As transcription factors derived from transposase, FAR-RED IMPAIRED RESPONSE1 (FAR1) and its homolog FHY3 play crucial roles in the regulation of light signaling and various stress responses by coordinating the expression of downstream target genes. Despite the extensive investigation of the FAR1/FHY3 family in Arabidopsis thaliana and other species, a comprehensive examination of these genes in maize has not been conducted thus far. In this study, we employed a genomic mining approach to identify 16 ZmFAR1 genes in the maize inbred line B73, which were further classified into five subgroups based on their phylogenetic relationships. The present study characterized the predicted polypeptide sequences, molecular weights, isoelectric points, chromosomal distribution, gene structure, conserved motifs, subcellular localizations, phylogenetic relationships, and cis-regulatory elements of all members belonging to the ZmFAR1 family. Furthermore, the tissue-specific expression of the 16 ZmFAR1 genes was analyzed using RNA-seq, and their expression patterns under far-red light conditions were validated in the ear and tassel through qRT-qPCR. The observed highly temporal and spatial expression patterns of these ZmFAR1 genes were likely associated with their specific functional capabilities under different light conditions. Further analysis revealed that six ZmFAR1 genes (ZmFAR1-1, ZmFAR1-10, ZmFAR1-11, ZmFAR1-12, ZmFAR1-14, and ZmFAR1-15) exhibited a response to simulated shading treatment and actively contributed to the development of maize ears. Through the integration of expression quantitative trait loci (eQTL) analyses and population genetics, we identified the presence of potential causal variations in ZmFAR1-14 and ZmFAR1-9, which play a crucial role in regulating the kernel row number and kernel volume weight, respectively. In summary, this study represents the initial identification and characterization of ZmFAR1 family members in maize, uncovering the functional variation in candidate regulatory genes associated with the improvement of significant agronomic traits during modern maize breeding.

Drought has become one of the most serious abiotic stresses influencing crop production worldwide. Understanding the molecular regulatory networks underlying drought adaption and tolerance in crops is of great importance for future breeding. microRNAs (miRNAs), as important components of post-transcriptional regulation, play crucial roles in drought response and adaptation in plants. Here, we report a miRNome analysis of two maize inbred lines with contrasting levels of drought tolerance under soil drought in the field. Differential expression analysis showed 11 and 34 miRNAs were uniquely responded to drought in H082183 (drought tolerant) and Lv28 (drought sensitive), respectively, in leaves. In roots, 19 and 23 miRNAs uniquely responded to drought in H082183 and Lv28, respectively. Expression analysis of these drought-responsive miRNA-mRNA modules revealed miR164-MYB, miR164-NAC, miR159-MYB, miR156-SPL and miR160-ARF showed a negative regulatory relationship. Further analysis showed that the miR164-MYB and miR164-NAC modules in the tolerant line modulated the stress response in an ABA (abscisic acid)-dependent manner, while the miR156-SPL and miR160-ARF modules in the sensitive line participated in the inhibition of metabolism in drought-exposed leaves. Together, our results provide new insight into not only drought-tolerance-related miRNA regulation networks in maize but also key miRNAs for further characterization and improvement of maize drought tolerance.

Drought is a major threat to maize growth and production. Understanding the molecular regulation network of drought tolerance in maize is of great importance. In this study, two maize inbred lines with contrasting drought tolerance were tested in the field under natural soil drought and well-watered conditions. In addition, the transcriptomes of their leaves was analyzed by RNA-Seq. In total, 555 and 2,558 genes were detected to specifically respond to drought in the tolerant and the sensitive line, respectively, with a more positive regulation tendency in the tolerant genotype. Furthermore, 4,700, 4,748, 4,403 and 4,288 genes showed differential expression between the two lines under moderate drought, severe drought and their well-watered controls, respectively. Transcription factors were enriched in both genotypic differentially expressed genes and specifically responsive genes of the tolerant line. It was speculated that the genotype-specific response of 20 transcription factors in the tolerance line and the sustained genotypically differential expression of 22 transcription factors might enhance tolerance to drought in maize. Our results provide new insight into maize drought tolerance-related regulation systems and provide gene resources for subsequent studies and drought tolerance improvement.

Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Artifact chimeric reads are enriched in next-generation sequencing data generated from formalin-fixed paraffin-embedded (FFPE) samples. Previous work indicated that these reads are characterized by erroneous split-read support that is interpreted as evidence of structural variants. Thus, a large number of false-positive structural variants are detected. To our knowledge, no tool is currently available to specifically call or filter structural variants in FFPE samples. To overcome this gap, we developed 2 R packages: SimFFPE and FilterFFPE.

Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (TH17) gene expression signatures (GES) in BRAFV600-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-TH17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global TH17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.

To effectively understand the underlying mechanisms of disease and inform the development of personalized therapies, it is critical to harness the power of differential co-expression (DCE) network analysis. Despite the promise of DCE network analysis in precision medicine, current approaches have a major limitation: they measure an average differential network across multiple samples, which means the specific etiology of individual patients is often overlooked. To address this, we present Cosinet, a DCE-based single-sample network rewiring degree quantification tool. By analyzing two breast cancer datasets, we demonstrate that Cosinet can identify important differences in gene co-expression patterns between individual patients and generate scores for each individual that are significantly associated with overall survival, recurrence-free interval, and other clinical outcomes, even after adjusting for risk factors such as age, tumor size, HER2 status, and PAM50 subtypes. Cosinet represents a remarkable development toward unlocking the potential of DCE analysis in the context of precision medicine.

Rice (Oryza sativa) is critical for human nutrition worldwide. Due to a growing population, cultivars that produce high yields in high salinity soil are of major importance. Here we describe the discovery and molecular characterization of a novel sea water adapted rice strain, Sea Rice 86 (SR86).

This study assessed the efficacy and tolerability of intravenous ibuprofen in the improvement of post-operative pain control and the reduction of opioid usage. Patients were randomly divided into placebo, ibuprofen 400 mg and ibuprofen 800 mg groups. All patients received patient-controlled intravenous morphine analgesia after surgery. The first dose of study drugs was administered intravenously 30 min before the end of surgery and then every 6 hours, for a total of 8 doses after surgery. The primary endpoint of this study was the mean amount of morphine used during the first 24 hours after surgery. Morphine use was reduced significantly in the ibuprofen 800 mg group compared with the placebo group (P = 0.04). Tramadol use was reduced significantly in the ibuprofen 400 mg and ibuprofen 800 mg groups compared with the placebo group (P < 0.01). The area under the curve of visual analog scale pain ratings was not different between groups. Safety assessments and side effects were not different between the three groups. Intravenous ibuprofen 800 mg was associated with a significant reduction in morphine requirements, and it was generally well tolerated for postoperative pain management in patients undergoing radical cervical cancer surgery.

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.

Recent studies highlighted the role of transcription factors in metabolic regulation during hematopoiesis and leukemia development. GFI1B is a transcriptional repressor that plays a critical role in hematopoiesis, and its expression is negatively related to the prognosis of acute myeloid leukemia (AML) patients. We earlier reported a change in the metabolic state of hematopoietic stem cells upon Gfi1b deletion. Here we explored the role of Gfi1b in metabolism reprogramming during hematopoiesis and leukemogenesis. We demonstrated that Gfi1b deletion remarkably activated mitochondrial respiration and altered energy metabolism dependence toward oxidative phosphorylation (OXPHOS). Mitochondrial substrate dependency was shifted from glucose to fatty acids upon Gfi1b deletion via upregulating fatty acid oxidation (FAO). On a molecular level, Gfi1b epigenetically regulated multiple FAO-related genes. Moreover, we observed that metabolic phenotypes evolved as cells progressed from preleukemia to leukemia, and the correlation between Gfi1b expression level and metabolic phenotype was affected by genetic variations in AML cells. FAO or OXPHOS inhibition significantly impeded leukemia progression of Gfi1b-KO MLL/AF9 cells. Finally, we showed that Gfi1b-deficient AML cells were more sensitive to metformin as well as drugs implicated in OXPHOS and FAO inhibition, opening new potential therapeutic strategies.

