KnockTF 2.0: a comprehensive gene expression profile database with knockdown/knockout of transcription (co-)factors in multiple species.

Transcription factors (TFs), transcription co-factors (TcoFs) and their target genes perform essential functions in diseases and biological processes. KnockTF 2.0 (http://www.licpathway.net/KnockTF/index.html) aims to provide comprehensive gene expression profile datasets before/after T(co)F knockdown/knockout across multiple tissue/cell types of different species. Compared with KnockTF 1.0, KnockTF 2.0 has the following improvements: (i) Newly added T(co)F knockdown/knockout datasets in mice, Arabidopsis thaliana and Zea mays and also an expanded scale of datasets in humans. Currently, KnockTF 2.0 stores 1468 manually curated RNA-seq and microarray datasets associated with 612 TFs and 172 TcoFs disrupted by different knockdown/knockout techniques, which are 2.5 times larger than those of KnockTF 1.0. (ii) Newly added (epi)genetic annotations for T(co)F target genes in humans and mice, such as super-enhancers, common SNPs, methylation sites and chromatin interactions. (iii) Newly embedded and updated search and analysis tools, including T(co)F Enrichment (GSEA), Pathway Downstream Analysis and Search by Target Gene (BLAST). KnockTF 2.0 is a comprehensive update of KnockTF 1.0, which provides more T(co)F knockdown/knockout datasets and (epi)genetic annotations across multiple species than KnockTF 1.0. KnockTF 2.0 facilitates not only the identification of functional T(co)Fs and target genes but also the investigation of their roles in the physiological and pathological processes.

eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.

Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.

Ribosomal frameshifting at normal codon repeats recodes functional chimeric proteins in human.

Ribosomal frameshifting refers to the process that ribosomes slip into +1 or -1 reading frame, thus produce chimeric trans-frame proteins. In viruses and bacteria, programmed ribosomal frameshifting can produce essential trans-frame proteins for viral replication or regulation of other biological processes. In humans, however, functional trans-frame protein derived from ribosomal frameshifting is scarcely documented. Combining multiple assays, we show that short codon repeats could act as cis-acting elements that stimulate ribosomal frameshifting in humans, abbreviated as CRFS hereafter. Using proteomic analyses, we identified many putative CRFS events from 32 normal human tissues supported by trans-frame peptides positioned at codon repeats. Finally, we show a CRFS-derived trans-frame protein (HDAC1-FS) functions by antagonizing the activities of HDAC1, thus affecting cell migration and apoptosis. These data suggest a novel type of translational recoding associated with codon repeats, which may expand the coding capacity of mRNA and diversify the regulation in human.

Leveraging LD eigenvalue regression to improve the estimation of SNP heritability and confounding inflation.

Heritability is a fundamental concept in genetic studies, measuring the genetic contribution to complex traits and bringing insights about disease mechanisms. The advance of high-throughput technologies has provided many resources for heritability estimation. Linkage disequilibrium (LD) score regression (LDSC) estimates both heritability and confounding biases, such as cryptic relatedness and population stratification, among single-nucleotide polymorphisms (SNPs) by using only summary statistics released from genome-wide association studies. However, only partial information in the LD matrix is utilized in LDSC, leading to loss in precision. In this study, we propose LD eigenvalue regression (LDER), an extension of LDSC, by making full use of the LD information. Compared to state-of-the-art heritability estimating methods, LDER provides more accurate estimates of SNP heritability and better distinguishes the inflation caused by polygenicity and confounding effects. We demonstrate the advantages of LDER both theoretically and with extensive simulations. We applied LDER to 814 complex traits from UK Biobank, and LDER identified 363 significantly heritable phenotypes, among which 97 were not identified by LDSC.

Cofea: correlation-based feature selection for single-cell chromatin accessibility data.

