Search Results (285)

Understanding host cell response to viral infection could lead to the identification of molecular targets that can be used for the development of diagnostics and therapeutics. In this study, we investigated human dendritic cell (DC) response to infections with Vaccinia (VAC) virus, a highly immunogenic poxvirus, and Venezuelan Equine Encephalitis (VEE) virus, a single-stranded positive-strand RNA alphavirus, using human gene expression microarrays. Comparative changes in DC mRNA expression resulting from infection by the two viruses at 1, 8, and 12 h post-infection (hpi) revealed distinct temporal dynamics. VAC infection triggered early and robust activation of pathways related to chromatin organization, DNA damage, and antigen presentation, while VEE infection exhibited delayed activation of immune signaling pathways, including interferon signaling and cytokine production. Shared pathways, such as interferon signaling and inflammasome activation, highlight universal antiviral responses and potential therapeutic targets. These findings provide a molecular framework affected by VAC and VEE that need to be validated with additional experiments, such as functional assays or in vivo studies. The specific up- or downregulation of these pathways at different time points likely dictates the overall outcome of the viral infection and could potentially lead to better understanding of the temporal regulatory dynamics of virus host response. Full article

Background: CD8A-related CD8α deficiency (Immunodeficiency 116) is a rare autosomal recessive primary immunodeficiency disease characterized by absent CD8⁺ T cells and variable sinopulmonary disease. Case Presentation: A seven-year-old boy from a consanguineous family was referred for chronic wet cough and “uncontrolled asthma” despite being prescribed high-dose inhaled corticosteroids and montelukast. He was hospitalized seven times over a two-year period for presumed asthma exacerbations complicated by pneumonia. An examination revealed bilateral crackles without wheezing. Throat culture tested positive for Haemophilus influenzae. CT imaging showed signs of chronic rhinosinusitis (maxillary mucosal thickening) and chronic airway disease with bronchiectatic changes. The patient’s immunoglobulin levels were within normal ranges for his age group. Flow cytometry revealed profound CD8⁺ T-cell lymphopenia (CD8⁺ 0.21%; 11 cells/µL; near-absent after excluding dual-positive cells) with expansion of CD3⁺CD4⁻CD8⁻ T cells (29.5%). CD8A gene sequencing identified a novel homozygous nonsense variant NM_001768.7:c.319C>T (p.Arg107Ter; GRCh38: chr2:86790412G>A), consistent with loss of CD8α and secondary loss of CD8β surface expression. A literature review identified three previously reported symptomatic patients (and two asymptomatic sisters in the first family), all with recurrent respiratory infections and variable structural lung disease. Conclusions: This case highlights CD8A deficiency as a rare mimic of pediatric asthma and expands the genotype spectrum with a truncating CD8A variant. Early lymphocyte immunophenotyping in children with recurrent sinopulmonary infections may prevent delayed diagnosis and progressive airway damage. Full article

Background/Aim: Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and an extremely poor prognosis. MicroRNAs (miRNAs), which regulate gene expression at the post-transcriptional level, have emerged as promising candidates for next-generation cancer therapeutics. The purpose of this study is to clarify the feasibility of miR-4711 as a potential therapeutic option against pancreatic cancer. Materials and Methods: The effects of miR-4711-5p were examined in pancreatic cancer cell lines with respect to cell proliferation, apoptosis, cancer stemness, cell cycle progression, and invasive capacity. RNA sequencing and in silico analyses were performed to identify potential target genes of miR-4711-5p. For in vivo safety evaluation, miR-4711-5p was formulated with super carbonate apatite, a delivery vehicle that is already amenable to large-scale production, and administered to cynomolgus monkeys. A nucleic acid dose equivalent to 10 times the effective dose observed in prior mouse efficacy studies was used. General clinical conditions, body weight, food consumption, ophthalmologic findings, electrocardiography, blood pressure, hematological and biochemical parameters, and histopathological changes were systematically assessed. Results: miR-4711-5p significantly suppressed cancer stemness, cell proliferation, and invasion, while inducing apoptosis and delaying cell cycle progression in pancreatic cancer cells. RNA sequencing and bioinformatic analyses identified MET, CTSA, and ANO1 as potential target genes of miR-4711-5p. In the cynomolgus monkey study, administration of miR-4711-5p formulated with super carbonate apatite resulted in no apparent differences compared with the control group in body weight, clinical observations, laboratory parameters, or histopathological findings, indicating the absence of treatment-related adverse effects even at a supra-therapeutic dose. Conclusions: These findings demonstrate that miR-4711-5p exerts potent antitumor effects against pancreatic cancer cells while exhibiting a favorable safety profile in a non-human primate model. Collectively, this study provides strong preclinical evidence supporting miR-4711-5p as a novel and safe therapeutic strategy for pancreatic cancer and represents an important step toward clinical application. Full article

