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Segregated pathways enable AtRGS1 endocytosis to transduce signal-specific responses in Arabidopsis .
Neisseria gonorrhoeae is a bacterial pathogen responsible for the sexually transmitted infection gonorrhea. Emergence of antimicrobial resistance (AMR) of N. gonorrhoeae worldwide has resulted in limited therapeutic choices for this infection. Men who seek treatment often have symptomatic urethritis; in contrast, gonococcal cervicitis in women is usually minimally symptomatic, but may progress to pelvic inflammatory disease. Previously, we reported the first analysis of gonococcal transcriptome expression determined in secretions from women with cervical infection. Here, we defined gonococcal global transcriptional responses in urethral specimens from men with symptomatic urethritis and compared these with transcriptional responses in specimens obtained from women with cervical infections and in vitro-grown N. gonorrhoeae isolates. This is the first comprehensive comparison of gonococcal gene expression in infected men and women. RNA sequencing analysis revealed that 9.4% of gonococcal genes showed increased expression exclusively in men and included genes involved in host immune cell interactions, while 4.3% showed increased expression exclusively in women and included phage-associated genes. Infected men and women displayed comparable antibiotic-resistant genotypes and in vitro phenotypes, but a 4-fold higher expression of the Mtr efflux pump-related genes was observed in men. These results suggest that expression of AMR genes is programed genotypically and also driven by sex-specific environments. Collectively, our results indicate that distinct N. gonorrhoeae gene expression signatures are detected during genital infection in men and women. We propose that therapeutic strategies could target sex-specific differences in expression of antibiotic resistance genes.
The production rates of prompt and non-prompt J/ψ and ψ(2S) mesons in their dimuon decay modes are measured using 2.1 and 11.4 fb -1 of data collected with the ATLAS experiment at the Large Hadron Collider, in proton–proton collisions at √s=7 and 8 respectively. Production cross-sections for prompt as well as non-prompt sources, ratios of ψ(2S) to J/ψ production, and the fractions of non-prompt production for J/ψ and ψ(2S) are measured as a function of meson transverse momentum and rapidity. Lastly, the measurements are compared to theoretical predictions.
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Corrections for five figures and six tables are noted for the paper, which do not affect the conclusions reported.
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Abstract not provided.
Rubisco activase (Rca) facilitates the release of sugar-phosphate inhibitors at Rubisco catalytic sites during CO2 fixation. Most plant species express two Rca isoforms, the larger Rca-α and the shorter Rca-β, either by alternative splicing from a single gene or expression from separate genes. The mechanism of Rubisco activation by Rca isoforms has been intensively studied in C3 plants. However, the functional role of Rca in C4 plants where Rubisco and Rca are located in a much higher [CO2] compartment is less clear. In this study, we selected four C4 bioenergy grasses and the model C4 grass setaria ( Setaria viridis ) to investigate the role of Rca in C4 photosynthesis. All five C4 grass species contained two Rca genes, one encoding Rca-α and the other Rca-β, which were positioned closely together in the genomes. A variety of abiotic stress-related motifs were identified in the Rca-α promoter of each grass, and while the Rca-β gene was constantly highly expressed at ambient temperature, Rca-α isoforms were expressed only at high temperature but never surpassed 30% of Rca-β content. The pattern of Rca-α induction on transition to high temperature and reduction on return to ambient temperature was the same in all five C4 grasses. In sorghum ( Sorghum bicolor ), sugarcane ( Saccharum officinarum ), and setaria, the induction rate of Rca-α was similar to the recovery rate of photosynthesis and Rubisco activation at high temperature. This association between Rca-α isoform expression and maintenance of Rubisco activation at high temperature suggests that Rca-α has a functional thermo-protective role in carbon fixation in C4 grasses by sustaining Rubisco activation at high temperature.
As the design complexity of modern accelerators grows, there is more interest in using advanced simulations that have fast execution time or yield additional insights like gradients. The FAST/IOTA facility has been working on implementing and experimentally validating an end-to-end digital twin that is both fast and gradient-aware, allowing for rapid prototyping of new software and experiments with minimal beam time costs. Our framework integrates physics and ML codes for linac and ring simulation through a set of generic interfaces between surrogate and physics-based sections. To reproduce device inputs and outputs, system state is exposed as a deterministic event loop in a specialized discrete event simulator architecture. Because Fermilab is undergoing control system transition, several APIs were implemented as final user interfaces - a fully asynchronous EPICS soft IOC, a gRPC-based Data Pool Manager (DPM), and legacy ACNET protocols. We discuss implementation details as well as challenges handling live data assimilation and future plans to extend modelling to main complex proton accelerators like PIPII and Booster.
