Genomic characteristics of adipose-derived stromal cells induced into neurons based on single-cell RNA sequencing.

Adipose-derived stromal cells (ADSCs) can be induced to differentiate into neurons, representing the most promising avenue for cell therapy. However, the molecular mechanism and genomic characteristics of the differentiation of ADSCs into neurons remain poorly understood. In this study, cells from the adult ADSCs group, induction 1h, 3h, 5h, 6h, and 8h groups were selected for single-cell RNA sequencing (scRNA-Seq). Samples from these seven-time points were sequenced and analyzed. The expression of neuron marker genes, including NES, MAP2, TMEM59L, PTK2B, CHN1, DNM1, NRSN2, FBLN2, SCAMP1, SLC1A1, DLG4, CDK5, and ENO2, was found to be low in the ADSCs group, but highly expressed in differentiated cell clusters. The expression of stem cell marker genes, including CCND1, IL1B, MMP1, MMP3, MYO10, and BMP2, was the highest in the ADSCs cluster. This expression decreased significantly with the extension of induction time. Gene ontology (GO) enrichment analysis of upregulated genes in the induced samples showed that the biological processes related to neuronal differentiation and development, such as neuronal differentiation, projection, and apoptosis, were significantly upregulated with a longer induction time during cell cluster differentiation. The results of the cell communication analysis demonstrated the gradual formation of complex neural network connections between ADSC-derived neurons through receptor and ligand pairs at 5h after the induction of differentiation.

Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. METHODS: Firstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein-protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. RESULTS: A total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. CONCLUSION: Diagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.

Multifaceted roles of IKZF1 gene, perspectives from bench to bedside.

The IKZF1 gene encodes a transcription factor that belongs to the family of zinc-finger DNA-binding proteins associated with chromatin remodeling. The protein product, IKAROS, had been proved to regulate lymphopoiesis. Subsequent mouse model studies have further confirmed its regulating role in lymphopoiesis as well as in hematopoiesis; besides, it associates with immune function, certain immune disorders like common variable immunodeficiency and dysgammaglobulinemia have been proved to be associated with germline IKZF1 mutations. Dysfunction of IKAROS also bears paramount significance in leukemic transformation and alterations of IKZF1 gene predicts a poor prognosis in hematological malignancies. As an independent prognostic marker, IKZF1 has been incorporated in the risk stratification of BCP-ALL and stratification-guided therapy has also been generated. In this review, we provide a concise and comprehensive overview on the multifaceted roles of IKZF1 gene.

Focal ground glass opacity of the lung in metachronous prostate and gastric cancer: A case report.

Chest computed tomography (CT) revealed a focal ground glass opacity (GGO) with a minimal solid area in a 75-year-old man. The shadow was located in the periphery of the right upper lobe and measured 11 mm in diameter. The patient had a medical history of metachronous prostate and gastric cancers. The patient had been treated with androgen deprivation therapy for prostate cancer for 12 years and underwent subtotal gastrectomy for triple gastric cancers 7 months before. Since primary lung adenocarcinoma was suspected, CT-assisted percutaneous needle biopsy was performed. Histology revealed the sheet-like and trabecular proliferation of atypical cells, suggesting that the lesion was moderately to poorly differentiated adenocarcinoma. Adenocarcinoma cells showed subepithelial extension causing the thickening of alveolar walls. A tumor thrombus was not detected in the blood or lymphatic vessels. Immunohistochemistry revealed that carcinoma cells were negative for cytokeratin 7 (CK7), CK20, thyroid transcription factor-1 and CDX2 and positive for prostate-specific antigen and P504S. Based on these findings, the patient was diagnosed with metastatic carcinoma from prostate cancer. The disease remained stable for 4 months after the diagnosis, and no new lesions were observed on chest CT. Metastatic carcinoma rarely presents with focal GGO. Lung biopsy is necessary to identify the pathology of the lesion, and the primary site needs to be confirmed by immunohistochemistry with specific markers, particularly in a case of metachronous multiple cancers. A tumor thrombus, which is suggestive of lymphangitic carcinomatosis or pulmonary tumor thrombotic microangiopathy, also needs to be evaluated.