Single-cell chromatin accessibility sequencing (scCAS) technologies have enabled characterizing the epigenomic heterogeneity of individual cells. However, the identification of features of scCAS data that are relevant to underlying biological processes remains a significant gap. Here, we introduce a novel method Cofea, to fill this gap. Through comprehensive experiments on 5 simulated and 54 real datasets, Cofea demonstrates its superiority in capturing cellular heterogeneity and facilitating downstream analysis. Applying this method to identification of cell type-specific peaks and candidate enhancers, as well as pathway enrichment analysis and partitioned heritability analysis, we illustrate the potential of Cofea to uncover functional biological process.

KAT8 functions in redox homeostasis and mitochondrial dynamics during mouse oocyte meiosis progression.

As a histone acetyltransferase, lysine acetyltransferase 8 (KAT8) participates in diverse biological processes. However, the effect of KAT8 on oocyte maturation in mice remains unclear. In this study, we found that mouse oocytes overexpressing Kat8-OE induced maturation failure manifested reduced rates of GVBD and first polar body emission. In addition, immunostaining results revealed that Kat8 overexpressing oocytes showed inappropriate mitochondrial distribution patterns, overproduction of reactive oxygen species (ROS), accumulation of phosphorylated γH2AX, hyperacetylation of α-tubulin, and severely disrupted spindle/chromosome organization. Moreover, we revealed that Kat8 overexpression induced a decline in SOD1 proteins and KAT8's interaction with SOD1 in mouse ovaries via immunoprecipitation. Western blotting data confirmed that Kat8-OE induced downregulation of SOD1 expression, which is a key factor for the decline of oocyte quality in advanced maternal age. Also, the injection of Myc-Sod1 cRNA could partially rescue maternal age-induced meiotic defects in oocytes. In conclusion, our data demonstrated that high level of KAT8 inhibited SOD1 activity, which in turn induced defects of mitochondrial dynamics, imbalance of redox homeostasis, and spindle/chromosome disorganization during mouse oocyte maturation.

The application potential of mepiquat chloride in soybean: improvement of yield characteristics and drought resistance.

BACKGROUND: Drought can result in yield losses, the application of plant growth regulators is an effective measure to improve drought resistance and yield. The objective of the study was to explore the application potential of mepiquat chloride (MC) in regulating soybean yield and drought resistance. METHODS: In this study, a three-year field experiment was designed and combined with drought experiments to measure the yield of popularized varieties during 2021-2022 and drought-resistant and drought-sensitive varieties were selected, and planted in the field in 2023. RESULTS: MC increased the yield of HN84 and HN87 for two consecutive years from 2021 to 2022 and improved their physiological characteristics under field conditions. Under M200 treatment, the yield of HN84 increased by 6.93% and 9.46%, and HN87 increased by 11.11% and 15.72%. Different concentrations of MC have different effects on soybeans. The maximum increase of SOD, POD and proline in HN84 under M400 treatment reached 71.92%, 63.26% and 71.54%, respectively; the maximum increase of SOD, POD and proline in HN87 under M200 treatment reached 21.96%, 93.49% and 40.45%, respectively. In 2023, the foliar application of MC improved the physiological characteristics of HN44 and HN65 under drought-stress conditions. On the eighth day of drought treatment, compared to the drought treatment, the leaf and root dry weight of HN44 under M100 treatment increased by 17.91% and 32.76%, respectively; the dry weight of leaves and roots of HN65 increased by 20.74% and 29.29% under M200 treatment, respectively. MC also reduced malondialdehyde (MDA) content, decreased antioxidant enzyme activity and proline content. In addition, different concentrations of MC increased the chlorophyll fluorescence parameters (Fs, Fv/Fm, YII, and SPAD). In the field, the plant height of the two varieties decreased significantly, the yield increased, the number of two-grain and three-grain pods increased, and the stem length at the bottom and middle decreased with MC induction. CONCLUSIONS: The application of 100-200 mg/L MC effectively improved drought resistance and increased yield. This study provided support for the rational application of MC in soybean production.

