Au-Pd cores in ceria (CeO2) hollow spheres (Au-Pd@h-CeO2) as nanoreactor for Suzuki cross-coupling reactions. Under visible light irradiation, the Au-Pd@h-CeO2 exhibited remarkable photocatalytic performance with a turnover frequency (TOF) value as high as 797 h-1. More impressively, the coupling reactions of aryl chlorides bearing electron-withdrawing groups proceeded better and afforded the corresponding desired products in good yields. Detailed structural, optical and photoelectrochemical characterizations unraveled that the enhanced photocatalytic efficiency of Au-Pd@h-CeO2 was attributed to the LSPR effect of controllable Au-Pd cores and their synergetic effect of hollow CeO2 shells. The merits of this hollow sphere architecture lied on as followed: (I) Incident light could be reflected and refracted between the inner cores and outer shells, which extended the trapping of incident light, and then enhanced the light harvesting efficiency; (II) the mesoporous architecture of CeO2 hollow spheres provided a huge specific surface area and numerous mesoporous channels, which could enhance the absorption of reactants and provided more active sites; (III) LSPR excitation of Au-Pd NPs and band-gap excitation of CeO2 simultaneously occurred under visible light illumination, inducing a more efficient separation and transfer of charge carriers. Furthermore, due to the confinment effect of CeO2 shells, the Au-Pd@h-CeO2 exhibited an excellent reusability after six cycles without significant deactivation of yield. Our findings provided a facile way to design highly efficient plasmonic-enhanced photocatalysts utilized for catalytic organic reactions.

The Origin, Function, Distribution, Quantification, and Research Advances of Extracellular DNA.

In nature, DNA is ubiquitous, existing not only inside but also outside of the cells of organisms. Intracellular DNA (iDNA) plays an essential role in different stages of biological growth, and it is defined as the carrier of genetic information. In addition, extracellular DNA (eDNA) is not enclosed in living cells, accounting for a large proportion of total DNA in the environment. Both the lysis-dependent and lysis-independent pathways are involved in eDNA release, and the released DNA has diverse environmental functions. This review provides an insight into the origin as well as the multiple ecological functions of eDNA. Furthermore, the main research advancements of eDNA in the various ecological environments and the various model microorganisms are summarized. Furthermore, the major methods for eDNA extraction and quantification are evaluated.

Broad-spectrum and effective rare earth enriching via Lanmodulin-displayed Yarrowia lipolytica.

The traditional mining processes of rare earth elements (REEs) are accompanied by the production of a large number of acid mine drainage rich in REEs. A wide-adaptive, low-cost and environmentally friendly biosorbent is an attractive technology to enrich and recycle REEs from the liquid wastes. To construct a broad-spectrum and efficient biosorbent, a novel REEs-binding protein Lanmodulin (LanM) is successfully displayed on the cell surface of a fungus, Yarrowia lipolytica, for the first time, and the adsorption capacities for various REEs are studied. The LanM-displayed Y. lipolytica shows significantly enhanced adsorption capacities for multiple REEs, achieving the highest reported values of 49.83 ± 2.87 mg Yb /g DCW, 50.38 ± 1.46 mg Tm /g DCW, 49.94 ± 3.61 mg Er /g DCW and 48.72 ± 3.09 mg Tb/g DCW, respectively. Moreover, the LanM-displayed Y. lipolytica possesses a high selectivity for REEs over other common metal cations and excellent suitability under acidic conditions. The kinetics and equilibrium analysis of biosorption processes agree well with the pseudo-first kinetic and Langmuir isotherm model. Based on the FTIR and SEM-EDS analysis, the chelation with phosphate/carboxylate groups dominates the Yb binding in LanM-displayed cells, and LanM enhances the adsorption performances by introducing more binding sites with high selectivity towards a wide range of REEs. Thus, the LanM-displayed Y. lipolytica investigated in this study exhibits prosperous potential for the enriching/removal of REEs from acid mine drainage.