Purpose: Hearing loss (HL) is a prevalent condition significantly impairing quality of life, with genetic mutations accounting for a substantial proportion of congenital cases, notably those involving the GJB2 gene encoding connexin 26. This study aims to analyze the current knowledge, feasibility, and challenges of gene therapy targeting GJB2-related HL, emphasizing both embryonic and postnatal interventions. Methods: A comprehensive scoping review was conducted across electronic databases up to October 2025, including studies focusing on GJB2-associated HL, gene therapy approaches, and the timing of interventions. Data extraction encompassed mutation types, animal models, delivery strategies, outcomes, and ethical considerations. Results: The results indicated over 467 GJB2 variants which could impair cochlear ion homeostasis and development. Animal models, mainly murine, demonstrated early-onset degeneration with limited recovery following delayed gene therapy, while early postnatal intervention showed greater efficacy. Viral vectors like AAV have been employed for targeted gene delivery via cochlear injections, achieving partial restoration of connexin expression and cochlear function, yet they have faced limitations including transduction efficiency, immune responses, and long-term stability. Challenges in translating these findings to humans have been compounded by anatomical, immunological, ethical, and safety issues, particularly regarding embryonic gene therapy and germline modifications. Ethical frameworks can vary internationally, highlighting the necessity for careful regulation. Conclusions: While promising advances in gene therapy for GJB2-related HL have been achieved in preclinical studies, significant scientific, technical, and ethical barriers must be addressed before clinical application, especially during embryogenesis. A multidisciplinary, cautious approach is essential to realize the potential of gene therapy in restoring natural hearing while safeguarding individual and societal interests. Full article

Pomegranate (Punica granatum L.) has attracted considerable attention for its anticancer potential; however, mechanistic studies employing bioactivity-guided fractions from geographically distinct landraces remain limited. Building on our previous report on the bioactivity and phytochemical profile of the Bidah pomegranate landrace, the present study applied bioactivity-guided fractionation to enrich biologically active constituents and investigate mitochondria-associated cellular responses in colorectal cancer cells (Caco-2 cells). A semi-polar fraction from Bidah pomegranate crude extract (B6) was evaluated for its antioxidant activity, cell viability, cell death morphology, mitochondrial membrane potential, transcriptional modulation of key regulatory genes, and phytochemical composition. High-performance liquid chromatography (HPLC) profiling of B6 revealed a chromatographic fingerprint with seven detectable peaks, including two major peaks at retention times of 7.577 and 8.602 min, together accounting for approximately 66% of the total chromatographic area, indicating the enrichment of major constituents. Consistent with this enrichment, the fraction exhibited potent DPPH radical scavenging activity at a microgram-range IC₅₀, suggesting the presence of redox-active phytochemicals. In cell-based assays, the fraction induced a dose-dependent reduction in metabolic viability, while acridine orange/propidium iodide (AO/PI) staining of Caco-2 cells revealed delayed, regulated cell death. JC-1 staining demonstrated a pronounced loss of mitochondrial membrane potential, consistent with early mitochondrial dysfunction. Gene expression analysis further revealed modulation of pro- and anti-apoptotic genes, alongside cell-cycle-associated and oxidative stress/inflammatory markers. Gas chromatography–mass spectrometry (GC–MS) profiling identified polyacetylenes, sterol derivatives, fatty acid esters, and terpenoids, providing chemical context for the observed mitochondrial perturbation. Collectively, the findings support a mitochondria-centered, regulated cell death response driven by a multi-component phytochemical matrix. This study advances mechanistic insight beyond crude extract analysis and highlights the sustainable biomedical value of the Bidah pomegranate landrace as an underutilized regional resource. Full article

