Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression.

Skp1⋅Cul1⋅F-box (SCF) ubiquitin ligase assembly is regulated by the interplay of substrate binding, reversible Nedd8 conjugation on Cul1, and the F-box protein (FBP) exchange factors Cand1 and Cand2. Detailed investigations into SCF assembly and function in reconstituted systems and Cand1/2 knockout cells informed the development of a mathematical model for how dynamical assembly of SCF complexes is controlled and how this cycle is coupled to degradation of an SCF substrate. Simulations predicted an unanticipated hypersensitivity of Cand1/2-deficient cells to FBP expression levels, which was experimentally validated. Together, these and prior observations lead us to propose the adaptive exchange hypothesis, which posits that regulation of the koff of an FBP from SCF by the actions of substrate, Nedd8, and Cand1 molds the cellular repertoire of SCF complexes and that the plasticity afforded by this exchange mechanism may enable large variations in FBP expression during development and in FBP gene number during evolution.

Modeling and analyzing single-cell multimodal data with deep parametric inference.

The proliferation of single-cell multimodal sequencing technologies has enabled us to understand cellular heterogeneity with multiple views, providing novel and actionable biological insights into the disease-driving mechanisms. Here, we propose a comprehensive end-to-end single-cell multimodal analysis framework named Deep Parametric Inference (DPI). DPI transforms single-cell multimodal data into a multimodal parameter space by inferring individual modal parameters. Analysis of cord blood mononuclear cells (CBMC) reveals that the multimodal parameter space can characterize the heterogeneity of cells more comprehensively than individual modalities. Furthermore, comparisons with the state-of-the-art methods on multiple datasets show that DPI has superior performance. Additionally, DPI can reference and query cell types without batch effects. As a result, DPI can successfully analyze the progression of COVID-19 disease in peripheral blood mononuclear cells (PBMC). Notably, we further propose a cell state vector field and analyze the transformation pattern of bone marrow cells (BMC) states. In conclusion, DPI is a powerful single-cell multimodal analysis framework that can provide new biological insights into biomedical researchers. The python packages, datasets and user-friendly manuals of DPI are freely available at https://github.com/studentiz/dpi.

scDMV: a zero-one inflated beta mixture model for DNA methylation variability with scBS-seq data.

MOTIVATION: The utilization of single-cell bisulfite sequencing (scBS-seq) methods allows for precise analysis of DNA methylation patterns at the individual cell level, enabling the identification of rare populations, revealing cell-specific epigenetic changes, and improving differential methylation analysis. Nonetheless, the presence of sparse data and an overabundance of zeros and ones, attributed to limited sequencing depth and coverage, frequently results in reduced precision accuracy during the process of differential methylation detection using scBS-seq. Consequently, there is a pressing demand for an innovative differential methylation analysis approach that effectively tackles these data characteristics and enhances recognition accuracy. RESULTS: We propose a novel beta mixture approach called scDMV for analyzing methylation differences in single-cell bisulfite sequencing data, which effectively handles excess zeros and ones and accommodates low-input sequencing. Our extensive simulation studies demonstrate that the scDMV approach outperforms several alternative methods in terms of sensitivity, precision, and controlling the false positive rate. Moreover, in real data applications, we observe that scDMV exhibits higher precision and sensitivity in identifying differentially methylated regions, even with low-input samples. In addition, scDMV reveals important information for GO enrichment analysis with single-cell whole-genome sequencing data that are often overlooked by other methods. AVAILABILITY AND IMPLEMENTATION: The scDMV method, along with a comprehensive tutorial, can be accessed as an R package on the following GitHub repository: https://github.com/PLX-m/scDMV.

The MdERF61-mdm-miR397b-MdLAC7b module regulates apple resistance to Fusarium solani via lignin biosynthesis.

Apple replant disease (ARD) is a worldwide problem that threatens the industry. However, the genetic mechanism underlying plant disease resistance against ARD remains unclear. In this study, a negative regulatory microRNA in Malus domestica, mdm-miR397b \, and its direct target MdLAC7b (Laccase) was selected for examination based on our previous small RNA and degradome sequencing results. Overexpressing the mdm-miR397b-MdLAC7b module altered the lignin deposition and JA contents in apple roots, which also led to increased resistance to Fusarium solani. Additionally, Y1H library screening using mdm-miR397b promoter recombinants identified a transcription factor, MdERF61, that represses mdm-miR397b transcriptional activity by directly binding to two GCC-boxes in the mdm-miR397b promoter. In summary, our results suggest that the MdERF61-mdm-miR397b-MdLAC7b module plays a crucial role in apple resistance to F. solani and offers insights for enhancing plant resistance to soilborne diseases in apple.