Abstract not provided.
Highlights: • Mesenchymal differentiation of adMSC causes adaptations of the energy metabolism. • Mesenchymal differentiation of adMSC comes along with changes in cell proliferation. • Osteogenic differentiation entails an increase of all metabolic pathways tested. • Adipogenic differentiation entails a decreasing capacity of carbohydrate metabolism. • Adipogenic differentiation indicates a shift towards lipid metabolism. Mesenchymal stromal/stem cells (MSC) are important in tissue homeostasis and regeneration due to their ability for self-renewal and multipotent differentiation. Differentiation, as well as proliferation, requires adaptations in the cell metabolism. However, only few data exist concerning the energy metabolism of non-differentiating and differentiating MSC. In this study we compared capacities of major energy metabolic pathways of MSC from human adipose tissue (adMSC) in vitro in the non-differentiated state with those of osteogenically or adipogenically differentiating adMSC. To this end we quantified the proliferation and differentiation status of adMSC and analyzed maximum enzyme capacities and several enzyme isoforms of major energy metabolic pathways regarding their activity and gene expression. We could show that non-differentiating and osteogenic cultivation conditions induced proliferation and showed increasing capacities of the glycolytic marker enzyme phosphofructokinase as well as the marker enzyme of the pentose phosphate pathway glucose-6-phosphate dehydrogenase. Adipogenic stimulation, which was accompanied by the absence of proliferation, reduced the glycolytic capacity (e.g. decreased glyceraldehyde 3-phosphate dehydrogenase capacity) and induced an increase in mitochondrial enzyme capacities. These changes in energy metabolism might represent an adaptation of adMSC to the high energy demand during proliferation and to the specific cellular functions during osteogenic or adipogenic differentiation respectively.
Highlights: • PLD and PIP5K1 are involved in the regulation of oligodendroglial cell morphological differentiation. • Inhibition of PLD or PIP5K1 decreases differentiation or myelin marker expression. • PLD and PIP5K1 regulate differentiation of oligodendrocyte precursor cells. • Inhibition of PLD or PIP5K1 decreases differentiation marker expression of oligodendrocyte precursor cells. Oligodendroglial cells (oligodendrocytes) differentiate to form the myelin that wraps neuronal axons in the central nervous system (CNS). This myelin sheath supports the propagation of saltatory conduction and protects axons from physical stresses. When oligodendrocytes do not normally differentiate to myelinate axons, their key functions as oligodendrocytes in the CNS are severely impaired. The molecular mechanics that control differentiation still remain to be clarified. Arf6 belongs to the small GTPase family and is known to be a positive regulator of oligodendrocyte differentiation. Here, we show that the phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase 1 (PIP5K1) molecules, the major effectors of Arf6, are involved in the regulation of oligodendrocyte differentiation. Knockdown of PLD1 or PIP5K type 1γ (PIP5K1C) by their respective specific siRNAs in mouse oligodendroglial FBD-102b cells inhibited morphological differentiation into structures bearing myelin-like processes; this finding is consistent with the concurrent changes in expression of differentiation and myelin marker proteins. Treatment with VU0155069 or UNC3230, specific inhibitors of PLD and PIP5K1, respectively, blunted morphological differentiation and decreased expression of myelin and differentiation marker proteins. Similar results have been obtained in studies using primary oligodendrocytes. These results suggest that the major Arf6 effector molecules PLD and PIP5K1 are among the molecules involved in the regulation of morphological differentiation in oligodendrocytes prior to myelination.