SPI1-mediated macrophage polarization aggravates age-related macular degeneration.

Objective: This study revealed a core regulator and common upstream mechanisms for the multifaceted pathological processes of age-related macular degeneration (AMD) and provided proof-of-concept for this new therapeutic target. Methods: Comprehensive gene expression analysis was performed using RNA sequencing of eye cup from old mice as well as laser-induced choroidal neovascularization (CNV) mouse model. Through integrative analysis and protein-protein interaction (PPI) analysis, common pathways and key transcription factor was identified simultaneously engaged in age-related retinal degeneration and CNV, the two typical pathological process of AMD. Subsequently, the expression changes of Spi1, the key regulator, as well as the alternation of the downstream mechanisms were validated in both models through qRT-PCR, Elisa, flow cytometry and immunofluorescence. Further, we assessed the impact of Spi1 knockdown in vitro and in vivo using gene intervention vectors carried by adeno-associated virus or lentivirus to test its potential as a therapeutic target. Results: Compared to corresponding controls, we found 1,939 and 1,319 genes differentially expressed in eye cups of old and CNV mice respectively. The integrative analysis identified a total of 275 overlapping DEGs, of which 150 genes were co-upregulated. PPI analysis verified a central transcription factor, SPI1. The significant upregulation of Spi1 expression was then validated in both models, accompanied by macrophage polarization towards the M1 phenotype. Finally, SPI1 suppression significantly inhibited M1 polarization of BMDMs and attenuated neovascularization in CNV mice. Conclusion: This study demonstrates that SPI1 exerts a pivotal role in AMD by regulation of macrophage polarization and innate immune response, offering promise as an innovative target for treating AMD.

A TrmBL2-like transcription factor mediates the growth phase-dependent expression of halolysin SptA in a concentration-dependent manner in Natrinema gari J7-2.

To cope with a high-salinity environment, haloarchaea generally employ the twin-arginine translocation (Tat) pathway to transport secretory proteins across the cytoplasm membrane in a folded state, including Tat-dependent extracellular subtilases (halolysins) capable of autocatalytic activation. Some halolysins, such as SptA of Natrinema gari J7-2, are produced at late-log phase to prevent premature enzyme activation and proteolytic damage of cellular proteins in haloarchaea; however, the regulation mechanism for growth phase-dependent expression of halolysins remains largely unknown. In this study, a DNA-protein pull-down assay was performed to identify the proteins binding to the 5'-flanking sequence of sptA encoding halolysin SptA in strain J7-2, revealing a TrmBL2-like transcription factor (NgTrmBL2). The ΔtrmBL2 mutant of strain J7-2 showed a sharp decrease in the production of SptA, suggesting that NgTrmBL2 positively regulates sptA expression. The purified recombinant NgTrmBL2 mainly existed as a dimer although monomeric and higher-order oligomeric forms were detected by native-PAGE analysis. The results of electrophoretic mobility shift assays (EMSAs) showed that NgTrmBL2 binds to the 5'-flanking sequence of sptA in a non-specific and concentration-dependent manner and exhibits an increased DNA-binding affinity with the increase in KCl concentration. Moreover, we found that a distal cis-regulatory element embedded in the neighboring upstream gene negatively regulates trmBL2 expression and thus participates in the growth phase-dependent biosynthesis of halolysin SptA. IMPORTANCE: Extracellular proteases play important roles in nutrient metabolism, processing of functional proteins, and antagonism of haloarchaea, but no transcription factor involved in regulating the expression of haloaechaeal extracellular protease has been reported yet. Here we report that a TrmBL2-like transcription factor (NgTrmBL2) mediates the growth phase-dependent expression of an extracellular protease, halolysin SptA, of haloarchaeon Natrinema gari J7-2. In contrast to its hyperthermophilic archaeal homologs, which are generally considered to be global transcription repressors, NgTrmBL2 functions as a positive regulator for sptA expression. This study provides new clues about the transcriptional regulation mechanism of extracellular protease in haloarchaea and the functional diversity of archaeal TrmBL2.

A NAC transcription factor MNAC3-centered regulatory network negatively modulates rice immunity against blast disease.