PlantExp: a platform for exploration of gene expression and alternative splicing based on public plant RNA-seq samples.

Over the last decade, RNA-seq has produced a massive amount of plant transcriptomic sequencing data deposited in public databases. Reanalysis of these public datasets can generate additional novel hypotheses not included in original studies. However, the large data volume and the requirement for specialized computational resources and expertise present a barrier for experimental biologists to explore public repositories. Here, we introduce PlantExp (https://biotec.njau.edu.cn/plantExp), a database platform for exploration of plant gene expression and alternative splicing profiles based on 131 423 uniformly processed publicly available RNA-seq samples from 85 species in 24 plant orders. In addition to two common retrieval accesses to gene expression and alternative splicing profiles by functional terms and sequence similarity, PlantExp is equipped with four online analysis tools, including differential expression analysis, specific expression analysis, co-expression network analysis and cross-species expression conservation analysis. With these online analysis tools, users can flexibly customize sample groups to reanalyze public RNA-seq datasets and obtain new insights. Furthermore, it offers a wide range of visualization tools to help users intuitively understand analysis results. In conclusion, PlantExp provides a valuable data resource and analysis platform for plant biologists to utilize public RNA-seq. datasets.

Adaptive exchange sustains cullin-RING ubiquitin ligase networks and proper licensing of DNA replication.

Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCFFBXO5-APC/C-GMNN and CUL4DTL-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.

Mendelian randomization analysis reveals a causal effect of Streptococcus salivarius on diabetic retinopathy through regulating host fasting glucose.

Diabetic retinopathy (DR) is one of leading causes of vision loss in adults with increasing prevalence worldwide. Increasing evidence has emphasized the importance of gut microbiome in the aetiology and development of DR. However, the causal relationship between gut microbes and DR remains largely unknown. To investigate the causal associations of DR with gut microbes and DR risk factors, we employed two-sample Mendelian Randomization (MR) analyses to estimate the causal effects of 207 gut microbes on DR outcomes. Inputs for MR included Genome-wide Association Study (GWAS) summary statistics of 207 taxa of gut microbes (the Dutch Microbiome Project) and 21 risk factors for DR. The GWAS summary statistics data of DR was from the FinnGen Research Project. Data analysis was performed in May 2023. We identified eight bacterial taxa that exhibited significant causal associations with DR (FDR < 0.05). Among them, genus Collinsella and species Collinsella aerofaciens were associated with increased risk of DR, while the species Bacteroides faecis, Burkholderiales bacterium_1_1_47, Ruminococcus torques, Streptococcus salivarius, genus Burkholderiales_noname and family Burkholderiales_noname showed protective effects against DR. Notably, we found that the causal effect of species Streptococcus salivarius on DR was mediated through the level of host fasting glucose, a well-established risk factor for DR. Our results reveal that specific gut microbes may be causally linked to DR via mediating host metabolic risk factors, highlighting potential novel therapeutic or preventive targets for DR.

FungiExp: a user-friendly database and analysis platform for exploring fungal gene expression and alternative splicing.

SUMMARY: Fungi form a large and heterogeneous group of eukaryotic organisms with diverse ecological niches. The high importance of fungi contrasts with our limited understanding of fungal lifestyle and adaptability to environment. Over the last decade, the high-throughput sequencing technology produced tremendous RNA-sequencing (RNA-seq) data. However, there is no comprehensive database for mycologists to conveniently explore fungal gene expression and alternative splicing. Here, we have developed FungiExp, an online database including 35 821 curated RNA-seq samples derived from 220 fungal species, together with gene expression and alternative splicing profiles. It allows users to query and visualize gene expression and alternative splicing in the collected RNA-seq samples. Furthermore, FungiExp contains several online analysis tools, such as differential/specific, co-expression network and cross-species gene expression conservation analysis. Through these tools, users can obtain new insights by re-analyzing public RNA-seq data or upload personal data to co-analyze with public RNA-seq data. AVAILABILITY AND IMPLEMENTATION: The FungiExp is freely available at https://bioinfo.njau.edu.cn/fungiExp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Wide-field illumination diffuse optical tomography within a framework of single-pixel time-domain spatial frequency domain imaging.