Background: Acute exercise induces measurable inflammatory and hematological responses, which may differ according to training status. Methods: Trained soccer players and sedentary controls completed a progressive exercise test until exhaustion. Blood samples were collected at six time points (up to 48 h post-exercise). Gene expression was assessed using real-time PCR, protein concentration via ELISA, and leukocyte, lymphocyte and neutrophil counts through routine hematology. Analyses included between-group comparisons, within-group time effects, and gene–protein correlations. Results: Sedentary individuals showed delayed increases in TNF-α mRNA (p < 0.05), whereas athletes maintained stable levels. Athletes exhibited consistently higher TNFR-1 expression (p < 0.05), while TNFR-2 showed no differences between groups. IL-4 expression was higher in athletes 30 min (p = 0.038) and 24 h after test (p = 0.002), whereas IL-4 protein decreased in sedentary subjects after 6 h (p = 0.009) and 24 h (p = 0.019). IL-4Rα was transiently elevated post-exercise in sedentary individuals and briefly suppressed in athletes (p = 0.041). Hematological responses showed stronger leukocytosis and neutrophilia in sedentary individuals. Conclusions: The temporal inflammatory patterns differed substantially between groups, indicating more efficient resolution dynamics in trained individuals. These findings highlight practical value for monitoring adaptation and recovery. Full article

Toscana virus (TOSV), a negative-sense RNA phlebovirus transmitted by Phlebotomus sandflies and endemic in Mediterranean regions, is an emerging pathogen capable of causing diseases ranging from mild febrile illness to severe central nervous system involvement. With no licensed vaccines or specific antiviral therapies available, the identification of novel therapeutic approaches is urgently needed. Microbial secondary metabolites have recently attracted attention for their broad-spectrum antiviral activities. Among them, monensin and brefeldin A have shown antiviral efficacy against a variety of viruses, often by disrupting viral protein trafficking and inducing Golgi-associated stress responses. However, their potential activity in the context of TOSV infection has not yet been explored. This study aimed to evaluate the in vitro antiviral activity of monensin and brefeldin A against TOSV and to gain mechanistic insights into their effects at the cellular level. Vero cells were infected with TOSV and treated with monensin (1.5–25 µM) or brefeldin A (10.9–175 nM) at different time points (4, 6, 12, 24 h). Cytotoxicity was assessed using MTT and hemolysis assays. Antiviral activity was measured via plaque reduction assays and quantitative real-time PCR targeting the viral L gene. Western blot analysis was performed to assess TFE3 expression, a transcription factor associated with the Golgi stress response. Monensin exhibited rapid antiviral activity, achieving IC₅₀ values of 2.7 µM and 2.5 µM at 4 and 6 h post-treatment, respectively, with dose-dependent suppression of viral L gene expression. Brefeldin A displayed a delayed effect, with maximal inhibition after 12 h (IC₅₀ = 66.9 nM). Monensin treatment induced a concentration-dependent upregulation of TFE3, while brefeldin A caused only a modest increase, suggesting differential activation of the Golgi stress response during TOSV infection. These findings support the potential of microbial metabolites as therapeutic candidates for emerging arboviral infections in the Mediterranean region. Full article

This research explored the impact of combining electrolyzed functional water (EFW) with modified atmosphere (MA) storage on postharvest ripening, aging, and lignin accumulation in Chinese thorny bamboo shoots. The effects of EFW combined with MA treatment on texture hardness, lignin content, and reactive oxygen metabolism were evaluated. The findings indicated that the EFW + MA treatment was superior in postponing weight reduction, minimizing the increase in shoot hardness and lignin build-up, avoiding epidermal browning, and successfully maintaining elevated activity levels of superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX), thus reducing oxidative stress and extending storage time. Moreover, compared with the control group, the EFW/MA treatment markedly reduced malondialdehyde (MDA) levels, thereby improving cellular integrity. In addition, KEGG enrichment analysis revealed that PAL, POD, and PPO, along with their corresponding gene expression levels, were significantly up- and down-regulated. The findings suggest that combining EFW and MA can effectively delay quality deterioration and inhibit lignification in bamboo, thereby preserving its freshness and nutritional value. Full article