Rational Design of Conjugated Acetylenic Polymers Enables a Two-Electron Water Oxidation Pathway for Enhanced Photosynthetic Hydrogen Peroxide Generation.

Herein, the design of conjugated acetylenic polymers (CAPs) featuring diverse spatial arrangements and intramolecular spacers of diacetylene moieties (─C≡C─C≡C─) for photocatalytic hydrogen peroxide (H2 O2 ) production from water and O2 , without the need for sacrificial agents, is presented. It is shown that the linear configuration of diacetylene moieties within conjugated acetylenic polymers (CAPs) induces a pronounced polarization of electron distribution, which imparts enhanced charge-carrier mobility when compared to CAPs' networks featuring cross-linked arrangements. Moreover, optimizing the intramolecular spacer between diacetylene moieties within the linear structure leads to the exceptional modulation of the band structures, specifically resulting in a downshifted valence band (VB) and rendering the two-electron water oxidation pathway thermodynamically feasible for H2 O2 production. Consequently, the optimized CAPs with a linear configuration (LCAP-2), featuring spatially separated reduction centers (benzene rings) and oxidation centers (diacetylene moieties), exhibit a remarkable H2 O2 yield rate of 920.1 µmol g-1 h-1 , superior than that of the linear LCAP-1 (593.2 µmol g-1 h-1 ) and the cross-linked CCAP (433.4 µmol g-1 h-1 ). The apparent quantum efficiency (AQE) and solar-to-chemical energy conversion (SCC) efficiency of LCAP-2 are calculated to be 9.1% (λ = 420 nm) and 0.59%, respectively, surpassing the performance of most previously reported conjugated polymers.

VILLIN2 regulates cotton defense against Verticillium dahliae by modulating actin cytoskeleton remodeling.

The active structural change of actin cytoskeleton is a general host response upon pathogen attack. This study characterized the function of the cotton (Gossypium hirsutum) actin-binding protein VILLIN2 (GhVLN2) in host defense against the soilborne fungus Verticillium dahliae. Biochemical analysis demonstrated that GhVLN2 possessed actin-binding, -bundling, and -severing activities. A low concentration of GhVLN2 could shift its activity from actin bundling to actin severing in the presence of Ca2+. Knockdown of GhVLN2 expression by virus-induced gene silencing reduced the extent of actin filament bundling and interfered with the growth of cotton plants, resulting in the formation of twisted organs and brittle stems with a decreased cellulose content of the cell wall. Upon V. dahliae infection, the expression of GhVLN2 was downregulated in root cells, and silencing of GhVLN2 enhanced the disease tolerance of cotton plants. The actin bundles were less abundant in root cells of GhVLN2-silenced plants than in control plants. However, upon infection by V. dahliae, the number of actin filaments and bundles in the cells of GhVLN2-silenced plants was raised to a comparable level as those in control plants, with the dynamic remodeling of the actin cytoskeleton appearing several hours in advance. GhVLN2-silenced plants exhibited a higher incidence of actin filament cleavage in the presence of Ca2+, suggesting that pathogen-responsive downregulation of GhVLN2 could activate its actin-severing activity. These data indicate that the regulated expression and functional shift of GhVLN2 contribute to modulating the dynamic remodeling of the actin cytoskeleton in host immune responses against V. dahliae.

Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer.

PURPOSE: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION: The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.

NET1 is a critical regulator of spindle assembly and actin dynamics in mouse oocytes.

