Prodrug-conjugated tumor-seeking commensals for targeted cancer therapy.

Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%.

ROS-induced translational regulation-through spatiotemporal differences in codon recognition-is a key driver of brown adipogenesis.

The role of translational regulation in brown adipogenesis is relatively unknown. Localized translation of mRNAs encoding mitochondrial components enables swift mitochondrial responses, but whether this occurs during brown adipogenesis, which involves massive mitochondrial biogenesis, has not been explored. Here, we used ribosome profiling and RNA-Seq, coupled with cellular fractionation, to obtain spatiotemporal insights into translational regulation. During brown adipogenesis, a translation bias towards G/C-ending codons is triggered first in the mitochondrial vicinity by reactive oxygen species (ROS), which later spreads to the rest of the cell. This translation bias is induced through ROS modulating the activity of the tRNA modification enzyme, ELP3. Intriguingly, functionally relevant mRNAs, including those encoding ROS scavengers, benefit from this bias; in so doing, ROS-induced translation bias both fuels differentiation and concurrently minimizes oxidative damage. These ROS-induced changes could enable sustained mitochondrial biogenesis during brown adipogenesis, and explain in part, the molecular basis for ROS hormesis.

Microbeam X-ray Reanalysis on Periodically Assembled Poly(ß-Hydroxybutyric acid-Co-ß-hydroxyvaleric acid) Tailored with Diluents.

Self-assembly of 3D interiors and iridescence properties of poly(ß-hydroxybutyric acid-co-ß-hydroxyvaleric acid) (PHBV) periodic crystals are examined using microcopy techniques and microbeam X-ray diffraction. Morphology of PHBV can be tailored by crystallizing in presence of poly(vinyl acetate) (PVAc) or poly(trimethylene adipate) (PTA) for displaying desired periodicity patterns. The regular alternate-layered lamellae of banded PHBV crystal aggregates, resembling the structures the natural mineral moonstone or nacre, are examined to elaborate the origin of light interference and formation mechanisms of periodic lamellar aggregation of PHBV spherulites. By using PHBV as a convenient model and the crystal diffraction data, this continuing work demonstrates unique methodology for effectively studying the periodic assembly in widely varying polymers with similar aggregates. Grating structures in periodically assembled polymer crystals can be tailored for microstructure with orderly periodicity.

Crystal-by-Crystal Assembly in Two Types of Periodically Banded Aggregates of Poly(p-Dioxanone).

The exterior and interior lamellar assemblies of poly(p-dioxanone) (PPDO) crystallized at 76 °C yield the most regular ones to interpret the 3D assembly mechanisms and potential for structural coloration iridescence, which are investigated using atomic-force microscopy (AFM), and scanning electron microscopy (SEM). PPDO displays two types of ring-banded spherulites within a range of Tc with dual-type birefringent spherulites (positive and negative-type) only within a narrow range of Tcs = 70−78 °C. At Tc > 80 °C, the inter-band spacing decreases from a maximum and the crystal assembly becomes irregularly corrupted and loses the capacity for light interference. Periodic grating assemblies are probed by in-depth 3D dissection into periodically banded crystal aggregates of poly(p-dioxanone) (PPDO) to disclose such layered gratings possessing iridescence features similar to nature's structural coloration. This work amply demonstrates that grating assembly by orderly stacked crystal layers is feasible not only for accounting for the periodic birefringent ring bands with polarized light but also the distinct iridescence by interfering with white light.

SI ATRP for the Surface Modifications of Optically Transparent Paper Films Made by TEMPO-Oxidized Cellulose Nanofibers.

Applications of cellulose nanofibers currently match the demands of biodegradable and renewable constituent biocomposites. In this study, we studied the process of preparing TEMPO-oxidized cellulose nanofibers (TOCNs). These nano-sized cellulose fibers (ca. 11 nm) can be fabricated to high transmittance and optically transparent paper (OP) films. Then the OP films can be facilely immobilized initiating sites for the subsequent surface-initiated atom transfer radical polymerization (SI ATRP). We investigated SI ATRP with styrene (St) kinetics and monitored chemical structure changes of the OP surfaces. The obtained OP-g-PSt significantly led to enhance thermal stability and alter the OP surface with hydrophobic compared to that of pristine OP film. Characterization was studied by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), UV-Vis spectroscopy, thermogravimetric analyzer (TGA), and water contact angle (WCA) measurements.

1,4-Bis((9H-Carbazol-9-yl)Methyl)Benzene-Containing Electrochromic Polymers as Potential Electrodes for High-Contrast Electrochromic Devices.

