Pluripotent stem cell-derived cardiomyocytes (CMs) have great potential in the development of new therapies for cardiovascular disease. In particular, human induced pluripotent stem cells (iPSCs) may ...prove especially advantageous due to their pluripotency, their self-renewal potential, and their ability to create patient-specific cell lines. Unfortunately, pluripotent stem cell-derived CMs are immature, with characteristics more closely resembling fetal CMs than adult CMs, and this immaturity has limited their use in drug screening and cell-based therapies. Extracellular matrix (ECM) influences cellular behavior and maturation, as does the geometry of the environment-two-dimensional (2D) versus three-dimensional (3D). We therefore tested the hypothesis that native cardiac ECM and 3D cultures might enhance the maturation of iPSC-derived CMs in vitro. We demonstrate that maturation of iPSC-derived CMs was enhanced when cells were seeded into a 3D cardiac ECM scaffold, compared with 2D culture. 3D cardiac ECM promoted increased expression of calcium-handling genes, Junctin, CaV1.2, NCX1, HCN4, SERCA2a, Triadin, and CASQ2. Consistent with this, we find that iPSC-derived CMs in 3D adult cardiac ECM show increased calcium signaling (amplitude) and kinetics (maximum upstroke and downstroke) compared with cells in 2D. Cells in 3D culture were also more responsive to caffeine, likely reflecting an increased availability of calcium in the sarcoplasmic reticulum. Taken together, these studies provide novel strategies for maturing iPSC-derived CMs that may have applications in drug screening and transplantation therapies to treat heart disease.
Three new triterpenoids, bonianic acids A (1) and B (2) and 3-O-acetyluncaric acid (3), were isolated from the leaves and twigs of Radermachera boniana, together with six known compounds, ursolic ...acid (4), oleanolic acid (5), 3-epi-oleanolic acid (6), 3α-O-acetyl-α-boswellic acid (7), ergosterol peroxide (8), and β-sitostenone (9). Ergosterol peroxide (8) and bonianic acids A (1) and B (2) exhibited significant activity against Mycobacterium tuberculosis H37Rv strain.
Stimulation of phosphatidylinositol 3′-kinase (PI3K) and protein kinase B (PKB) is implicated in the regulation of protein synthesis in various cells. One mechanism involves PI3K/PKB-dependent ...phosphorylation of 4E-BP1, which dissociates from eIF4E, allowing initiation of translation from the 7-methylGTP cap of mRNAs. We examined the effects of insulin and H2O2 on this pathway in neonatal cardiac myocytes. Cardiac myocyte protein synthesis was increased by insulin, but was inhibited by H2O2. PI3K inhibitors attenuated basal levels of protein synthesis and inhibited the insulin-induced increase in protein synthesis. Insulin or H2O2 increased the phosphorylation (activation) of PKB through PI3K, but, whereas insulin induced a sustained response, the response to H2O2 was transient. 4E-BP1 was phosphorylated in unstimulated cells, and 4E-BP1 phosphorylation was increased by insulin. H2O2 stimulated dephosphorylation of 4E-BP1 by increasing protein phosphatase (PP1/PP2A) activity. This increased the association of 4E-BP1 with eIF4E, consistent with H2O2 inhibition of protein synthesis. The effects of H2O2 were sufficient to override the stimulation of protein synthesis and 4E-BP1 phosphorylation induced by insulin. These results indicate that PI3K and PKB are important regulators of protein synthesis in cardiac myocytes, but other factors, including phosphatase activity, modulate the overall response. (Circ Res. 2000;86:1252-1258.)
Two new glucosides, 3-methoxy-4-hydroxyphenylpropane-7,8-(6′-benzoyl-2′,1′-O-β-glucopyranosyl)-7,8,9-trio (
1), and 2-hydroxyphenyl-4-caffeoyl-β-
d-glucoside (
2) were isolated from the stem bark of
...Xylosma longifolia (Flacourtiaceae), together with seven known compounds, 8-hydroxy-6-methoxy-pentylisocoumarin (
3), xylosmacin (
4), 2-(6-benzoyl-β-
d-glucopyranosyloxy)-7-(l,2,6-trihydroxy-5-oxocyclohex-3-enoyl)-5-hydroxybenzyl alcohol (
5), friedelin (
6), epifriedelanol (
7), atraric acid (
8) and methyl orsellinate (
9). The structures of the isolates were established on the basis of their spectral data, including mass spectrometry and 2D-NMR. The compound 8-hydroxy-6-methoxy-pentylisocoumarin (
3) exhibited an MIC value of 40.5
μg/mL against
Mycobacterium tuberculosis.
