Nonalcoholic steatohepatitis (NASH) is associated with caspase activation. However, a role for pro-inflammatory caspases or inflammasomes has not been explored in diet-induced liver injury. Our aims ...were to examine the role of caspase-1 in high fat-induced NASH. C57BL/6 wild-type and caspase 1-knockout (Casp1(-/-)) mice were placed on a 12-week high fat diet. Wild-type mice on the high fat diet increased hepatic expression of pro-caspase-1 and IL-1β. Both wild-type and Casp1(-/-) mice on the high fat diet gained more weight than mice on a control diet. Hepatic steatosis and TG levels were increased in wild-type mice on high fat diet, but were attenuated in the absence of caspase-1. Plasma cholesterol and free fatty acids were elevated in wild-type, but not Casp1(-/-) mice, on high fat diet. ALT levels were elevated in both wild-type and Casp1(-/-) mice on high fat diet compared to control. Hepatic mRNA expression for genes associated with lipogenesis was lower in Casp1(-/-) mice on high fat diet compared to wild-type mice on high fat diet, while genes associated with fatty acid oxidation were not affected by diet or genotype. Hepatic Tnfα and Mcp-1 mRNA expression was increased in wild-type mice on high fat diet, but not in Casp1(-/-) mice on high fat diet. αSMA positive cells, Sirius red staining, and Col1α1 mRNA were increased in wild-type mice on high fat diet compared to control. Deficiency of caspase-1 prevented those increases. In summary, the absence of caspase-1 ameliorates the injurious effects of high fat diet-induced obesity on the liver. Specifically, mice deficient in caspase-1 are protected from high fat-induced hepatic steatosis, inflammation and early fibrogenesis. These data point to the inflammasome as an important therapeutic target for NASH.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In flowering plants, precise timing of the floral transition is crucial to maximize chances of reproductive success, and as such, this process has been intensively studied. FLOWERING LOCUS T (FT) and ...TERMINAL FLOWER1 (TFL1) have been identified as closely related eukaryotic phosphatidylethanolamine-binding proteins ('EuPEBPs') that integrate multiple environmental stimuli, and act antagonistically to determine the optimal timing of the floral transition. Extensive research has demonstrated that FT acts similar to hormonal signals, being transported in the phloem from its primary site of expression in leaves to its primary site of action in the shoot meristem; TFL1 also appears to act as a mobile signal. Recent work implicates FT, TFL1, and the other members of the EuPEBP family, in the control of other important processes, suggesting that the EuPEBP family may be key general regulators of developmental transitions in flowering plants. In eudicots, there are a small number of EuPEBP proteins, but in monocots, and particularly grasses, there has been a large, but uncharacterized expansion of EuPEBP copy number, with unknown consequences for the EuPEBP function.
To systematically characterize the evolution of EuPEBP proteins in flowering plants, and in land plants more generally, we performed a high-resolution phylogenetic analysis of 701 PEBP sequences from 208 species. We refine previous models of EuPEBP evolution in early land plants, demonstrating the algal origin of the family, and pin-pointing the origin of the FT/TFL1 clade at the base of monilophytes. We demonstrate how a core set of genes (MFT1, MFT2, FT, and TCB) at the base of flowering plants has undergone differential evolution in the major angiosperm lineages. This includes the radical expansion of the FT family in monocots into 5 core lineages, further re-duplicated in the grass family to 12 conserved clades.
We show that many grass FT proteins are strongly divergent from other FTs and are likely neo-functional regulators of development. Our analysis shows that monocots and eudicots have strongly divergent patterns of EuPEBP evolution.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Regulation of plant height and stem elongation has contributed significantly to improvement of cereal productivity by reducing lodging and improving distribution of assimilates to the inflorescence ...and grain. In wheat, genetic control of height has been largely contributed by the Reduced height-1 alleles that confer gibberellin insensitivity; the beneficial effects of these alleles are associated with less favourable effects involving seedling emergence, grain quality, and inflorescence architecture that have driven new research investigating genetic variation of stem growth. Here, we show that TEOSINTE BRANCHED1 (TB1) regulates height of wheat, with TB1 being expressed at low levels in nodes of the main culm prior to elongation, and increased dosage of TB1 restricting elongation of stem internodes. The effect of TB1 on stem growth is not accompanied by poor seedling emergence, as transgenic lines with increased activity of TB1 form longer coleoptiles than null transgenic controls. Analysis of height in a multiparent mapping population also showed that allelic variation for TB1 on the B genome influences height, with plants containing the variant TB-B1b allele being taller than those with the wild-type TB-B1a allele. Our results show that TB1 restricts height and stem elongation in wheat, suggesting that variant alleles that alter the expression or function of TB1 could be used as a new source of genetic diversity for optimizing architecture of wheat in breeding programmes.
Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which ...allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using "liquid biopsies" to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Circadian rhythms are ubiquitous in eukaryotes, and coordinate numerous aspects of behaviour, physiology and metabolism, from sleep/wake cycles in mammals to growth and photosynthesis in plants. This ...daily timekeeping is thought to be driven by transcriptional-translational feedback loops, whereby rhythmic expression of 'clock' gene products regulates the expression of associated genes in approximately 24-hour cycles. The specific transcriptional components differ between phylogenetic kingdoms. The unicellular pico-eukaryotic alga Ostreococcus tauri possesses a naturally minimized clock, which includes many features that are shared with plants, such as a central negative feedback loop that involves the morning-expressed CCA1 and evening-expressed TOC1 genes. Given that recent observations in animals and plants have revealed prominent post-translational contributions to timekeeping, a reappraisal of the transcriptional contribution to oscillator function is overdue. Here we show that non-transcriptional mechanisms are sufficient to sustain circadian timekeeping in the eukaryotic lineage, although they normally function in conjunction with transcriptional components. We identify oxidation of peroxiredoxin proteins as a transcription-independent rhythmic biomarker, which is also rhythmic in mammals. Moreover we show that pharmacological modulators of the mammalian clock mechanism have the same effects on rhythms in Ostreococcus. Post-translational mechanisms, and at least one rhythmic marker, seem to be better conserved than transcriptional clock regulators. It is plausible that the oldest oscillator components are non-transcriptional in nature, as in cyanobacteria, and are conserved across kingdoms.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The circadian clock provides robust, ∼24 hr biological rhythms throughout the eukaryotes. The clock gene circuit in plants comprises interlocking transcriptional feedback loops, reviewed in 1, ...whereby the morning-expressed transcription factors CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) repress the expression of evening genes, notably TIMING OF CAB EXPRESSION 1 (TOC1). EARLY FLOWERING 3 (ELF3) has been implicated as a repressor of light signaling to the clock 2, 3 and, paradoxically, as an activator of the light-induced genes CCA1 and LHY 4, 5. We use cca1-11 lhy-21 elf3-4 plants to separate the repressive function of ELF3 from its downstream targets CCA1 and LHY. We further demonstrate that ELF3 associates physically with the promoter of PSEUDO-RESPONSE REGULATOR 9 (PRR9), a repressor of CCA1 and LHY expression, in a time-dependent fashion. The repressive function of ELF3 is thus consistent with indirect activation of LHY and CCA1, in a double-negative connection via a direct ELF3 target, PRR9. This mechanism reconciles the functions of ELF3 in the clock network during the night and points to further effects of ELF3 during the day.
► ELF3 is a regulator of TOC1, PRR9, GI, and PRR7 gene expression ► Repression by ELF3 is genetically separable from repression by LHY and CCA1 ► ELF3 physically associates with the promoter of PRR9 in a time-dependent manner
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Circadian clocks were, until recently, seen as a consequence of rhythmic transcription of clock components, directed by transcriptional/translational feedback loops (TTFLs). Oscillations of protein ...modification were then discovered in cyanobacteria 1, 2. Canonical posttranslational signaling processes have known importance for clocks across taxa 3–11. More recently, evidence from the unicellular eukaryote Ostreococcus tauri revealed a transcription-independent, rhythmic protein modification 12 shared in anucleate human cells 13. In this study, the Ostreococcus system reveals a central role for targeted protein degradation in the mechanism of circadian timing. The Ostreococcus clockwork contains a TTFL involving the morning-expressed CCA1 and evening-expressed TOC1 proteins 14. Cellular CCA1 and TOC1 protein content and degradation rates are analyzed qualitatively and quantitatively using luciferase reporter fusion proteins. CCA1 protein degradation rates, measured in high time resolution, feature a sharp clock-regulated peak under constant conditions. TOC1 degradation peaks in response to darkness. Targeted protein degradation, unlike transcription and translation, is shown to be essential to sustain TTFL rhythmicity throughout the circadian cycle. Although proteasomal degradation is not necessary for sustained posttranslational oscillations in transcriptionally inactive cells, TTFL and posttranslational oscillators are normally coupled, and proteasome function is crucial to sustain both.