We present a wide-field illumination time-domain (TD) diffusion optical tomography (DOT) for three-dimensional (3-D) reconstruction within a shallow region under the illuminated surface of the turbid medium. The methodological foundation is laid on the single-pixel spatial frequency domain (SFD) imaging that facilitates the adoption of the well-established time-correlated single-photon counting (TCSPC)-based TD detection and generalized pulse spectrum techniques (GPST)-based reconstruction. To ameliorate the defects of the conventional diffusion equation (DE) in the forward modeling of TD-SFD-DOT, mainly the low accuracy in the near-field region and in profiling early-photon migration, we propose a modified model employing the time-dependent δ-P1 approximation and verify its improved accuracy in comparison with both the Monte Carlo and DE-based ones. For a simplified inversion process, a modified GPST approach is extended to TD-SFD-DOT that enables the effective separation of the absorption and scattering coefficients using a steady-state equivalent strategy. Furthermore, we set up a single-pixel TD-SFD-DOT system that employs the TCSPC-based TD detection in the SFD imaging framework. For assessments of the reconstruction approach and the system performance, phantom experiments are performed for a series of scenarios. The results show the effectiveness of the proposed methodology for rapid 3-D reconstruction of the absorption and scattering coefficients within a depth range of about 5 mean free pathlengths.

Extended Kalman filtering for enhancing a cyclic pattern-updating scheme of single-pixel dynamic fluorescence spatial frequency domain imaging: publisher's note.

This publisher's note contains a correction to Opt. Lett.48, 5443 (2023)10.1364/OL.495099.

Photo/Mechanical/Acidic Multi-Stimuli Responses and Information Encryption Design of Acylhydrazone Derivative.

Stimuli-responsive crystalline materials have received much attention for being potential candidates of smart materials. However, the occurrence of polymorphism-driven stimuli responses in crystalline materials remains interesting but rare. Herein, three polymorphs of an acylhydrazone derivative, N'-[(E)-(1-benzofuran-2-yl) methylidene] pyridine -4-carbohydrazide (BFMP) were prepared. Form-1 undergoes a photomechanical response via E→Z photoisomerization under UV irradiation, accompanied by a decrease in fluorescence intensity and a change from colorless to yellow. Two types of Z→E thermal isomerization mechanisms with significant differences in conversion rate were observed at different temperatures in form-1. The solid-melt-solid transition has a faster conversion rate compared to the solid-solid transition due to freedom from lattice confinement. The transition from form-2 to form-3 can be achieved under grinding, coupled with a significant decrease in fluorescence intensity. The similar molecular stacking pattern of form-2 and form-3 provides a structural basis for the grinding-induced crystalline transition behavior. In addition, the presence of the pyridine moiety imparts an acidochromic property. The combination of photochromism and acidochromism explores the possible applications of acylhydrazone derivatives in information encryption.

Cloning and characterization of a novel nitric oxide synthase gene from Exiguobacterium profundum and its expression in Escherichia coli.

The recognition and characterization of gene-encoded nitric oxide synthase (NOS) from Exiguobacterium profundum are reported in this study. A new gene was sequenced and cloned from E. profundum and heterologously expressed in E. coli for functional identification, followed by protein purification using the His-tag. The stability and activity characteristics of the recombinant NOS were evaluated using different concentrations of IPTG at various time points. A band of approximately 42 kDa was observed by SDS-PAGE. The Km value of NOS, calculated based on the Michaelis-Menten equation was 0.59 µmol/L. Additionally, homologous sequence alignment analysis indicated that the new NOS shared 80.48 % similarity with the same protein from Bacillus subtilis and Umezawaea. The construction of the NOS expression vector and the purification of the recombinant protein provide a foundation for further functional research and inhibitor development.

Death associated protein like 1 acts as a novel tumor suppressor in melanoma by increasing the stability of P21 protein.

Melanoma is a primary malignant tumor with high lethality, which occurs in the skin and eye tissues, while the molecular mechanisms of melanomagenesis remain largely unknown. Here, we show that death-associated protein-like 1 (DAPL1) expression is lower in melanoma tissues than in paracancerous tissues or nevus tissues, and Uveal melanoma patients with lower DAPL1 expression have a poorer survival rate than those with higher expression of DAPL1. Overexpression of DAPL1 inhibits proliferation of cultured melanoma cells, whereas knockdown of DAPL1 increases cell proliferation. Tumor transplantation experiment results also demonstrate that DAPL1 inhibits tumorigenesis of melanoma cells both in subretinal and subcutaneous tissues of nude mice in vivo. Finally, DAPL1 inhibits proliferation of melanoma cells by increasing the protein level of P21 via decreasing the ubiquitin mediated degradation of P21 and promoting its stability. Conversely, knockdown of P21 neutralizes the effects of inhibition of DAPL1 on melanoma cell proliferation and enhances the severity of melanoma tumorigenesis. These results suggest that DAPL1 is a novel melanoma tumor suppressor gene and thus a potential therapeutic target for melanoma.

Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

Electrical tree properties of grafted polypropylene studied by electro-luminescence and free radical excitation analysis.

The electrical tree in grafted polypropylene (PP) is inhibited compared with that of pure PP. To understand the free radicals that are generated during the treeing process, we study the electron paramagnetic resonance (EPR) spectra. Additionally, to provide a clearer explanation of the suppression of electrical trees, this research uses electroluminescence (EL) and excitation computation. These methods help us to observe the movement of electrons and to understand the geometric and electronic structures involved. In pure PP, the energy required to excite the electrons is approximately the same as the band gap of PP while electrons are easier to be excited in grafted PP than in pure PP, because the band gap is narrower. As a result, though the electrical tree length is shorter in PP-g-MMA, the EPR signal is more intense because of the uneven distribution of electrons.

SETDB1: Progress and prospects in cancer treatment potential and inhibitor research.

SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.

Co-pyrolysis of alkali-fused fly ash and corn stover to synthesize biochar composites for remediating lead-contaminated soil.

Fly ash (FA) is mainly composed of silica, alumina, and other metal oxide components, and has a positive stabilizing effect on soil heavy metals. Biochar composites produced from FA and corn stover (CS) can improve its remediation performance. Therefore, a batch of biochar composites (alkali-fused FA-CS biochars, ABs), synthesized via co-pyrolysis of CS and alkali-fused FA (AFFA) at different temperatures of 300, 500, and 700 °C (AB300-1, AB500-1, and AB700-1) and CS to AFFA mass ratios of 10:1, 10:2, and 10:5 (AB500-1, AB500-2, and AB500-5), was used to remediate lead (Pb)-contaminated soil. Compared with pristine biochars (BCs), ABs were enriched with oxygen-containing functional groups (Si-O-Si and Si-O) and aromatic structures. The ABs prepared at lower pyrolytic temperature (≤500 °C) and lower ratio of CS to AFFA (10:1) showed higher yield and stability. The contents of Toxicity Characteristic Leaching Procedure (TCLP)-extractable Pb and DTPA-CaCl2-triethanolamine (DTPA)-extractable Pb were generally lower in the soils amended with ABs than BCs. Compared with other ABs such as AB300-1, AB500-2, AB500-5, and AB700-1, the soil amended with AB500-1 had lower contents of TCLP and DTPA-extractable Pb (24% reduction), exhibiting superior performance in stabilizing Pb in the soil. The gradual decrease of DTPA-extractable Pb content in the soil with increasing dosage of AB500-1 amendments suggests that AB500-1 facilitated the conversion of bioavailable Pb to the stable and less toxic residual fractions. Specifically, the highest percentage of residual fraction of Pb in soil amended with AB500-1 was 14%. Correlation analyses showed that the soil DTPA-extractable Pb content decreased with the increase of soil pH and cation-exchange capacity (CEC) value. ABs stabilize Pb in the soils mainly via electrostatic attraction, precipitation, cation-π interaction, cation exchange, and complexation. These findings provide insights for producing functionalized biochar composites from industrial waste like FA and biomass waste for remediating the soils polluted by heavy metals.

Identification, characterisation and expression analysis of peanut sugar invertase genes reveal their vital roles in response to abiotic stress.

KEY MESSAGE: Sucrose invertase activity is positively related to osmotic and salt stress resistance in peanut. Sucrose invertases (INVs) have important functions in plant growth and response to environmental stresses. However, their biological roles in peanut are still not fully revealed. In this research, we identified 42 AhINV genes in the peanut genome. They were highly conserved and clustered into three groups with 24 segmental duplication events occurred under purifying selection. Transcriptional expression analysis exhibited that they were all ubiquitously expressed, and most of them were up-regulated by osmotic and salt stresses, with AhINV09, AhINV23 and AhINV19 showed the most significant up-regulation. Further physiochemical analysis showed that the resistance of peanut to osmotic and salt stress was positively related to the high sugar content and sucrose invertase activity. Our results provided fundamental information on the structure and evolutionary relationship of INV gene family in peanut and gave theoretical guideline for further functional study of AhINV genes in response to abiotic stress.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

INTRODUCTION: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. HIGHLIGHTS: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aß) positron emission tomography (PET) burden and Aß-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aß42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aß PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia.

INTRODUCTION: The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability. METHODS: Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank. RESULTS: Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets. DISCUSSION: Our study contributes to the current body of evidence on the genetic etiology of ADRD. HIGHLIGHTS: Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-ß process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.