NAC transcription factors (TFs) are pivotal in plant immunity against diverse pathogens. Here, we report the functional and regulatory network of MNAC3, a novel NAC TF, in rice immunity. MNAC3, a transcriptional activator, negatively modulates rice immunity against blast and bacterial leaf blight diseases and pathogen-associated molecular pattern (PAMP)-triggered immune responses. MNAC3 binds to a CACG cis-element and activates the transcription of immune-negative target genes OsINO80, OsJAZ10, and OsJAZ11. The negative function of MNAC3 in rice immunity depends on its transcription of downstream genes such as OsINO80 and OsJAZ10. MNAC3 interacts with immunity-related OsPP2C41 (a protein phosphatase), ONAC066 (a NAC TF), and OsDjA6 (a DnaJ chaperone). ONAC066 and OsPP2C41 attenuate MNAC3 transcriptional activity, while OsDjA6 promotes it. Phosphorylation of MNAC3 at S163 is critical for its negative functions in rice immunity. OsPP2C41, which plays positive roles in rice blast resistance and chitin-triggered immune responses, dephosphorylates MNAC3, suppressing its transcriptional activity on the target genes OsINO80, OsJAZ10, and OsJAZ11 and promoting the translocation of MNAC3 from nucleus to cytoplasm. These results establish a MNAC3-centered regulatory network in which OsPP2C41 dephosphorylates MNAC3, attenuating its transcriptional activity on downstream immune-negative target genes in rice. Together, these findings deepen our understanding of molecular mechanisms in rice immunity and offer a novel strategy for genetic improvement of rice disease resistance.

Role of ZNF334 in cervical cancer: implications for EMT reversal and tumor suppression.

Zinc-finger proteins are involved in many biological processes. However, the role of Zinc-finger protein 334 (ZNF334) in cervical cancer remains unidentified. This study showed that promoter methylation of ZNF334 was responsible for its reduced expression. ZNF334 suppressed malignant biological behaviors in cervical cancer. Notably, ZNF334 reversed the EMT process both in vitro and in vivo. RNA-seq coupled with bioinformatics analysis caught P3H3 which is upregulated by ZNF334. Dual-luciferase reporter and Chromatin immunoprecipitation assays illustrated that ZNF334 directly regulate P3H3. Knockdown of P3H3 attenuated the reversal of EMT induced by ZNF334. Additionally, ZNF334 overexpression sensitized cervical cancer cells to the cytotoxic effects of paclitaxel, cyclosporine and sunitinib. In conclusions, this study illustrated that DNA methylation-based silencing ZNF334 played a vital role in cervical cancer, by regulating P3H3 in turn affects EMT. ZNF334 has the potential to become a novel diagnostic biomarker and a potential treatment target for cervical cancer.

Tissue expression and promoter activity analysis of the porcine TNFSF11 gene.

Tumour necrosis factor (TNF) superfamily member 11 (TNFSF11), also known as RANKL, plays a crucial role in regulating several physiological and pathological activities. Additionally, it is a vital factor in bone physiology, and the sex hormone progesterone regulates the expansion of stem cells and the proliferation of mammary epithelial cells. It is essential for animal growth and reproductive physiological processes. This study aimed to evaluate the tissue-specific expression characteristics and promoter activity of the TNFSF11 gene in pigs. As a result, the study examined the presence of TNFSF11 expression in the tissues of Xiangsu pigs at 0.6 and 12 months of age. Moreover, the core promoter region of TNFSF11 was also identified by utilizing a combination of bioinformatic prediction and dual-luciferase activity tests. Finally, the effect of transcription factors on the transcriptional activity of the core promoter region was determined using site-directed mutagenesis. TNFSF11 was uniformly expressed in all tissues; however, its expression in muscles was comparatively low. The core promoter region of TNFSF11 was located in the -555 to -1 region. The prediction of the transcription start site of TNFSF11 gene-2000 ∼ + 500bp showed that there was a CpG site in 17 ∼ + 487bp. Analysis of mutations in the transcription factor binding sites revealed that mutations in the Stat5b, Myog, Trl, and EN1 binding sites had significant effects on the transcriptional activity of the TNFSF11 gene, particularly following the EN1 binding site mutation (P < 0.001). This study provides insights into both the tissue-specific expression patterns of TNFSF11 in the tissues of Xiangsu pigs and the potential regulatory effects of transcription factors on its promoter activity. These results may be helpful for future research aimed at clarifying the expression and role of the porcine TNFSF11 gene.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Dissecting the structural and functional consequences of the evolutionary proline-glycine deletion in the wing 1 region of the forkhead domain of human FoxP1.