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.

GFI1 is a transcriptional repressor and plays a pivotal role in regulating the differentiation of hematopoietic stem cells (HSCs) towards myeloid and lymphoid cells. Serial transplantation of Gfi1 deficient HSCs repopulated whole hematopoietic system but in a competitive setting involving wild-type HSCs, they lose this ability. The underlying mechanisms to this end are poorly understood. To better understand this, we used different mouse strains that express either loss of both Gfi1 alleles (Gfi1-KO), with reduced expression of GFI1 (GFI1-KD) or wild-type Gfi1/GFI1 (Gfi1-/GFI1-WT; corresponding to the mouse and human alleles). We observed that loss of Gfi1 or reduced expression of GFI1 led to a two to four fold lower number of HSCs (defined as Lin-Sca1+c-Kit+CD150+CD48-) compared to GFI1-WT mice. To study the functional influence of different levels of GFI1 expression on HSCs function, HSCs from Gfi1-WT (expressing CD45.1 + surface antigens) and HSCs from GFI1-KD or -KO (expressing CD45.2 + surface antigens) mice were sorted and co-transplanted into lethally irradiated host mice. Every 4 weeks, CD45.1+ and CD45.2 + on different lineage mature cells were analyzed by flow cytometry. At least 16 weeks later, mice were sacrificed, and the percentage of HSCs and progenitors including GMPs, CMPs and MEPs in the total bone marrow cells was calculated as well as their CD45.1 and CD45.2 expression. In the case of co-transplantation of GFI1-KD with Gfi1-WT HSCs, the majority of HSCs (81% ± 6%) as well as the majority of mature cells (88% ± 10%) originated from CD45.2 + GFI1-KD HSCs. In the case of co-transplantation of Gfi1-KO HSCs with Gfi1-WT HSCs, the majority of HSCs originated from CD45.2+ and therefore from Gfi1-KO (61% ± 20%); however, only a small fraction of progenitors and mature cells originated from Gfi1-KO HSCs (<1%). We therefore in summary propose that GFI1 has a dose-dependent role in the self-renewal and differentiation of HSCs.

Fundamental to viral biology is identification and annotation of viral genes and their function. Determining the level of coronavirus gene expression is inherently difficult due to the positive stranded RNA genome and the identification of subgenomic RNAs (sgRNAs) that are required for expression of most viral genes. We developed a bioinformatic pipeline to analyze metatranscriptomic data from 20 independent studies encompassing 588 individual samples and 10 coronavirus species. This comparative analysis defined a core sgRNA repertoire for SARS-CoV-2 and found novel sgRNAs that could encode functional short peptides. Relevant to coronavirus infectivity and transmission, we also observed that the ratio of Spike sgRNA to Nucleocapsid one is highest in SARS-CoV-2, among the β-coronaviruses examined. Furthermore, the adjustment of this ratio can be made by modifications to the viral RNA replication machinery, representing a form of viral gene regulation that may be involved in host adaption.

Attention has become focused on resveratrol not only because of its role in grapevine fungal resistance but also because of its benefits in human health. This report describes the Chinese wild grapevine Vitis quinquangularis accession Danfeng-2 in relation to the high resveratrol content of its ripe berries. In this study, we used isobaric tags for relative and absolute quantification (iTRAQ) tandem mass spectrometry strategy to quantify and identify proteome changes, resulting in the detection of a total of 3,751 proteins produced under natural conditions. Among the proteins quantified, a total of 578 differentially expressed proteins were detected between Danfeng-2 and Cabernet Sauvignon during berry development. Differentially expressed proteins are involved in secondary metabolism, biotic stress, abiotic stress and transport activity and indicate novel biological processes in Chinese wild grapevine. Eleven proteins involved in phenylpropanoid metabolism and stilbene synthesis were differently expressed between Danfeng-2 and Cabernet Sauvignon at the veraison stage of berry development. These findings suggest that Chinese wild V. quinquangularis accession Danfeng-2 is an extremely important genetic resource for grape breeding and especially for increasing the resveratrol content of European grape cultivars for disease resistance and for improved human nutritional benefits.

