Fruit have evolved a sophisticated tissue and cellular architecture to secure plant reproductive success. Postfertilization growth is perhaps the most dramatic event during fruit morphogenesis. ...Several studies have proposed that fertilized ovules and developing seeds initiate signaling cascades to coordinate and promote the growth of the accompanying fruit tissues. This dynamic process allows the fruit to conspicuously increase its size and acquire its final shape and means for seed dispersal. All these features are key for plant survival and crop yield. Despite its importance, we lack a high-resolution spatiotemporal map of how postfertilization fruit growth proceeds at the cellular level. In this study, we have combined live imaging, mutant backgrounds in which fertilization can be controlled, and computational modeling to monitor and predict post-fertilization fruit growth in Arabidopsis. We have uncovered that, unlike leaves, sepals, or roots, fruit do not exhibit a spatial separation of cell division and expansion domains; instead, there is a separation into temporal stages with fertilization as the trigger for transitioning to cell expansion, which drives postfertilization fruit growth. We quantified the coordination between fertilization and fruit growth by imaging no transmitting tract (ntt) mutants, in which fertilization fails in the bottom half of the fruit. By combining our experimental data with computational modeling, we delineated the mobility properties of the seed-derived signaling cascades promoting growth in the fruit. Our study provides the basis for generating a comprehensive understanding of the molecular and cellular mechanisms governing fruit growth and shape.
Abstract
Background
Large-scale image sets acquired by automated microscopy of perturbed samples enable a detailed comparison of cell states induced by each perturbation, such as a small molecule ...from a diverse library. Highly multiplexed measurements of cellular morphology can be extracted from each image and subsequently mined for a number of applications.
Findings
This microscopy dataset includes 919 265 five-channel fields of view, representing 30 616 tested compounds, available at “The Cell Image Library” (CIL) repository. It also includes data files containing morphological features derived from each cell in each image, both at the single-cell level and population-averaged (i.e., per-well) level; the image analysis workflows that generated the morphological features are also provided. Quality-control metrics are provided as metadata, indicating fields of view that are out-of-focus or containing highly fluorescent material or debris. Lastly, chemical annotations are supplied for the compound treatments applied.
Conclusions
Because computational algorithms and methods for handling single-cell morphological measurements are not yet routine, the dataset serves as a useful resource for the wider scientific community applying morphological (image-based) profiling. The dataset can be mined for many purposes, including small-molecule library enrichment and chemical mechanism-of-action studies, such as target identification. Integration with genetically perturbed datasets could enable identification of small-molecule mimetics of particular disease- or gene-related phenotypes that could be useful as probes or potential starting points for development of future therapeutics.
microRNA regulation of fruit growth José Ripoll, Juan; Bailey, Lindsay J; Mai, Quynh-Anh ...
Nature plants,
03/2015, Letnik:
1, Številka:
4
Journal Article
Recenzirano
Growth is a major factor in plant organ morphogenesis and is influenced by exogenous and endogenous signals including hormones. Although recent studies have identified regulatory pathways for the ...control of growth during vegetative development, there is little mechanistic understanding of how growth is controlled during the reproductive phase. Using Arabidopsis fruit morphogenesis as a platform for our studies, we show that the microRNA miR172 is critical for fruit growth, as the growth of fruit is blocked when miR172 activity is compromised. Furthermore, our data are consistent with the FRUITFULL (FUL) MADS-domain protein and Auxin Response Factors (ARFs) directly activating the expression of a miR172-encoding gene to promote fruit valve growth. We have also revealed that MADS-domain (such as FUL) and ARF proteins directly associate in planta. This study defines a novel and conserved microRNA-dependent regulatory module integrating developmental and hormone signalling pathways in the control of plant growth.
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human ...tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
Towards patient-based cancer therapeutics Schreiber, Stuart L; Shamji, Alykhan F; Clemons, Paul A ...
Nature biotechnology,
201009, 2010-Sep, 2010-9-00, 20100901, Letnik:
28, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Orienting cancer drug discovery to the patient requires relating the genetic features of tumors to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them. ...PUBLICATION ABSTRACT
Abstract
Background
Hepatitis E virus (HEV) variants belonging to Orthohepevirus species A (HEV-A) are the primary cause of human hepatitis E. However, we previously reported that Orthohepevirus ...species C genotype 1 (HEV-C1), a divergent HEV variant commonly found in rats, also causes hepatitis in humans. Here, we present a clinical-epidemiological investigation of human HEV-C1 infections detected in Hong Kong, with an emphasis on outcomes in immunocompromised individuals.
Methods
A surveillance system for detecting human HEV-C1 infections was established in Hong Kong. Epidemiological and clinical characteristics of HEV-C1 cases identified via this system between 1 August 2019 and 31 December 2020 were retrieved. Phylogenetic analysis of HEV-C1 strain sequences was performed. Infection outcomes of immunocompromised individuals with HEV-A and HEV-C1 infections were analyzed.