The human FoxP transcription factors dimerize via three-dimensional domain swapping, a unique feature among the human Fox family, as result of evolutionary sequence adaptations in the forkhead domain. This is the case for the conserved glycine and proline residues in the wing 1 region, which are absent in FoxP proteins but present in most of the Fox family. In this work, we engineered both glycine (G) and proline-glycine (PG) insertion mutants to evaluate the deletion events in FoxP proteins in their dimerization, stability, flexibility, and DNA-binding ability. We show that the PG insertion only increases protein stability, whereas the single glycine insertion decreases the association rate and protein stability and promotes affinity to the DNA ligand.

Architecture and dynamics of the abscisic acid gene regulatory network.

The plant hormone abscisic acid (ABA) regulates essential processes in plant development and responsiveness to abiotic and biotic stresses. ABA perception triggers a post-translational signaling cascade that elicits the ABA gene regulatory network (GRN), encompassing hundreds of transcription factors (TFs) and thousands of transcribed genes. To further our knowledge of this GRN, we performed an RNA-seq time series experiment consisting of 14 time points in the 16 h following a one-time ABA treatment of 5-week-old Arabidopsis rosettes. During this time course, ABA rapidly changed transcription levels of 7151 genes, which were partitioned into 44 coexpressed modules that carry out diverse biological functions. We integrated our time-series data with publicly available TF-binding site data, motif data, and RNA-seq data of plants inhibited in translation, and predicted (i) which TFs regulate the different coexpression clusters, (ii) which TFs contribute the most to target gene amplitude, (iii) timing of engagement of different TFs in the ABA GRN, and (iv) hierarchical position of TFs and their targets in the multi-tiered ABA GRN. The ABA GRN was found to be highly interconnected and regulated at different amplitudes and timing by a wide variety of TFs, of which the bZIP family was most prominent, and upregulation of genes encompassed more TFs than downregulation. We validated our network models in silico with additional public TF-binding site data and transcription data of selected TF mutants. Finally, using a drought assay we found that the Trihelix TF GT3a is likely an ABA-induced positive regulator of drought tolerance.

The effect of exogenous melatonin on waterlogging stress in Clematis.

Clematis is the queen of the vines, being an ornamental plant with high economic value. Waterlogging stress reduces the ornamental value of the plant and limits its application. Melatonin plays an important role in plant resistance to abiotic stresses. In this study, the physiological responses and gene expression levels of two wild species, namely, Clematis tientaiensis and Clematis lanuginosa, and two horticultural varieties, namely, 'Sen-No-Kaze' and 'Viva Polonia,' under waterlogging stress were analyzed to determine the effect of melatonin on waterlogging tolerance. The results showed that the waterlogging tolerances of C. lanuginosa and 'Sen-No-Kaze' were relatively poor, but were significantly improved by concentrations of 100 µmol·L-1 and 50 µmol·L-1 melatonin. C. tientaiensis and 'Viva Polonia' had relatively strong tolerance to waterlogging, and this was significantly improved by 200 µmol·L-1 melatonin. Under waterlogging stress, the relative conductivity and H2O2 content of Clematis increased significantly; the photosynthetic parameters and chlorophyll contents were significantly decreased; photosynthesis was inhibited; the contents of soluble protein and soluble sugars were decreased. Effective improvement of waterlogging tolerance after exogenous melatonin spraying, the relative conductivity was decreased by 4.05%-27.44%; the H2O2 content was decreased by 3.84%-23.28%; the chlorophyll content was increased by 35.59%-103.36%; the photosynthetic efficiency was increased by 25.42%-45.86%; the antioxidant enzyme activities of APX, POD, SOD, and CAT were increased by 28.03%-158.61%; the contents of proline, soluble protein, and soluble sugars were enhanced, and cell homeostasis was improved. Transcription sequencing was performed on wild Clematis with differences in waterlogging tolerance, and nine transcription factors were selected that were highly correlated with melatonin and that had the potential to improve waterlogging tolerance, among which LBD4, and MYB4 were significantly positively correlated with the antioxidant enzyme system, and bHLH36, DOF36, and WRKY4 were significantly negatively correlated. Photosynthetic capacity was positively correlated with DOF36 and WRKY4 while being significantly negatively correlated with MYB4, MOF1, DOF47, REV1 and ABR1. Melatonin could enhance the flooding tolerance of Clematis by improving photosynthetic efficiency and antioxidant enzyme activity. This study provides an important basis and reference for the application of melatonin in waterlogging-resistant breeding of Clematis.