BACKGROUND: Neuroepithelial transforming gene 1 (NET1) is a RhoA subfamily guanine nucleotide exchange factor that governs a wide array of biological processes. However, its roles in meiotic oocyte remain unclear. We herein demonstrated that the NET1-HACE1-RAC1 pathway mediates meiotic defects in the progression of oocyte maturation. METHODS: NET1 was reduced using a specific small interfering RNA in mouse oocytes. Spindle assembly, chromosomal alignment, the actin cap, and chromosomal spreads were visualized by immunostaining and analyzed under confocal microscopy. We also applied mass spectroscopy, and western blot analysis for this investigation. RESULTS: Our results revealed that NET1 was localized to the nucleus at the GV stage, and that after GVBD, NET1 was localized to the cytoplasm and predominantly distributed around the chromosomes, commensurate with meiotic progression. NET1 resided in the cytoplasm and significantly accumulated on the spindle at the MI and MII stages. Mouse oocytes depleted of Net1 exhibited aberrant first polar body extrusion and asymmetric division defects. We also determined that Net1 depletion resulted in reduced RAC1 protein expression in mouse oocytes, and that NET1 protected RAC1 from degradation by HACE1, and it was essential for actin dynamics and meiotic spindle formation. Importantly, exogenous RAC1 expression in Net1-depleted oocytes significantly rescued these defects. CONCLUSIONS: Our results suggest that NET1 exhibits multiple roles in spindle stability and actin dynamics during mouse oocyte meiosis.

Role of FBXL5 in redox homeostasis and spindle assembly during oocyte maturation in mice.

As an E3 ubiquitin ligase, F-box and leucine-rich repeat protein 5 (FBXL5) participates in diverse biologic processes. However, the role of Fbxl5 in mouse oocyte meiotic maturation has not yet been fully elucidated. The present study revealed that mouse oocytes depleted of Fbxl5 were unable to complete meiosis, as Fbxl5 silencing led to oocyte meiotic failure with reduced rates of GVBD and polar body extrusion. In addition, Fbxl5 depletion induced aberrant mitochondrial dynamics as we noted the overproduction of reactive oxygen species (ROS) and the accumulation of phosphorylated γH2AX with Fbxl5 knockdown. We also found that Fbxl5-KD led to the abnormal accumulation of CITED2 proteins in mouse oocytes. Our in vitro ubiquitination assay showed that FBXL5 interacted with CITED2 and that it mediated the degradation of CITED2 protein through the ubiquitination-proteasome pathway. Collectively, our data revealed critical functions of FBXL5 in redox hemostasis and spindle assembly during mouse oocyte maturation.

Unveiling the Mechanism and Kinetics of Pollutant Attenuation by Free Radicals Triggered from Goethite in Water Distribution Systems.

Investigating the fate of persistent organic pollutants in water distribution systems (WDSs) is of great significance for preventing human health risks. The role of iron corrosion scales in the migration and transformation of organics in such systems remains unclear. Herein, we determined that hydroxyl (•OH), chlorine, and chlorine oxide radicals are generated by Fenton-like reactions due to the coexistence of oxygen vacancy-related Fe(II) on goethite (a major constituent of iron corrosion scales) and hypochlorous acid (HClO, the main reactive chlorine species of residual chlorine at pH ∼ 7.0). •OH contributed mostly to the decomposition of atrazine (ATZ, model compound) more than other radicals, producing a series of relatively low-toxicity small molecular intermediates. A simplified kinetic model consisting of mass transfer of ATZ and HClO, •OH generation, and ATZ oxidation by •OH on the goethite surface was developed to simulate iron corrosion scale-triggered residual chlorine oxidation of organic compounds in a WDS. The model was validated by comparing the fitting results to the experimental data. Moreover, the model was comprehensively applicable to cases in which various inorganic ions (Ca2+, Na+, HCO3-, and SO42-) and natural organic matter were present. With further optimization, the model may be employed to predict the migration and accumulation of persistent organic pollutants under real environmental conditions in the WDSs.

Transforming Plain LaMnO3 Perovskite into a Powerful Ozonation Catalyst: Elucidating the Mechanisms of Simultaneous A and B Sites Modulation for Enhanced Toluene Degradation.