Four 1,4-bis((9H-carbazol-9-yl)methyl)benzene-containing polymers (PbCmB, P(bCmB-co-bTP), P(bCmB-co-dbBT), and P(bCmB-co-TF)) were electrosynthesized onto ITO transparent conductive glass and their spectral and electrochromic switching performances were characterized. The PbCmB film displayed four types of color variations (bright gray, dark gray, dark khaki, and dark olive green) from 0.0 to 1.2 V. P(bCmB-co-bTP) displayed a high transmittance variation (∆T = 39.56% at 685 nm) and a satisfactory coloration efficiency (η = 160.5 cm2∙C-1 at 685 nm). Dual-layer organic electrochromic devices (ECDs) were built using four bCmB-containing polycarbazoles and poly(3,4-ethylenedioxythiophene) (PEDOT) as anodes and a cathode, respectively. PbCmB/PEDOT ECD displayed gainsboro, dark gray, and bright slate gray colors at -0.4 V, 1.0 V, and 2.0 V, respectively. The P(bCmB-co-bTP)/PEDOT ECD showed a high ∆T (40.7% at 635 nm) and a high coloration efficiency (η = 428.4 cm2∙C-1 at 635 nm). The polycarbazole/PEDOT ECDs exhibited moderate open circuit memories and electrochemical redox stability. The characterized electrochromic properties depicted that the as-prepared polycarbazoles had a satisfactory application prospect as an electrode for the ECDs.

Superior Crystallization Kinetics Caused by the Remarkable Nucleation Effect of Graphene Oxide in Novel Ternary Biodegradable Polymer Composites.

In this study, novel ternary composites were prepared, including biodegradable poly(ethylene succinate) (PESu), poly(ethylene glycol) (PEG), and graphene oxide (GO). We have conducted a comprehensive study on whether GO can successfully promote the crystallization behaviors of PESu in the ternary composites. The results of isothermal crystallization demonstrated that with the increase of GO content in the composite (at a fixed PESu/PEG ratio), the Avrami rate constant k gradually increased, indicating that the crystallization rate was faster when GO was added to the composite. The same phenomenon was also found for nonisothermal crystallization. It was found that the Mo model can adequately describe the nonisothermal crystallization behaviors of the composites. The analyses demonstrated that the F(T) value estimated from the Mo model decreased when the GO content was increased. This result implied that GO promoted the nonisothermal crystallization of PESu in the ternary PESu/PEG/GO composites. Discussions on nucleation activity and microscopy observations confirmed that GO can act as a nucleation agent to further enhance the crystallization of the composites. The significant nucleation effect of GO on PESu in its novel ternary composite was first discovered in this study.

Global translation during early development depends on the essential transcription factor PRDM10.

Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse developmental roles. PRDM10 is a yet uncharacterized family member, and its function in vivo is unknown. Here, we report an essential requirement for PRDM10 in pre-implantation embryos and embryonic stem cells (mESCs), where loss of PRDM10 results in severe cell growth inhibition. Detailed genomic and biochemical analyses reveal that PRDM10 functions as a sequence-specific transcription factor. We identify Eif3b, which encodes a core component of the eukaryotic translation initiation factor 3 (eIF3) complex, as a key downstream target, and demonstrate that growth inhibition in PRDM10-deficient mESCs is in part mediated through EIF3B-dependent effects on global translation. Our work elucidates the molecular function of PRDM10 in maintaining global translation, establishes its essential role in early embryonic development and mESC homeostasis, and offers insights into the functional repertoire of PRDMs as well as the transcriptional mechanisms regulating translation.

Novel AU-rich proximal UTR sequences (APS) enhance CXCL8 synthesis upon the induction of rpS6 phosphorylation.

The role of ribosomal protein S6 (rpS6) phosphorylation in mRNA translation remains poorly understood. Here, we reveal a potential role in modulating the translation rate of chemokine (C-X-C motif) ligand 8 (CXCL8 or Interleukin 8, IL8). We observed that more CXCL8 protein was being secreted from less CXCL8 mRNA in primary macrophages and macrophage-like HL-60 cells relative to other cell types. This correlated with an increase in CXCL8 polyribosome association, suggesting an increase in the rate of CXCL8 translation in macrophages. The cell type-specific expression levels were replicated by a CXCL8- UTR-reporter (Nanoluc reporter flanked by the 5' and 3' UTR of CXCL8). Mutations of the CXCL8-UTR-reporter revealed that cell type-specific expression required: 1) a 3' UTR of at least three hundred bases; and 2) an AU base content that exceeds fifty percent in the first hundred bases of the 3' UTR immediately after the stop codon, which we dub AU-rich proximal UTR sequences (APS). The 5' UTR of CXCL8 enhanced expression at the protein level and conferred cell type-specific expression when paired with a 3' UTR. A search for other APS-positive mRNAs uncovered TNF alpha induced protein 6 (TNFAIP6), another mRNA that was translationally upregulated in macrophages. The elevated translation of APS-positive mRNAs in macrophages coincided with elevated rpS6 S235/236 phosphorylation. Both were attenuated by the ERK1/2 signaling inhibitors, U0126 and AZD6244. In A549 cells, rpS6 S235/236 phosphorylation was induced by TAK1, Akt or PKA signaling. This enhanced the translation of the CXCL8-UTR-reporters. Thus, we propose that the induction of rpS6 S235/236 phosphorylation enhances the translation of mRNAs that contain APS motifs, such as CXCL8 and TNFAIP6. This may contribute to the role of macrophages as the primary producer of CXCL8, a cytokine that is essential for immune cell recruitment and activation.

