Histone/Protein Deacetylase 11 Targeting Promotes Foxp3+ Treg Function.

Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases

Dynamic Interactions between TIP60 and p300 Regulate FOXP3 Function through a Structural Switch Defined by a Single Lysine on TIP60

SummaryThe human FOXP3 molecule is an oligomeric transcriptional factor able to mediate activities that characterize T regulatory cells, a class of lymphocytes central to the regulation of immune responses. The activity of FOXP3 is regulated at the posttranslational level, in part by two histone acetyltransferases (HATs): TIP60 and p300. TIP60 and p300 work cooperatively to regulate FOXP3 activity. Initially, p300 and TIP60 interactions lead to the activation of TIP60 and facilitate acetylation of K327 of TIP60, which functions as a molecular switch to allow TIP60 to change binding partners. Subsequently, p300 is released from this complex, and TIP60 interacts with and acetylates FOXP3. Maximal induction of FOXP3 activities is observed when both p300 and TIP60 are able to undergo cooperative interactions. Conditional knockout of TIP60 in Treg cells significantly decreases the Treg population in the peripheral immune organs, leading to a scurfy-like fatal autoimmune disease

Studies in the seedling phenology and role of seedling in clonally propagated species Hellenia speciosa (J.Koenig) S.D.Dutta

Hellenia speciosa (J. Koenig) S.D.Dutta, a clonally propagated plant, widely known as crepe ginger, is an important medicinal plant of tropical Asia. It is a rich source of diosgenin- a phytosteroid sapogenin used in the commercial synthesis of progesterone. Despite clonal propagation, the plant produces a substantial number of viable seeds, which later become short-lived seedlings. Therefore, this research aims to comprehend the phenological behaviour of the seedling and its significance in clonal development. The study will also help understand the role of ramets in establishment vis-à-vis rapid colonization of the plant. Studies on seed germination and phenology of seedling genet have revealed significant phenological and morphological features. Seed germination is of epigeal and phanerocotylar type producing seedling genet with orbicular obovate cotyledon, glabrous hypocotyl and spiromonostichous phyllotaxy. Leaf shape varies from narrowly ovate to lanceolate. Horizontal rhizome develops from the base of the seedling epicotyl and produces 4-5 ramets in the same growing season. Morphometry of leaf length and breadth of seedling is positively correlated with that of reproductive ramet of the previous growing season (leaf length: r=0.99, p<0.001; leaf breadth: r= 0.79, p<0.05). The plant shows rhizomatous dependency for maturity as seedling genets are short-lived. So it could be concluded that the primary role of the short-lived seedling genet is to provide a foundation for rhizome development. Additionally, the seedling appears as a miniature of the adult reproductive ramet. Here, during the first growing season, the species allocate more resources for the vegetative growth of its ramet rather than reproductive development. The reproductive development starts from the next growing season

Cationic amphiphiles: promising carriers of genetic materials in gene therapy

The clinical success of gene therapy critically depends on the use of efficient and safe gene delivery reagents. The present tutorial review is aimed at inspiring young researchers and students to take up the unsolved challenges in using cationic amphiphiles as safe gene transfer reagents. The review highlights important structure-activity studies in the field to date including the use of cationic amphiphiles for receptor specific targeted gene therapy and for delivery of siRNAs in the emerging field of RNA interference

The use of RGDGWK-lipopeptide to selectively deliver genes to mouse tumor vasculature and its complexation with p53 to inhibit tumor growth