Enhancing cereal grain quality while maintaining yield stability represents a pressing global challenge for sustainable agricultural development. Optimizing grain quality in cereal crops, which account for more than 60% of global dietary energy, relies heavily on managing nitrogen dynamics during the heading and grain-filling stages. Late-stage nitrogen application (from heading to early grain-filling stages) optimizes the temporal dynamics of nitrogen supply and exhibits substantial regulatory potential in mediating the yield–quality trade-off. Nitrogen availability can profoundly influence source–sink dynamics, carbon–nitrogen metabolic coordination, and the biosynthesis of storage reserves. This systematic review consolidates current understanding of the molecular and physiological mechanisms by which late-stage nitrogen application affects grain development and final quality in cereals, with a particular focus on major cereal crops including wheat, rice, and malting barley, which represent contrasting quality objectives and nitrogen management requirements. At the physiological level, late-stage nitrogen application delays functional leaf senescence, sustains photosynthetic carbon assimilation capacity, facilitates assimilate transport and partition to developing grains, and optimizes the accumulation dynamics and compositional profiles of starch and protein. At the molecular level, this review elucidates the sequential regulatory cascades governing nitrogen signal perception and transduction, the coordinated transcriptional networks underlying carbon–nitrogen metabolic crosstalk, and the expression dynamics of genes encoding starch biosynthetic enzymes and storage proteins. Integrating those recent research advances, this review also highlights several critical challenges currently facing the field. To address these challenges, we delineate promising avenues for future research including constructing time-series multi-omics frameworks, employing genome-editing technologies to functionally validate key regulatory genes and integrating artificial intelligence and big data analytics. The goal of this review is to establish a theoretical basis for precision nitrogen management strategies designed to optimize cereal crop production, targeting high yield, superior quality, and improved nitrogen use efficiency concurrently. Full article

Background/Objectives: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare and extremely aggressive subtype of non-Hodgkin lymphoma that most frequently involves the nasal cavity and upper aerodigestive tract. Primary isolated oral manifestation is exceptionally uncommon and may mimic odontogenic or infectious diseases, delaying diagnosis. We report a case of ENKTCL-NT presenting initially as a destructive oral lesion without sinonasal involvement at diagnosis. Methods: A 32-year-old man with progressive palatal ulceration underwent clinical and imaging assessment (panoramic radiography and staging ^18F-FDG PET–CT) and repeated biopsies. Diagnosis was established using histopathology (H&E), immunohistochemistry (T-cell markers and cytotoxic profile), EBV detection by EBER in situ hybridization, and T-cell receptor gamma (TCRG) gene rearrangement analysis. Results: The lesion presented as a hemorrhagic, ulcerative palatal destruction covered by pseudomembranous exudate and was complicated by fungal infection, periostitis, and severe dental inflammatory foci, contributing to diagnostic delay. Histopathological examination revealed extensive necrosis with a dense atypical lymphoid infiltrate; angiocentric and angiodestructive growth was identified in one biopsy specimen. Tumor cells expressed T-cell markers (CD2, CD3, CD5, CD7; heterogeneous) and cytotoxic markers (TIA-1) and showed CD30 and CD56 positivity, with EBV positivity confirmed by EBER in situ hybridization. Molecular analysis demonstrated monoclonal TCRG rearrangement, and Ki-67 indicated high proliferative activity. Initial PET–CT demonstrated an intensely FDG-avid, locally invasive lesion without distant organ involvement. The patient was treated with L-asparaginase-based SMILE chemotherapy followed by radiotherapy (50 Gy), achieving marked initial clinical improvement and partial metabolic response; however, systemic relapse subsequently occurred with refractory disease despite salvage therapy and immunotherapy. Conclusions: This case highlights the substantial diagnostic challenge posed by isolated oral extranodal NK/T-cell lymphoma, nasal type, which may closely mimic benign inflammatory or infectious conditions and lead to significant diagnostic delay. Persistent, progressive, or therapy-resistant oral ulcerations should prompt early consideration of hematologic malignancy. Timely biopsy with comprehensive immunophenotyping, EBV testing, and close multidisciplinary collaboration are essential for accurate diagnosis and may contribute to earlier diagnosis and improved patient outcomes in these rare and atypical presentations. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

Hypomyelinating leukodystrophies (HLDs) are a group of hereditary CNS disorders characterized by hypomyelination and, sometimes, repeated cycles of demyelination and remyelination. In HLDs, various genetic mutations in the responsible genes disrupt the morphogenesis of oligodendrocytes (oligodendroglial cells), which wrap neuronal axons with their differentiated myelin sheaths. A stop-loss mutation (c.622T-C or c.622T-G) in the gene encoding claudin family tetraspan plasma membrane protein claudin-11 (CLDN11) is associated with HLD22, which is characterized by incomplete differentiation and hypomyelination or delayed myelination in the brain. Herein, we describe for the first time that a CLDN11 mutant protein with an additional amino acid sequence due to the stop-loss mutation, but not the wild-type protein, leads to decreased expression of oligodendroglial differentiation marker proteins in the FBD-102b oligodendroglial progenitor cell line, the model undergoing its differentiation, at both the molecular and morphological levels. Consistently, mutant CLDN11 exhibited decreased morphological differentiation with a reduced ability to extend processes. These cells contained punctate structures that were partially localized in the endoplasmic reticulum (ER) and stimulated phosphorylation of c-Jun N-terminal kinase (JNK) and eukaryotic translation initiation factor 2A (eIF2A) kinase, ER stress-responsible kinases. Hesperetin, a neuroprotective flavonoid that can downregulate ER stress, recovered the differentiation abilities of these cells. Notably, the effects were related to decreased phosphorylation of ER stress-responsible kinases. JNK was found to be present in a co-precipitate with the hesperetin core, whereby hesperetin inhibited signaling through c-Jun as a negative regulator of differentiation. These findings indicate that the HLD22-associated mutant protein can cause an ER stress response, decreasing cell morphological differentiation. In addition, this study offers possible therapeutic implications for the as-yet-unexplored mechanisms involved in HLD22, at least at the molecular and cellular levels. Full article