► CCA1 protein degradation rate is clock regulated ► Sensitivity of the circadian clock to proteasomal inhibition is phase independent ► Nontranscriptional rhythms only rely on the proteasome while coupled to the TTFL
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The stability of winter wheat-flowering-date is crucial for ensuring consistent and robust crop performance across diverse climatic conditions. However, the impact of climate change on ...wheat-flowering-dates remains uncertain. This study aims to elucidate the influence of climate change on wheat-flowering-dates, predict how projected future climate conditions will affect flowering date stability, and identify the most stable wheat genotypes in the study region. We applied a multi-locus genotype-based (MLG-based) model for simulating wheat-flowering-dates, which we calibrated and evaluated using observed data from the Northern China winter wheat region (NCWWR). This MLG-based model was employed to project flowering dates under different climate scenarios. The simulated flowering dates were then used to assess the stability of flowering dates under varying allelic combinations in projected climatic conditions. Our MLG-based model effectively simulated flowering dates, with a root mean square error (RMSE) of 2.3 days, explaining approximately 88.5 % of the genotypic variation in flowering dates among 100 wheat genotypes. We found that, in comparison to the baseline climate, wheat-flowering-dates are expected to shift earlier within the target sowing window by approximately 11 and 14 days by 2050 under the Representative Concentration Pathways 4.5 (RCP4.5) and RCP8.5 climate scenarios, respectively. Furthermore, our analysis revealed that wheat-flowering-date stability is likely to be further strengthened under projected climate scenarios due to early flowering trends. Ultimately, we demonstrate that the combination of Vrn and Ppd genes, rather than individual Vrn or Ppd genes, plays a critical role in wheat-flowering-date stability. Our results suggest that the combination of Ppd-D1a with winter genotypes carrying the vrn-D1 allele significantly contributes to flowering date stability under current and projected climate scenarios. These findings provide valuable insights for wheat breeders and producers under future climatic conditions.
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•The multi-locus genotype-based (MLG-based) model accurately simulated flowering dates.•Wheat-flowering-dates are expected to shift earlier within the target sowing window.•Wheat-flowering-date stability is likely to be further strengthened under projected climate scenarios.•The combination of Ppd-D1a with vrn-D1 allele enhances flowering date stability in current and future climates.•This work provides greater flexibility in selecting sowing dates under future climatic conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
FLOWERING LOCUS T (FT) is a central integrator of environmental signals that regulates the timing of vegetative to reproductive transition in flowering plants. In model plants, these environmental ...signals have been shown to include photoperiod, vernalization, and ambient temperature pathways, and in crop species, the integration of the ambient temperature pathway remains less well understood. In hexaploid wheat, at least 5 FT‐like genes have been identified, each with a copy on the A, B, and D genomes. Here, we report the characterization of FT‐B1 through analysis of FT‐B1 null and overexpression genotypes under different ambient temperature conditions. This analysis has identified that the FT‐B1 alleles perform differently under diverse environmental conditions; most notably, the FT‐B1 null produces an increase in spikelet and tiller number when grown at lower temperature conditions. Additionally, absence of FT‐B1 facilitates more rapid germination under both light and dark conditions. These results provide an opportunity to understand the FT‐dependent pathways that underpin key responses of wheat development to changes in ambient temperature. This is particularly important for wheat, for which development and grain productivity are sensitive to changes in temperature.
The physiology and development of wheat respond dramatically to increases in ambient growth temperature. To combat the adverse effects of this response, we need to understand its genetic and molecular basis. Here, we present the characterization of the FLOWERING LOCUS T (FT)‐B1 mediated temperature responses to flowering, plant architecture, germination, and gene expression. We show that FT‐B1 alleles respond differently under diverse temperatures and that the absence of FT‐B1 enhances germination and increases spikelet production at lower temperatures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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