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► In this study we described the isolation, structural elucidation of two new compounds, 3-methoxy-4-hydroxyphenylpropane-7,8-(6′-benzoyl-2′,1′-O-β-glucopyranosyl)-7,8,9-trio, and 2-hydroxyphenyl-4-caffeoyl-β-
d-glucoside. ► We examined the activity against
Mycobacterium tuberculosis H37Rv for all isolates. ► We found that compound 8-hydroxy-6-methoxy-3-pentylisocoumarin was active against
M. tuberculosis H37Rv with an MIC value of 40.5
μg/mL. This was the first time that the biological activity was reported for 8-hydroxy-6-methoxy-3-pentylisocoumarin.
Two new glucosides, 3-methoxy-4-hydroxyphenylpropane-7,8-(6′-benzoyl-2′,1′-O-β-glucopyranosyl)-7,8,9-trio (
1), and 2-hydroxyphenyl-4-caffeoyl-β-
d-glucoside (
2), together with seven known compounds were isolated from the stem bark of
Xylosma longifolia (Flacourtiaceae). The structures of the isolates were established on the basis of their spectral data, including mass spectrometry and 2D-NMR. The compound 8-hydroxy-6-methoxy-pentylisocoumarin (
3) exhibited an MIC value of 40.5
μg/mL against
M. tuberculosis.
Three new triterpenoids, bonianic acids A (
1
), and B (
2
) and 3-
O
-acetyluncaric acid (
3
) were isolated from the leaves and twigs of
Radermachera boniana
(Bignoniaceae), together with six known ...compounds ursolic acid (
4
), oleanolic acid (
5
), 3-epi-oleanolic acid (
6
), 3α-
O
-acetyl-α-boswellic acid (
7
), ergosterol peroxide (
8
), and
β
-sitostenone (
9
). Ergosterol peroxide (
8
), bonianic acids A (
1
) and B (
2
) exhibited significant activity against
Mycobacterium tuberculosis
H
37
Rv strain.
Anatomical positioning of memory lymphocytes within barrier tissues accelerates secondary immune responses and is thought to be essential for protection at mucosal surfaces. However, it remains ...unclear whether resident memory in the female reproductive tract (FRT) is required for Chlamydial immunity. Here, we describe efficient generation of tissue-resident memory CD4 T cells and memory lymphocyte clusters within the FRT after vaginal infection with
Despite robust establishment of localized memory lymphocytes within the FRT, naïve mice surgically joined to immune mice, or mice with only circulating immunity following intranasal immunization, were fully capable of resisting
infection via the vaginal route. Blocking the rapid mobilization of circulating memory CD4 T cells to the FRT inhibited this protective response. These data demonstrate that secondary protection in the FRT can occur in the complete absence of tissue-resident immune cells. The ability to confer robust protection to barrier tissues via circulating immune memory provides an unexpected opportunity for vaccine development against infections of the FRT.
Southeast Asia is considered to have some of the highest levels of marine plastic pollution in the world. It is therefore vitally important to increase our understanding of the impacts and risks of ...plastic pollution to marine ecosystems and the essential services they provide to support the development of mitigation measures in the region. An interdisciplinary, international network of experts (Australia, Indonesia, Ireland, Malaysia, the Philippines, Singapore, Thailand, the United Kingdom, and Vietnam) set a research agenda for marine plastic pollution in the region, synthesizing current knowledge and highlighting areas for further research in Southeast Asia. Using an inductive method, 21 research questions emerged under five non-predefined key themes, grouping them according to which: (1) characterise marine plastic pollution in Southeast Asia; (2) explore its movement and fate across the region; (3) describe the biological and chemical modifications marine plastic pollution undergoes; (4) detail its environmental, social, and economic impacts; and, finally, (5) target regional policies and possible solutions. Questions relating to these research priority areas highlight the importance of better understanding the fate of marine plastic pollution, its degradation, and the impacts and risks it can generate across communities and different ecosystem services. Knowledge of these aspects will help support actions which currently suffer from transboundary problems, lack of responsibility, and inaction to tackle the issue from its point source in the region. Being profoundly affected by marine plastic pollution, Southeast Asian countries provide an opportunity to test the effectiveness of innovative and socially inclusive changes in marine plastic governance, as well as both high and low-tech solutions, which can offer insights and actionable models to the rest of the world.
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•Established key research questions for marine plastic pollution in Southeast Asia•Need to better understand fate, degradation and impacts of plastics regionally•Suffers from transboundary problems, lack of responsibility and inaction•Further research needed to support development of mitigation measures in the region
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