Highlights: • miR-193a-3p was decreased during osteoblast differentiation. • Inhibition of miR-193a-3p promoted osteoblast differentiation. • LRG4 was a target gene of miR-193a-3p. • miR-193a-3p regulates osteoblast differentiation by LGR4/ATF4. Emerging evidence indicates that microRNAs (miRNAs) are crucial regulators of osteoblast differentiation. A previous study has reported that miR-193a-3p expression is altered during the induction of osteoblast differentiation. However, the precise biological function and regulatory mechanism of miR-193a-3p during osteoblast differentiation remains unclear. In this study, we aimed to investigate the precise role and underlying mechanism of miR-193a-3p in regulating osteoblast differentiation. The results showed that miR-193a-3p expression was significantly down-regulated during the induction of osteoblast differentiation. Functional experiments demonstrated that the overexpression of miR-193a-3p impeded osteoblast differentiation while miR-193a-3p inhibition promoted osteoblast differentiation. Bioinformatics analysis and a luciferase assay revealed that leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a critical regulator of osteoblast differentiation, was a target gene of miR-193a-3p. We showed that miR-193a-3p negatively regulated the expression of LGR4 and activating transcription factor 4 (ATF4). Moreover, the knockdown of LGR4 or ATF4 significantly reversed the promotion effect of miR-193a-3p inhibition on osteoblast differentiation. Overall, these findings demonstrate that miR-193a-3p regulates osteoblast differentiation by modulating LGR4/ATF4 signaling and suggests that the miR-193a-3p/LGR4/ATF4 regulation axis may play an important role in regulating bone remodeling.
Bovine muscle-derived satellite cells (MDSCs) are important for animal growth. In this study, the effect of transcription elongation factor A3 (TCEA3) on bovine MDSC differentiation was investigated. Western blotting, immunofluorescence assays, and cytoplasmic and nuclear protein isolation and purification techniques were used to determine the expression pattern and protein localization of TCEA3 in bovine MDSCs during in vitro differentiation. TCEA3 expression was upregulated using the CRISPR/Cas9 technique to study its effects on MDSC differentiation in vitro. TCEA3 expression gradually increased during the in vitro differentiation of bovine MDSCs and peaked on the 5th day of differentiation. TCEA3 was mainly localized in the cytoplasm of bovine MDSCs, and its expression was not detected in the nucleus. The level of TCEA3 was relatively higher in myotubes at a higher degree of differentiation than during early differentiation. After transfection with a TCEA3-activating plasmid vector (TCEA3 overexpression) for 24 h, the myotube fusion rate, number of myotubes, and expression levels of the muscle differentiation-related loci myogenin (MYOG) and myosin heavy chain 3 (MYH3) increased significantly during the in vitro differentiation of bovine MDSCs. After transfection with a TCEA3-inhibiting plasmid vector for 24 h, the myotube fusion rate, number of myotubes, and expression levels of MYOG and MYH3 decreased significantly. Our results indicated, for the first time, that TCEA3 promotes the differentiation of bovine MDSCs and have implications for meat production and animal rearing. - Highlights: • Muscle-derived satellite cell differentiation is promoted by TCEA3. • TCEA3 protein was localized in the cytoplasm, but not nuclei of bovine MDSCs. • TCEA3 levels increased as myotube differentiation increased. • TCEA3 affected myotube fusion, myotube counts, and MYOG and MYH3 levels.
Highlights: • Vibsanin A sensitizes AML cells to tyrosine kinase inhibitor (TKI)-induced differentiation. • Both PKC activation and Lyn induction contribute to combination-induced AML cell differentiation. • The combination treatment enhanced the activation of the Raf/MEK/ERK cascade. • Vibsanin A coupled with TKIs may lead to new applications of differentiation-based approaches for AML. Differentiation therapies have been proposed to overcome the impaired cell differentiation in acute myeloid leukemia (AML). However, thus far the all-trans retinoic acid-based differentiation therapy has been the only successful modality in treating acute promyelocytic leukemia. Here, we showed that vibsanin A, a novel protein kinase C (PKC) activator, sensitized AML cells to tyrosine kinase inhibitor (TKI)-induced differentiation. Vibsanin A augmented the ability of TKIs to induce growth inhibition and G1 cell cycle arrest of AML cells. Mechanistically, PKC activation was involved in the differentiation-inducing effects of combining vibsanin A with TKIs. Moreover, we found that vibsanin A enhanced TKI-induced Lyn expression and suppression of Lyn interfered with AML cell differentiation, indicating an essential role for Lyn expression in the combination-induced differentiation. Finally, combining vibsanin A and TKIs enhanced the activation of the Raf/MEK/ERK cascade. Together, this is the first study to evaluate the synergy of vibsanin A and TKIs in AML cell differentiation. Our study lays the foundation in assessing new opportunities for the combination of vibsanin A and TKIs as a promising approach for future differentiation therapy.