Accurate Location in Dynamic Traffic Environment Using Semantic Information and Probabilistic Data Association.

High-accurate and real-time localization is the fundamental and challenging task for autonomous driving in a dynamic traffic environment. This paper presents a coordinated positioning strategy that is composed of semantic information and probabilistic data association, which improves the accuracy of SLAM in dynamic traffic settings. First, the improved semantic segmentation network, building on Fast-SCNN, uses the Res2net module instead of the Bottleneck in the global feature extraction to further explore the multi-scale granular features. It achieves the balance between segmentation accuracy and inference speed, leading to consistent performance gains on the coordinated localization task of this paper. Second, a novel scene descriptor combining geometric, semantic, and distributional information is proposed. These descriptors are made up of significant features and their surroundings, which may be unique to a traffic scene, and are used to improve data association quality. Finally, a probabilistic data association is created to find the best estimate using a maximum measurement expectation model. This approach assigns semantic labels to landmarks observed in the environment and is used to correct false negatives in data association. We have evaluated our system with ORB-SLAM2 and DynaSLAM, the most advanced algorithms, to demonstrate its advantages. On the KITTI dataset, the results reveal that our approach outperforms other methods in dynamic traffic situations, especially in highly dynamic scenes, with sub-meter average accuracy.

A cationic iridium(III) complex containing a thiosemicarbazide unit: Synthesis and application for turn-on chemiluminescent detection of Hg2.

A novel cationic iridium(III) complex [(ppy)2Ir(bPCPC)]PF6 (ppy: 2-phenylpyridine; bPCPC: 2-([2,2'-bipyridine]-4-carbonyl)-N-phenylhydrazinecarbothioamide) containing a thiosemicarbazide unit was designed and synthesized. The thiosemicarbazide unit was a sensitive functional group to Hg2+, when it reacted with Hg2+, it was desulphurized and thus led to the formation of 1,3,4-oxadiazole, [(ppy)2Ir(bPCPC)]PF6 resultantly was used as a "turn-on" chemodosimeter for luminescent detection of Hg2+ in DMF/PBS buffer solution at pH = 7-11. Except for Ag+, recognition capability of [(ppy)2Ir(bPCPC)]PF6 to Hg2+ was not interfered by other common metal ions (Co2+, Li+, Zn2+, Pb2+, K+, Al3+, Na+, Mn2+, Cu2+, Fe2+, Fe3+, Cr3+, Ba2+, Mg2+, Ni2+ and Ca2+). The detection limit was 1.83 × 10-9 mol∙L-1 (0.37 ppb), which indicated the complex was a highly sensitive chemiluminescent detection reagent of Hg2+.

Prognostic and Immunotherapeutic Roles of KRAS in Pan-Cancer.

KRAS is one well-established tumor-driver gene associated with cancer initiation, development, and progression. Nonetheless, comparative studies of the relevance of KRAS across diverse tumors remain sparse. We explored the KRAS expression and prognostic values in diverse cancer types via multiple web-based bioinformatics tools, including cBioPortal, Oncomine, PrognoScan, Kaplan-Meier Plotter, etc. We found that KRAS is highly expressed in various malignancies compared to normal cohorts (BRCA, CHOL, ESCA, HNSC, LIHC, LUAD, LUSC, and STAD) and less expressed in COAD, KIRC, READ, and THCA than in normal samples. We observed the dysregulation of the DNA methylation of KRAS in cancers and discovered that numerous oncogenic and tumor-suppressive transcription factors bind the KRAS promoter region. Pan-cancer analysis also showed that a high level of KRAS is associated with poor outcomes. Additionally, KRAS is remarkably correlated with the level of immune cell infiltration and tumorigenic gene signatures. In conclusion, our findings reveal novel insights into KRAS expression and its biological functions in diverse cancer types, indicating that KRAS could serve as a prognostic biomarker and is associated with immune infiltrates.