In vivo selection of phage display libraries have been exploited successfully in the past to isolate various high affinity conformationally strained cyclic peptide ligands (CX5-7C, peptides flanked by a cysteine residue on each side) for integrin receptors capable of selectively homing to tumor vasculatures. Previously, such phase display library studies have shown that integrin α5β1 binds with high affinity to cyclic peptides containing CRGDGWC motif. Herein we show that a lipopeptide with just the RGDGW motif (without the flanking cysteine groups) covalently attached to the lysine residue of a monolysinylated cationic amphiphile (RGDGWK-lipopeptide 1) delivers genes to cultured cells preferably via α5β1 integrins. Importantly, remarkable tumor growth inhibition was observed when the electrostatic complex of the RGDGWK-lipopeptide 1 and the anti-cancer p53 gene was intravenously administered in C57BL/6 J mice bearing the aggressive B16F10 tumor. Immunohistochemical staining of mice tumor cryosections with vasculature markers combined with monitoring expression of the green fluorescence protein in the same tumor cryosections revealed that the RGDGWK-lipopeptide 1 targets genes to tumor vasculatures. The colocalization of the TUNEL (terminal deoxyuridine triphosphate nick-end labeling, a widely used marker of apoptosis) and VE-cadherin (markers of tumor endothelial cells) positive cells in tumor cryosections support the notion that the remarkable tumor growth inhibition property of the RGDGWK-lipopeptide 1:p53 complex is initiated through apoptosis of the tumor endothelial cells

Searching the factual factor in emission tweaking of a reported bisindole based self aggregation sensitive organic emitter: The missing link

A bis-indole derivative, 3,3′-bisindolyl(phenyl)methane (BIPM), is studied by using steady-state and time-resolved optical spectroscopy in several pure and mixed solvents to investigate its solvent sensitive photophysical behavior. The micro-environments possess diverse and captivating influences on the photophysical properties of luminophores. Therefore, the comprehensive understanding of the interplay between the micro-solvent parameters and the spectroscopic properties of various probes is a must before developing advanced photo-functional materials. Previously, BIPM exhibited a unique bell-patterned emission yield modulation with changing the composition of DiOx-H2O binary mixture where all the primary micro-parameters (polarity, proticity and viscosity) of the solvent system varied simultaneously. Therefore, here we intend to unveil the independent and specific effects of the solvent microparameters on the overall spectroscopic behaviour of BIPM. The probe reveals very attractive and complex photophysics and expresses high sensitivity towards the micro-polarity, proticity, and viscosity. The radiationless transitions are majorly affected by the local solvent parameters resulting significant changes in the emission efficiency of BIPM. The microparameters individually direct the QY of BIPM in three different ways, increasing, decreasing and increasing-then-decreasing patterns, that are rather uncommon. Besides the opportunity of optical sensing the liquid micro-environment based on the solvent-sensitivity of the probe, BIPM also demonstrates its wide applicability considering the easy-modulation of its emission efficiency in any way through controlling the solvent microparameters only

First simultaneous estimates of the water pool core size and the interfacial thickness of a cationic water-in-oil microemulsion by combined use of chemical trapping and time-resolved fluorescence quenching

The first simultaneous experimental estimates of the water pool core size (Rw) and the interfacial thickness (d) of a cationic water-in-oil microemulsion, CTAB/isooctane/n-hexanol/water, was achieved by the combined use of chemical trapping and the time-resolved fluorescence quenching. Our estimated values of Rw=29.1 ± 1.5 Å compares reasonably well with the reported size of the water pool core (32 Å) of a structurally and compositionally similar CTAB/dodecane/n-hexanol/water cationic water-in-oil microemulsion (Atik, S. S.; Thomas, J. K. J. Am. Chem. Soc. 1981, 103, 4367), and our estimated interfacial thickness (6.3 Å ± 0.3) is consistent with the recently estimated thickness for the hydration layer (10 Å) of the cationic CTAB/n-hexane/n-pentanol/water water-in-oil microemulsions (Giustini, M. et al. J. Phys. Chem. 1996, 100, 3190). To our knowledge, this is the first simultaneous experimental estimate of the size of the water pool core and interfacial thickness of a cationic water-in-oil microemulsion using a chemical reaction

Rapid, Simple, and Versatile Manufacturing of Recombinant Adeno-Associated Viral Vectors at Scale

Lock et al. describe a scaled recombinant AAV production method suitable for large animal studies; this method is based upon polyethylenimine transfection and supernatant harvest. According to the authors, the method is high-yielding, versatile for the production of vectors with different serotypes and transgenes and simple enough that it may be performed in most laboratories with a minimum of specialized techniques and equipment