MicroRNAs (miRNAs) play significant roles in multiple diseases by regulating the expression of their target genes. Type 2 diabetes mellitus (T2DM) is a chronic endocrine and metabolic disease with complex mechanisms. T2DM can result in diabetic osteoporosis (DO), which is characterized by bone loss, decreased bone mineral density and increased bone fractures. The promotion of osteogenic differentiation of osteoblasts is an effective way to treat osteoporosis. In the present study, high glucose (HG) and free fatty acids (FFA) were employed to mimic T2DM in MC3T3-E1 cells. To induce osteogenic differentiation, MC3T3-E1 cells were cultured in osteogenic medium. The results showed that osteogenic differentiation was significantly suppressed by HG and FFA. We found that miR-132 expression was significantly upregulated and much higher in HG-FFA–induced cells than other selected miRNAs, indicating that miR-132 might play an important role in DO. Furthermore, overexpression of miR-132 markedly inhibited the expression of key markers of osteogenic differentiation and alkaline phosphatase (ALP) activity. Reciprocally, inhibition of miR-132 restored osteogenic differentiation, even under treatment with HG-FFA. We also showed that Sirtuin 1 (Sirt1) was one of the target genes of miR-132, whose expression was controlled by miR-132. Ectopic expression of Sirt1 reversed the decrease in osteogenic differentiation caused by miR-132 and HG-FFA. These results demonstrated the direct role of miR-132 in suppressing osteogenic differentiation through downregulating Sirt1. Moreover, we demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) was a downstream molecule of Sirt1, and its knockout by PPARβ/δ siRNA significantly abolished the promotive effects of Sirt1 on osteogenic differentiation, indicating that Sirt1 functioned in a PPARβ/δ–dependent manner. Taken together, we provide crucial evidence that miR-132 plays a key role in regulating osteogenic differentiation through Sirt1 in a PPARβ/δ–dependent manner, indicating that miR-132 and Sirt1-PPARβ/δ may act as potential therapeutic targets for T2DM–induced osteoporosis. - Highlights: • MiR-132 participates in regulating osteogenic differentiation of MC3T3-E1 cells. • Sirt1 is a target gene of miR-132. • Sirt1 is the effector of miR-132 in regulating osteogenic differentiation. • MiR-132-Sirt1 regulates osteogenic differentiation in a PPARβ/δ–dependent manner.
Highlights: • miR-374b expression was upregulated during NSC differentiation. • miR-374b promoted NSC proliferation and differentiation to neurons. • Hes1 was identified as a target gene of miR-374b. • miR-374b regulated NSC proliferation and differentiation by Hes1 Accumulating evidence has documented that microRNAs (miRNAs) are critical regulators of neural stem cell (NSC) proliferation and differentiation. MiRNA-374b (miR-374b) has been reported to play an important role in regulating various cellular processes, such as proliferation and differentiation. However, whether miR-374b is involved in NSC proliferation and differentiation remains unclear. In this study, we investigated the potential role of miR-374b in regulating NSC proliferation and differentiation to elucidate the underlying molecular mechanism. Our results showed that miR-374b expression was significantly upregulated during NSC differentiation. Functional experiments showed that overexpression of miR-374b promoted NSC proliferation and differentiation to neurons. By contrast, miR-374b inhibition showed the opposite effect. Hairy and enhancer of split 1 (Hes1), a master regulator of neurogenesis, was predicted as a potential target gene of miR-374b by bioinformatics analysis. Dual-luciferase reporter assays showed that miR-374b could directly target the 3′-untranslated region of Hes1. Further experiments showed that miR-374b negatively regulated the mRNA and protein expression of Hes1 in NSCs. Moreover, overexpression of Hes1 significantly reversed the miR-374b overexpression-mediated effect on NSC proliferation and differentiation. In addition, knockdown of Hes1 abrogated the miR-374b inhibition-mediated effect on NSC proliferation and differentiation. Taken together, these results demonstrate that miR-374b regulates the proliferation and differentiation of NSCs through targeting Hes1 and suggest that miR-374b is a potential target for modulating NSC-mediated neurogenesis.