Herein, we propose preferential dissolution paired with Cu-doping as an effective method for synergistically modulating the A- and B-sites of LaMnO3 perovskite. Through Cu-doping into the B-sites of LaMnO3, specifically modifying the B-sites, the double perovskite La2CuMnO6 was created. Subsequently, partial La from the A-sites of La2CuMnO6 was etched using HNO3, forming novel La2CuMnO6/MnO2 (LCMO/MnO2) catalysts. The optimized catalyst, featuring an ideal Mn:Cu ratio of 4.5:1 (LCMO/MnO2-4.5), exhibited exceptional catalytic ozonation performance. It achieved approximately 90% toluene degradation with 56% selectivity toward CO2, even under ambient temperature (35 °C) and a relatively humid environment (45%). Modulation of A-sites induced the elongation of Mn-O bonds and decrease in the coordination number of Mn-O (from 6 to 4.3) in LCMO/MnO2-4.5, resulting in the creation of abundant multivalent Mn and oxygen vacancies. Doping Cu into B-sites led to the preferential chemisorption of toluene on multivalent Cu (Cu(I)/Cu(II)), consistent with theoretical predictions. Effective electronic supplementary interactions enabled the cycling of multiple oxidation states of Mn for ozone decomposition, facilitating the production of reactive oxygen species and the regeneration of oxygen vacancies. This study establishes high-performance perovskites for the synergistic regulation of O3 and toluene, contributing to cleaner and safer industrial activities.

H3K56 deacetylation and H2A.Z deposition are required for aberrant heterochromatin spreading.

Crucial mechanisms are required to restrict self-propagating heterochromatin spreading within defined boundaries and prevent euchromatic gene silencing. In the filamentous fungus Neurospora crassa, the JmjC domain protein DNA METHYLATION MODULATOR-1 (DMM-1) prevents aberrant spreading of heterochromatin, but the molecular details remain unknown. Here, we revealed that DMM-1 is highly enriched in a well-defined 5-kb heterochromatin domain upstream of the cat-3 gene, hereby called 5H-cat-3 domain, to constrain aberrant heterochromatin spreading. Interestingly, aberrant spreading of the 5H-cat-3 domain observed in the dmm-1KO strain is accompanied by robust deposition of histone variant H2A.Z, and deletion of H2A.Z abolishes aberrant spreading of the 5H-cat-3 domain into adjacent euchromatin. Furthermore, lysine 56 of histone H3 is deacetylated at the expanded heterochromatin regions, and mimicking H3K56 acetylation with an H3K56Q mutation effectively blocks H2A.Z-mediated aberrant spreading of the 5H-cat-3 domain. Importantly, genome-wide analyses demonstrated the general roles of H3K56 deacetylation and H2A.Z deposition in aberrant spreading of heterochromatin. Together, our results illustrate a previously unappreciated regulatory process that mediates aberrant heterochromatin spreading.

A data-adaptive Bayesian regression approach for polygenic risk prediction.

MOTIVATION: Polygenic risk score (PRS) has been widely exploited for genetic risk prediction due to its accuracy and conceptual simplicity. We introduce a unified Bayesian regression framework, NeuPred, for PRS construction, which accommodates varying genetic architectures and improves overall prediction accuracy for complex diseases by allowing for a wide class of prior choices. To take full advantage of the framework, we propose a summary-statistics-based cross-validation strategy to automatically select suitable chromosome-level priors, which demonstrates a striking variability of the prior preference of each chromosome, for the same complex disease, and further significantly improves the prediction accuracy. RESULTS: Simulation studies and real data applications with seven disease datasets from the Wellcome Trust Case Control Consortium cohort and eight groups of large-scale genome-wide association studies demonstrate that NeuPred achieves substantial and consistent improvements in terms of predictive r2 over existing methods. In addition, NeuPred has similar or advantageous computational efficiency compared with the state-of-the-art Bayesian methods. AVAILABILITY AND IMPLEMENTATION: The R package implementing NeuPred is available at https://github.com/shuangsong0110/NeuPred. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

mRNA expression profile reveals differentially expressed genes in splenocytes of experimental autoimmune encephalomyelitis model.