Applications of Copolymers Consisting of 2,6-di(9H-carbazol-9-yl)pyridine and 3,6-di(2-thienyl)carbazole Units as Electrodes in Electrochromic Devices.

A series of carbazole-based polymers (PdCz, P(dCz2-co-dTC1), P(dCz2-co-dTC2), P(dCz1-co-dTC2), and PdTC) were deposited on indium tin oxide (ITO) conductive electrodes using electrochemical polymerization. The as-prepared P(dCz2-co-dTC2) displayed a high ΔT (57.0%) and multichromic behaviors ranging from yellowish green, greenish gray, gray to purplish gray in different redox states. Five organic electrochromic devices (ECDs) were built using dCz- and dTC-containing homopolymers and copolymers as anodic materials, and poly(3,4-(2,2-dimethylpropylenedioxy)thiophene) (PProdot-Me2) as the cathodic material. The P(dCz2-co-dTC2)/PProdot-Me2 ECD presented remarkable electrochromic behaviors from the bleached to colored states. Moreover, P(dCz2-co-dTC2)/PProdot-Me2 ECD displayed a high optical contrast (ΔT, 45.8%), short switching time (ca. 0.3 s), high coloration efficiency (528.8 cm2 C-1) at 580 nm, and high redox cycling stability.

Isothermal and Nonisothermal Crystallization Kinetics of Poly(ε-caprolactone) Blended with a Novel Ionic Liquid, 1-Ethyl-3-propylimidazolium Bis(trifluoromethanesulfonyl)imide.

Recently, ionic liquids (ILs) and biodegradable polymers have become crucial functional materials in green sustainable science and technology. In this study, we investigated the influence of a novel IL, 1-ethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide ([EPrI][TFSI]), on the crystallization kinetics of a widely studied biodegradable polymer, poly(ε-caprolactone) (PCL). To obtain a comprehensive understanding, both the isothermal and nonisothermal crystallization kinetics of the PCL blends were studied. Incorporating [EPrI][TFSI] reduced the isothermal and nonisothermal crystallization rates of PCL. Regarding isothermal crystallization, the small k and 1/t0.5 values of the blend, estimated using the Avrami equation, indicated that [EPrI][TFSI] decreased the rate of isothermal crystallization of PCL. The Mo model adequately described the nonisothermal crystallization kinetics of the blends. Increasing the [EPrI][TFSI] content caused the rate-related parameter F(T) to increase. This indicated that the crystallization rate of PCL decreased when [EPrI][TFSI] was incorporated. The spherulite appearance temperature of the blending sample was found to be lower than that of neat PCL under a constant cooling rate. The analysis of the effective activation energy proposed that the nonisothermal crystallization of PCL would not be favorited when the [EPrI][TFSI] was incorporated into the blends. The addition of [EPrI][TFSI] would not change the crystal structures of PCL according to the results of wide angle X-ray diffraction. Fourier transform infrared spectroscopy suggested that interactions occurred between [EPrI][TFSI] and PCL. The crystallization kinetics of PCL were inhibited when [EPrI][TFSI] was incorporated.

Electrochromic Devices Based on Poly(2,6-di(9H-carbazol-9-yl)pyridine)-Type Polymer Films and PEDOT-PSS.