In this paper, a complete analysis is presented to study a reaction–diffusion system of general gene expression with two time delays and with Neumann boundary conditions. The global existence of a unique strong solution and the existence of an attractor are established. Using delays as bifurcation parameters, we obtain critical values so that the Hopf bifurcation occurs at a unique equilibrium point. Numerical simulations are provided to illustrate both the stability of the equilibrium point and the emergence of bifurcations. For steady-state solutions, the Maximum Principle is used to obtain the bounds of positive solutions. The conditions for the system to have constant solutions are also investigated. Full article

DNA methylation regulates plant growth by modulating gene expression; however, its contribution to hormone responsiveness and photomorphogenesis remains only partially understood. We examined Arabidopsis thaliana DNA methylation mutants met1 and drm1, drm2, and cmt3 (ddc) under defined light regimes and following exogenous treatments with auxin, gibberellin, and the auxin transport inhibitor TIBA. Hypocotyl elongation and cotyledon expansion exhibited strong light dependency across all genotypes, with met1 seedlings developing a consistently reduced cotyledon area and ddc seedlings displaying impaired hypocotyl elongation under specific light qualities. Exogenous auxin inhibited growth in all genotypes, whereas GA₃ promoted elongation in hypocotyls and roots (by approximately 75–80% and 15–35%, respectively, in Col0 and met1), with ddc exhibiting delayed and non-linear dose-dependent sensitivity. Quantitative RT–PCR analysis revealed differential expression of genes involved in auxin transport (PIN1, PIN3, PIN7), auxin signalling (ARF7, IAA3, LAX3), circadian regulation (TOC1, LHY, CCA1), and light signalling (PIFs, HY5, HYH), supporting a link between DNA methylation status and coordinated regulation of hormone-, light-, and clock-controlled transcriptional networks. Together, these findings demonstrate that MET1- and DRM/CMT-dependent methylation pathways integrate epigenetic regulation with environmental and hormonal cues, modulating the intensity, timing, and organ specificity of growth responses, thereby fine-tuning growth plasticity during early Arabidopsis seedling development. Full article

This study comprehensively characterizes the PEBP gene family in Cymbidium sinense, an orchid with a prolonged vegetative phase that limits its industrial production. Genome-wide analysis identified six CsPEBPs, classified into FT-like, TFL1-like, and MFT-like subfamilies. Evolutionary, gene structure, and collinearity analyses revealed both conservation and lineage-specific diversification of these genes. CsFTL3, a distinctive FT-like member, displayed notably high expression during the bud undifferentiated stage, followed by a sharp downregulation upon floral initiation. Functional studies identified CsFTL3 as a key floral repressor. Heterologous overexpression in Arabidopsis delayed flowering time from 32.0 days (wild-type) to 63.0–75.3 days (transgenic) and increased rosette leaf number from 12.6 to 33.0–34.5, while its knockdown via virus-induced gene silencing (VIGS) in C. sinense accelerated floral bud development and upregulated flowering-promoter genes. Phylogenetically, CsFTL3 falls within the flowering repressor FT-I clade, and multiple sequence alignment identified critical amino acid substitutions (Y134S, W138L, Q140E) that likely underpin its functional divergence from typical flowering promoters. Furthermore, promoter analysis revealed an enrichment of light-, hormone-, and stress-responsive cis-elements, and its expression was modulated by gibberellin (GA), abscisic acid (ABA), and low-temperature treatments. Predicted protein–protein interaction and transcriptional regulatory networks provide preliminary insights into its complex regulation. We conclude that CsFTL3 acts as a crucial floral inhibitor, integrating environmental and endogenous cues to repress flowering. These findings offer fundamental insights into the molecular mechanisms of flowering in orchids and provide a valuable genetic resource for molecular breeding programs aimed at achieving precise flowering time control. Full article