Genetic factors explaining anthocyanin pigmentation differences.

BACKGROUND: Anthocyanins are important contributors to coloration across a wide phylogenetic range of plants. Biological functions of anthocyanins span from reproduction to protection against biotic and abiotic stressors. Owing to a clearly visible phenotype of mutants, the anthocyanin biosynthesis and its sophisticated regulation have been studied in numerous plant species. Genes encoding the anthocyanin biosynthesis enzymes are regulated by a transcription factor complex comprising MYB, bHLH and WD40 proteins. RESULTS: A systematic comparison of anthocyanin-pigmented vs. non-pigmented varieties was performed within numerous plant species covering the taxonomic diversity of flowering plants. The literature was screened for cases in which genetic factors causing anthocyanin loss were reported. Additionally, transcriptomic data sets from four previous studies were reanalyzed to determine the genes possibly responsible for color variation based on their expression pattern. The contribution of different structural and regulatory genes to the intraspecific pigmentation differences was quantified. Differences concerning transcription factors are by far the most frequent explanation for pigmentation differences observed between two varieties of the same species. Among the transcription factors in the analyzed cases, MYB genes are significantly more prone to account for pigmentation differences compared to bHLH or WD40 genes. Among the structural genes, DFR genes are most often associated with anthocyanin loss. CONCLUSIONS: These findings support previous assumptions about the susceptibility of transcriptional regulation to evolutionary changes and its importance for the evolution of novel coloration phenotypes. Our findings underline the particular significance of MYBs and their apparent prevalent role in the specificity of the MBW complex.

Interface-guided phenotyping of coding variants in the transcription factor RUNX1.

Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous leukemia cells and categorize them into three functionally distinct groups, wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic, that we validate in orthogonal assays. LoF-like variants dominate the DNA-binding site and are recurrent in cancer; however, recurrence alone does not predict functional impact. Hypomorphic variants share characteristics with LoF-like but favor protein interactions, promoting gene expression indicative of nerve growth factor (NGF) response and cytokine recruitment of neutrophils. Accessible DNA near differentially expressed genes frequently contains RUNX1-binding motifs. Finally, we reclassify 16 variants of uncertain significance and train a classifier to predict 103 more. Our work demonstrates the potential of targeting protein interactions to better define the landscape of phenotypes reachable by missense mutations.

Passion fruit HD-ZIP genes: Characterization, expression variance, and overexpression PeHB31 enhanced drought tolerance via lignin pathway.

The HD-ZIP (homeodomain-leucine zipper) genes hold significant importance in transcriptional regulation, especially in plant development and responses to abiotic stresses. However, a comprehensive study targeting HD-ZIP family members in passion fruit has been absent. In our current research, 34 HD-ZIP family members (PeHBs) were identified by bioinformatics analysis. Transcriptome analysis revealed that PeHBs exhibited distinct expression patterns when subjected to the four different abiotic stresses, and significant differential expression of PeHBs was also found among the three developmental stages of the fruit and between the purple and yellow genotype passion fruit leaves. An integrated metabolome and transcriptome analysis further revealed that the HD-ZIP III class gene PeHB31 (homologous to ATHB8), was co-upexpressed with lignans in yellow fruit P. edulis (commonly used as a resistance rootstock) when compared to purple fruit P. edulis. The transformation of Arabidopsis and yeast with the PeHB31 gene showed an enhancement in their capacity to withstand drought conditions. Notably, the transgenic Arabidopsis plants exhibited an increase in lignin content within the vascular tissues of their stems. This research lays the groundwork for future studies on the control mechanisms of lignin biosynthesis by HD-ZIP genes (especially HD-ZIP classes III and I) involved in drought tolerance.

Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

Wheat NAC transcription factor NAC5-1 is a positive regulator of senescence.

Wheat (Triticum aestivum L.) is an important source of both calories and protein in global diets, but there is a trade-off between grain yield and protein content. The timing of leaf senescence could mediate this trade-off as it is associated with both declines in photosynthesis and nitrogen remobilization from leaves to grain. NAC transcription factors play key roles in regulating senescence timing. In rice, OsNAC5 expression is correlated with increased protein content and upregulated in senescing leaves, but the role of the wheat ortholog in senescence had not been characterized. We verified that NAC5-1 is the ortholog of OsNAC5 and that it is expressed in senescing flag leaves in wheat. To characterize NAC5-1, we combined missense mutations in NAC5-A1 and NAC5-B1 from a TILLING mutant population and overexpressed NAC5-A1 in wheat. Mutation in NAC5-1 was associated with delayed onset of flag leaf senescence, while overexpression of NAC5-A1 was associated with slightly earlier onset of leaf senescence. DAP-seq was performed to locate transcription factor binding sites of NAC5-1. Analysis of DAP-seq and comparison with other studies identified putative downstream target genes of NAC5-1 which could be associated with senescence. This work showed that NAC5-1 is a positive transcriptional regulator of leaf senescence in wheat. Further research is needed to test the effect of NAC5-1 on yield and protein content in field trials, to assess the potential to exploit this senescence regulator to develop high-yielding wheat while maintaining grain protein content.

Genome-wide transcript expression analysis reveals major chickpea and lentil genes associated with plant branching.

The search for elite cultivars with better architecture has been a demand by farmers of the chickpea and lentil crops, which aims to systematize their mechanized planting and harvesting on a large scale. Therefore, the identification of genes associated with the regulation of the branching and architecture of these plants has currently gained great importance. Herein, this work aimed to gain insight into transcriptomic changes of two contrasting chickpea and lentil cultivars in terms of branching pattern (little versus highly branched cultivars). In addition, we aimed to identify candidate genes involved in the regulation of shoot branching that could be used as future targets for molecular breeding. The axillary and apical buds of chickpea cultivars Blanco lechoso and FLIP07-318C, and lentil cultivars Castellana and Campisi, considered as little and highly branched, respectively, were harvested. A total of 1,624 and 2,512 transcripts were identified as differentially expressed among different tissues and contrasting cultivars of chickpea and lentil, respectively. Several gene categories were significantly modulated such as cell cycle, DNA transcription, energy metabolism, hormonal biosynthesis and signaling, proteolysis, and vegetative development between apical and axillary tissues and contrasting cultivars of chickpea and lentil. Based on differential expression and branching-associated biological function, ten chickpea genes and seven lentil genes were considered the main players involved in differentially regulating the plant branching between contrasting cultivars. These collective data putatively revealed the general mechanism and high-effect genes associated with the regulation of branching in chickpea and lentil, which are potential targets for manipulation through genome editing and transgenesis aiming to improve plant architecture.

FOXM1 transcriptional regulation.

FOXM1 is a key transcriptional regulator involved in various biological processes in mammals, including carbohydrate and lipid metabolism, aging, immune regulation, development, and disease. Early studies have shown that FOXM1 acts as an oncogene by regulating cell proliferation, cell cycle, migration, metastasis, and apoptosis, as well as genes related to diagnosis, treatment, chemotherapy resistance, and prognosis. Researchers are increasingly focusing on FOXM1 functions in tumor microenvironment, epigenetics, and immune infiltration. However, researchers have not comprehensively described FOXM1's involvement in tumor microenvironment shaping, epigenetics, and immune cell infiltration. Here we review the role of FOXM1 in the formation and development of malignant tumors, and we will provide a comprehensive summary of the role of FOXM1 in transcriptional regulation, interacting proteins, tumor microenvironment, epigenetics, and immune infiltration, and suggest areas for further research.