2,6-Di(9H-carbazol-9-yl)pyridine (DiCP) was synthesized and its corresponding homopolymer (PDiCP) and copolymers (P(DiCP-co-CPDT), P(DiCP-co-CPDT2), P(DiCP-co-CPDTK), and P(DiCP-co-CPDTK2)) were synthesized electrochemically. The anodic copolymer with DiCP:cyclopentadithiophene ketone (CPDTK) = 1:1 feed molar ratio showed high transmittance change (ΔT%) and colouration efficiency (η), which were measured as 39.5% and 184.1 cm² C-1 at 1037 nm, respectively. Electrochromic devices (ECDs) were composed of PDiCP, P(DiCP-co-CPDT), P(DiCP-co-CPDT2), P(DiCP-co-CPDTK), and P(DiCP-co-CPDTK2) as anodically-colouring polymers, and poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT-PSS) as cathodically-colouring polymers. P(DiCP-co-CPDTK)/PEDOT-PSS ECD showed light silverish-yellow at 0.0 V, light grey at 0.7 V, grey at 1.3 V, light greyish blue at 1.7 V, and greyish blue at 2.0 V. Moreover, P(DiCP-co-CPDTK)/PEDOT-PSS ECD presented high ΔT (38.2%) and high η (633.8 cm² C-1) at 635 nm.

Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo.

Cardiac regeneration may revolutionize treatment for heart failure but endogenous progenitor-derived cardiomyocytes in the adult mammalian heart are few and pre-existing adult cardiomyocytes divide only at very low rates. Although candidate genes that control cardiomyocyte cell cycle re-entry have been implicated, expression heterogeneity in the cardiomyocyte stress-response has never been explored. Here, we show by single nuclear RNA-sequencing of cardiomyocytes from both mouse and human failing, and non-failing adult hearts that sub-populations of cardiomyocytes upregulate cell cycle activators and inhibitors consequent to the stress-response in vivo. We characterize these subgroups by weighted gene co-expression network analysis and discover long intergenic non-coding RNAs (lincRNA) as key nodal regulators. KD of nodal lincRNAs affects expression levels of genes related to dedifferentiation and cell cycle, within the same gene regulatory network. Our study reveals that sub-populations of adult cardiomyocytes may have a unique endogenous potential for cardiac regeneration in vivo.Adult mammalian cardiomyocytes are predominantly binucleated and unable to divide. Using single nuclear RNA-sequencing of cardiomyocytes from mouse and human failing and non-failing adult hearts, See et al. show that some cardiomyocytes respond to stress by dedifferentiation and cell cycle re-entry regulated by lncRNAs.

Investigations on Green Blends Comprising Biodegradable Polymer and Ionic Liquid.

The green blends of an ionic liquid, 1-ethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide {[EPrI][TFSI]}, and a biodegradable polymer, poly(3-hydroxybutyrate) (PHB), were investigated in this study. The influence of an ionic liquid on the crystallization behaviors of a biodegradable polymer was explored. In the blends, the presence of [EPrI][TFSI] decreased the Tg and Tm of PHB. Incorporating [EPrI][TFSI] in the blends reduced the degree of crystallinity of PHB, inferring that the [EPrI][TFSI] weakened the crystallization of PHB. It further showed retarded isothermal and non-isothermal crystallization for PHB with the presence of [EPrI][TFSI]. The smaller K and 1/t0.5 estimated by the Avrami equation for the blends indicated that [EPrI][TFSI] weakened the isothermal crystallization of PHB with exhibiting the slower crystallization rate. The present study also discussed non-isothermal crystallization of the blends. We found that the Mo model, which is generally used to discuss the non-isothermal crystallization, adequately described the non-isothermal behaviors of the [EPrI][TFSI]/PHB blends. By increasing the [EPrI][TFSI] content, the rate-related parameter F(T) systematically increased, inferring a decreased crystallization rate of PHB with the addition of [EPrI][TFSI] in the blends. The FTIR results suggested an ion⁻dipole interaction between [EPrI][TFSI] and PHB. This proposes the occurrence of possible complexation between [EPrI][TFSI] and PHB.

Current mode atomic force microscopy (C-AFM) study for local electrical characterization of conjugated polymer blends.

A blend of regioregular poly(3-hexylthiophene) (P3HT) and poly{[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2), which has the potential for polymer solar cells application, was prepared for current mode atomic force microscopy (C-AFM) measurements in this study. Phase-separated domains and the local electrical characteristics of P3HT/P(NDI2OD-T2) blends were investigated by the C-AFM.

Highly ordered nanostructured surfaces obtained with silica-filled diblock-copolymer micelles as templates.

In this work, we present the size-controlled preparation of silica-filled micelle cores and their self-assembly behavior, which is dependent on the block lengths, different coating techniques, and substrates. Furthermore, we present a way to use these structures as templates for highly ordered magnetic nanostructures, revealed by Ar-ion milling. The resulting structures were characterized by different imaging and scattering techniques and model simulations were performed. The characterization of the obtained nanostructured surfaces has be performed with atomic force microscopy, by scanning electron microscopy, grazing-incidence X-ray small-angle scattering, and X-ray reflectivity measurements. The magneto-optical Kerr effect was utilized to investigate magnetic properties.