Experimental autoimmune encephalomyelitis (EAE) is a mouse model that can be used to investigate aetiology, pathogenesis, and treatment approaches for multiple sclerosis (MS). A novel integrated bioinformatics approach was used to understand the involvement of differentially expressed genes (DEGs) in the spleen of EAE mice through data mining of existing microarray and RNA-seq datasets. We screened differentially expressed mRNAs using mRNA expression profile data of EAE spleens taken from Gene Expression Omnibus (GEO). Functional and pathway enrichment analyses of DEGs were performed by Database for Annotation, Visualization, and Integrated Discovery (DAVID). Subsequently, the DEGs-encoded protein-protein interaction (PPI) network was constructed. The 784 DEGs in GSE99300 A.SW PP-EAE mice spleen mRNA profiles, 859 DEGs in GSE151701 EAE mice spleen mRNA profiles, and 646 DEGs in GSE99300 SJL/J PP-EAE mice spleen mRNA profiles were explored. Functional enrichment of 55 common DEGs among 3 sub-datasets revealed several immune-related terms, such as neutrophil extravasation, leucocyte migration, antimicrobial humoral immune response mediated by an antimicrobial peptide, toll-like receptor 4 bindings, IL-17 signalling pathway, and TGF-beta signalling pathway. In the screening of 10 hub genes, including MPO, ELANE, CTSG, LTF, LCN2, SELP, CAMP, S100A9, ITGA2B, and PRTN3, and in choosing and validating the 5 DEGs, including ANK1, MBOAT2, SLC25A21, SLC43A1, and SOX6, the results showed that SLC43A1 and SOX6 were significantly decreased in EAE mice spleen. Thus this study offers a list of genes expressed in the spleen that might play a key role in the pathogenesis of EAE.

OBF1 and Oct factors control the germinal center transcriptional program.

OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by chromatin immunoprecipitation-sequencing that OBF1 extensively colocalizes with OCT1 and OCT2. We found that these factors also often colocalize with transcription factors of the ETS family. Furthermore, we showed that OBF1, OCT2, and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation in mouse and human GC B cells. Short hairpin RNA knockdown experiments demonstrated that OCT1, OCT2, and OBF1 regulate each other and are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance, such as BCL6, are downregulated, whereas genes related to exit from the GC program, such as IRF4, are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived lymphoma cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls an essential regulatory node in GC differentiation.

Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling.

BACKGROUND: Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression. METHODS: APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram. RESULTS: Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-ß, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1ß, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1. CONCLUSIONS: Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-ß pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.

Role of brain-derived neurotrophic factor in endotoxaemia-induced acute lung injury.

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which is a pulmonary manifestation of a systemic reactive inflammatory syndrome, is a serious disease with high mortality, and sepsis is an important risk factor in the development of ALI. Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family. It plays an essential role in the regulation of the modification of synaptic efficacy and brain metabolic activity and enhances neuronal survival. However, the role and underlying mechanism of BDNF in sepsis-induced ALI remain unclear. Here, we sought to observe the expression of BDNF in the lung tissues of mice. C57BL/6J mice were divided randomly into two groups: saline (n = 4) and lipopolysaccharide (LPS) (n = 4). We found that BDNF expression was elevated in the lung tissues of septic mice. Furthermore, we found that BDNF colocalized with aquaporin 5, a marker for type I alveolar epithelial cells, by immunofluorescence staining. In addition, we also found that tropomyosin-related kinase B, the specific receptor of BDNF, colocalized with surfactant protein C, a marker for type II alveolar epithelial cells, by immunofluorescence staining. Finally, the present study indicated that BDNF may alleviate excessive LPS-induced autophagy in alveolar epithelial cells. Overall, we hypothesize that BDNF expression increases in the lung tissues of septic mice as a compensatory mechanism to ameliorate sepsis-induced ALI by inhibiting excessive alveolar epithelial cell autophagy.