Subcellular engineering of lipase dependent pathways directed towards lipid related organelles for highly effectively compartmentalized biosynthesis of triacylglycerol derived products in Yarrowia lipolytica.

As an alternative to in vitro lipase dependent biotransformation and to traditional assembly of pathways in cytoplasm, the present study focused on targeting lipase dependent pathways to a subcellular compartment lipid body (LB), in combination with compartmentalization of associated pathways in other lipid relevant organelles including endoplasmic reticulum (ER) and peroxisome for efficient in vivo biosynthesis of fatty acid methyl esters (FAMEs) and hydrocarbons, in the context of improving Yarrowia lipolytica lipid pool. Through knock in and knock out of key genes involved in triacylglycerols (TAGs) biosynthesis and degradation, the TAGs content was increased to 51.5%, from 7.2% in parent strain. Targeting lipase dependent pathway to LB gave a 10-fold higher FAMEs titer (1028.0 mg/L) compared to cytosolic pathway (102.8 mg/L). Furthermore, simultaneously targeting lipase dependent pathway to LB, ER and peroxisome gave rise to the highest FAMEs titer (1644.8 mg/L). The subcellular compartment engineering strategy was extended to other lipase dependent pathways for fatty alkene and alkane biosynthesis, which resulted in a 14-fold titer enhancement compared to traditional cytosolic pathways. We developed yeast subcellular cell factories by directing lipase dependent pathways towards the TAGs storage organelle LB for efficient biosynthesis of TAG derived chemicals for the first time. The successful exploration of targeting metabolic pathways towards LB centered organelles is expected to promote subcellular compartment engineering for other lipid derived product biosynthesis.

A genetically-encoded synthetic self-assembled multienzyme complex of lipase and P450 fatty acid decarboxylase for efficient bioproduction of fatty alkenes.

We develop an efficient and economic cascade multienzymes for fatty alkene bioproduction based on the lipase hydrolysis coupled to the P450 decarboxylation in the form of multiple enzyme complex. One step preparation of a multienzyme complex was based on a mixture of cell extracts including dockerin-enzyme fusions and one cohesin-cellulose binding module (CBM) fusion through high specific interaction of dockerin and cohesin. Simultaneously, the CBM was bound to cellulose carrier to form co-immobilized multienzyme. The key factors affecting overall efficiency of alkene bioproduction including substrate channeling of hydrolysis and decarboxylation, the ratio and position of two enzymes, stability were all addressed by genetically engineering of the synthetic CBM-cohesin fusions. The multienzymes exhibited more than 9.2 fold enhancement in initial reaction rate and much higher conversion yields (69%-72%) compared to mixture of free enzyme counterpart. The enzymatic cascade based multienzymes could efficiently convert renewable triglycerides to alkenes.

High-Level Production of a Thermostable Mutant of Yarrowia lipolytica Lipase 2 in Pichia pastoris.

As a promising biocatalyst, Yarrowia lipolytica lipase 2 (YlLip2) is limited in its industrial applications due to its low thermostability. In this study, a thermostable YlLip2 mutant was overexpressed in Pichia pastoris and its half-life time was over 30 min at 80 °C. To obtain a higher protein secretion level, the gene dosage of the mutated lip2 gene was optimized and the lipase activity was improved by about 89%. Then, the YlLip2 activity of the obtained strain further increased from 482 to 1465 U/mL via optimizing the shaking flask culture conditions. Subsequently, Hac1p and Vitreoscilla hemoglobin (VHb) were coexpressed with the YlLip2 mutant to reduce the endoplasmic reticulum stress and enhance the oxygen uptake efficiency in the recombinant strains, respectively. Furthermore, high-density fermentations were performed in a 3 L bioreactor and the production of the YlLip2 mutant reached 9080 U/mL. The results demonstrated that the expression level of the thermostable YlLip2 mutant was predominantly enhanced via the combination of these strategies in P. pastoris, which forms a consolidated basis for its large-scale production and future industrial applications.