Results
HEV-C1 accounted for 8 of 53 (15.1%) reverse-transcription polymerase chain reaction (RT-PCR)–confirmed HEV infections in Hong Kong during the study period, raising the total number of HEV-C1 infections detected in the city to 16. Two distinct HEV-C1 strain groups caused human infections. Patients were elderly and/or immunocompromised; half tested negative for HEV immunoglobulin M. Cumulatively, HEV-C1 accounted for 9 of 21 (42.9%) cases of hepatitis E recorded in immunocompromised patients in Hong Kong. Immunocompromised HEV-C1 patients progressed to persistent hepatitis at similar rates (7/9 77.8%) as HEV-A patients (10/12 75%). HEV-C1 patients responded to oral ribavirin, although response to first course was sometimes poor or delayed.
Conclusions
Dedicated RT-PCR–based surveillance detected human HEV-C1 cases that evade conventional hepatitis E diagnostic testing. Immunosuppressed HEV-C1–infected patients frequently progress to persistent HEV-C1 infection, for which ribavirin is a suitable treatment option.
Orthohepevirusspecies C (commonly known as rat hepatitis E virus) causes hepatitis in humans, with high rates of persistent infection in immunocompromised patients. Ribavirin is an effective antiviral for this condition, although suboptimal responses to the first course can occur.
Free flap tissue transfer has become the gold standard for reconstruction of composite head and neck defects. We sought to investigate the efficacy and morbidity of these procedures in the elderly. ...We retrospectively reviewed 245 head and neck free flap procedures (234 patients). Patients were stratified by age group (≥ or <65 years). Univariate and multivariate analyses were used to evaluate the following primary outcomes – free flap survival, postoperative medical and surgical complications and 30-day mortality. We found that free flap success and surgical complication rates were similar between the two age groups. Overall flap success and perioperative mortality rates were 94.3% and 2.1% respectively. Medical complications were significantly more common in the elderly group (p < 0.001) and this correlated with comorbidity (OR = 2.81, p = 0.044) and advanced tumour stage (OR = 10.20, p = 0.029). Age was not independently associated with poor outcomes in our cohort. We then performed a systematic review of similar case-control studies worldwide and compared their findings with our results. We conclude that advanced age does not preclude free flap success in head and neck reconstruction. Rather, the presence of comorbidity appears to predict the development of medical complications postoperatively. Elderly patients with low comorbidity scores may be offered free flap reconstruction with less reservation.
In oxygenic photosynthesis, light-driven oxidation of water to molecular oxygen is carried out by the oxygen-evolving complex (OEC) in photosystem II (PS II). Recently, we reported the ...roomtemperature structures of PS II in the four (semi)stable S-states, S₁, S₂, S₃, and S₀, showing that a water molecule is inserted during the S₂ → S₃ transition, as a new bridging O(H)-ligand between Mn1 and Ca. To understand the sequence of events leading to the formation of this last stable intermediate state before O₂ formation, we recorded diffraction and Mn X-ray emission spectroscopy (XES) data at several time points during the S₂ → S₃ transition. At the electron acceptor site, changes due to the two-electron redox chemistry at the quinones, QA and QB, are observed. At the donor site, tyrosine YZ and His190 H-bonded to it move by 50 μs after the second flash, and Glu189 moves away from Ca. This is followed by Mn1 and Mn4 moving apart, and the insertion of OX(H) at the open coordination site of Mn1. This water, possibly a ligand of Ca, could be supplied via a “water wheel”-like arrangement of five waters next to the OEC that is connected by a large channel to the bulk solvent. XES spectra show that Mn oxidation (τ of ∼350 μs) during the S₂ → S₃ transition mirrors the appearance of OX electron density. This indicates that the oxidation state change and the insertion of water as a bridging atom between Mn1 and Ca are highly correlated.
In oxygenic photosynthesis, light-driven oxidation of water to molecular oxygen is carried out by the oxygen-evolving complex (OEC) in photosystem II (PS II). Recently, we reported the ...room-temperature structures of PS II in the four (semi)stable S-states, S
, S
, S
, and S
, showing that a water molecule is inserted during the S
→ S
transition, as a new bridging O(H)-ligand between Mn1 and Ca. To understand the sequence of events leading to the formation of this last stable intermediate state before O
formation, we recorded diffraction and Mn X-ray emission spectroscopy (XES) data at several time points during the S
→ S
transition. At the electron acceptor site, changes due to the two-electron redox chemistry at the quinones, Q
and Q
, are observed. At the donor site, tyrosine Y
and His190 H-bonded to it move by 50 µs after the second flash, and Glu189 moves away from Ca. This is followed by Mn1 and Mn4 moving apart, and the insertion of O
(H) at the open coordination site of Mn1. This water, possibly a ligand of Ca, could be supplied via a "water wheel"-like arrangement of five waters next to the OEC that is connected by a large channel to the bulk solvent. XES spectra show that Mn oxidation (τ of ∼350 µs) during the S
→ S
transition mirrors the appearance of O
electron density. This indicates that the oxidation state change and the insertion of water as a bridging atom between Mn1 and Ca are highly correlated.
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