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or -KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

This study aims to explore the molecular mechanisms of Lycium barbarum polysaccharide (LBP) in alleviating type 2 diabetes through intestinal flora modulation. A high-fat diet (HFD) combined with streptozotocin (STZ) was applied to create a diabetic model. The results indicated that LBP effectively alleviated the symptoms of hyperglycemia, hyperlipidemia, and insulin resistance in diabetic mice. A high dosage of LBP exerted better hypoglycemic effects than low and medium dosages. In diabetic mice, LBP significantly boosted the activities of CAT, SOD, and GSH-Px and reduced inflammation. The analysis of 16S rDNA disclosed that LBP notably improved the composition of intestinal flora, increasing the relative abundance of Bacteroides, Ruminococcaceae_UCG-014, Intestinimonas, Mucispirillum, Ruminococcaceae_UCG-009 and decreasing the relative abundance of Allobaculum, Dubosiella, Romboutsia. LBP significantly improved the production of short-chain fatty acids (SCFAs) in diabetic mice, which corresponded to the increase in the beneficial genus. According to Spearman's correlation analysis, Cetobacterium, Streptococcus, Ralstonia. Cetobacterium, Ruminiclostridium, and Bifidobacterium correlated positively with insulin, whereas Cetobacterium, Millionella, Clostridium_sensu_stricto_1, Streptococcus, and Ruminococcaceae_UCG_009 correlated negatively with HOMA-IR, HDL-C, ALT, AST, TC, and lipopolysaccharide (LPS). These findings suggested that the mentioned genus may be beneficial to diabetic mice's hypoglycemia and hypolipidemia. The up-regulation of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and insulin were remarkably reversed by LBP in diabetic mice. The real-time PCR (RT-PCR) analysis illustrated that LBP distinctly regulated the glucose metabolism of diabetic mice by activating the IRS/PI3K/Akt signal pathway. These results indicated that LBP effectively alleviated the hyperglycemia and hyperlipidemia of diabetic mice by modulating intestinal flora.

Acute myeloid leukemia (AML) is a group of hematological cancers with metabolic heterogeneity. Oxidative phosphorylation (OXPHOS) has been reported to play an important role in the function of leukemic stem cells and chemotherapy-resistant cells and are associated with inferior prognosis in AML patients. However, the relationship between metabolic phenotype and genetic mutations are yet to be explored. In the present study, we demonstrate that AML cell lines have high metabolic heterogeneity, and AML cells with MLL/AF9 have upregulated mitochondrial activity and mainly depend on OXPHOS for energy production. Furthermore, we show that metformin repressed the proliferation of MLL/AF9 AML cells by inhibiting mitochondrial respiration. Together, this study demonstrates that AML cells with an MLL/AF9 genotype have a high dependency on OXPHOS and could be therapeutically targeted by metformin.

Leukemia is characterized by the presence of highly malignant tumors formed in the hematopoietic system. Artesunate (Art), a semi-synthetic derivative of artemisinin, is commonly used as an antimalarial drug and has been proven to possess anticancer potential.

Mosquito-borne diseases affect over half of the human population globally. Multiple studies have shown that chemical insecticides are ineffective because of resistance. Therefore, environmentally safe mosquito population control tools need to be developed. Ribonucleic acid interference (RNAi) is a reverse genetic mechanism recently introduced as a new pest control tool. This technique represents a new class of biorational technology that could combat the increased global incidence of insecticide resistance. The technique has the potential of becoming a critical component of integrated vector control programs.