HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms.

Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.

SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis.

Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT-decidual cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up-regulate cell migration. We further showed that secreted frizzled-related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase-transformed human endometrial stromal cells (T-HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3-knockdown T-HESC monolayer. Our results suggest that GCM1 up-regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.-Wang, L.-J., Lo, H.-F., Lin, C.-F., Ng, P.-S., Wu, Y.-H., Lee, Y.-S., Cheong, M.-L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis.

Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11.

N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Experimental Study and Modelling of Fresh Behaviours of Basalt Fibre-Reinforced Mortar Based on Average Water Film Thickness and Fibre Factor.

Though previous studies have indicated that the fresh behaviours of plain mortar/concrete are mainly governed by the average water film thickness (AWFT), whether the concept of AWFT is also applicable to fibrous mortar/concrete still needs to be explored. Furthermore, for fibrous mortar/concrete, it is obvious that the fibres added also have certain effects on the fresh behaviours. In two previous studies on basalt fibre-reinforced mortar (BFRM), the integral effects of the AWFT and fibre dosage as well as the integral effects of the AWFT and fibre length were individually investigated. In this study, a fibre factor (FF) defined as the fibre volume multiplied by the fibre aspect ratio was employed and 24 extra mortar groups were tested. A total of 68 mortar groups were applied in numerical analysis. The results of the regression analysis yielded good correlations of the workability, fluidity, cohesiveness, and adhesiveness of BFRM with the AWFT and FF, suggesting that the AWFT and FF are together the governing parameters controlling the fresh behaviours of BFRM. Hence, the AWFT and FF may be used to develop a model for the fresh properties of BFRM.

Microplastics impede larval urchin selective feeding.

Microplastics are emergent threats to marine organisms as ingestion can cause a multitude of physiological problems. Suspension feeders, including marine invertebrate larvae, are particularly susceptible to ingesting microplastics due to similarities in physical appearance to algal cells. Larval feeding involves multiple stages: the capture and subsequent selection of particles followed by ingestion from the mouth to the stomach, digestion, and finally, egestion. Yet, little is known about which aspect of the feeding process is disrupted by microplastics. Here, we determine if prior exposure to microplastics alters the feeding behavior of the larval sea urchin Heliocidaris crassispina. We conducted two experiments: a food handling experiment studied larval survival, growth, and time required to fill and vacate the stomach; and a particle selection experiment analyzed changes in the ability of the larvae to selectively ingest algal cells over microplastics. In both experiments, larvae were pre-exposed to algae only (control), the addition of 10 µm polystyrene beads at 1 bead mL-1 or 1000 beads mL-1 until 3- or 7-days post-fertilization. Previous exposure to microplastics lengthened stomach filling time and impaired particle selection. While there was no significant change in survivorship and larval arm length, these sub-lethal impacts on larval feeding likely have more severe ramifications in vivo where food is limited, and thus, potentially threaten post-settlement success.

Bioinspired Photo-Cross-Linking of Stretched Solid Silks for Enhanced Strength.

In this study, solid fibroin fibers (FFs) were directly cross-linked by employing a ruthenium-mediated redox pair under visible light at room temperature for the first time. The chemical cross-link through dityrosine connection was confirmed by Fourier-transform infrared (FTIR) spectroscopy, fluorescence spectra, and a solubility test. The resultant cross-link density of fibers was calculated based on their swelling ratio evaluation in LiBr solution. Further applying stretch to the fibers during irradiation increased the fiber strength to higher values. The break stress and Young's modulus of photo-cross-linked 15% stretch FFs reached a 60-90% increase in comparison to the original FFs in dry and wet conditions. This approach constitutes an easy and straightforward strategy for strengthening FFs, which is scalable industrially to enhance FFs in a wide range of applications.

Destructive-Treatment-Free Rapid Polymer-Assisted Metal Deposition for Versatile Electronic Textiles.

Highly conductive, durable, and breathable metal-coated textiles are critical building block materials for future wearable electronics. In order to enhance the metal adhesion on the textile surface, existing solution-based approaches to preparing these materials require time-consuming presynthesis and/or premodification processes, typically in the order of tens of minutes to hours, on textiles prior to metal plating. Herein, we report a UV-induced rapid polymer-assisted metal deposition (r-PAMD) that offers a destructive-treatment-free process to deposit highly conductive metals on a wide variety of textile materials, including cotton, polyester, nylon, Kevlar, glass fiber, and carbon cloth. In comparison to the state of the arts, r-PAMD significantly shortens the modification time to several minutes and is compatible with the roll-to-roll fabrication manner. Moreover, the deposited metals show outstanding adhesion, which withstands rigorous flexing, abrasion, and machine washing tests. We demonstrate that these metal-coated textiles are suitable for applications in two vastly different fields, being wearable and washable sensors, and lithium batteries.

Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation.

The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.

Bacterial cellulose reinforced double-network hydrogels for shape memory strand.

Tough hydrogels with shape memory property are highly desirable for actuators and smart engineering materials. Herein, super-tough polyacrylamide/iota-carrageenan double-network hydrogels were synthesized via a one-pot radical polymerization and strengthened by incorporating bacterial cellulose microclusters, through the intermolecular hydrogen bonds and topological interlock between microclusters and polymer network. Such hydrogels were able to withstand over 200 kPa of tensile stress, or be stretched over 27 times of initial length, and reached a high toughness of ∼2000 kJ/m3. By tension-drying and post-annealing treatments on the strongest hydrogel, dry strands were fabricated to withstand over 100 MPa of tensile stress. Moreover, these strands presented water-stimulated shape memory by a recovery ratio of 84.3 % in 4 min. Based on these characteristics, this super-tough hydrogel may serve as smart textile or actuator for a variety of applications.

Large papillary fibroelastoma of right atrium, an unusual case of respiratory distress in a young man.

BACKGROUND: Papillary fibroelastomas are rare but benign cardiac tumour that are often found on cardiac valvular surfaces. Their clinical manifestations ranging from clinically asymptomatic to substantial complications that are usually secondary to systemic embolism. Multiple theories have been proposed to explain the pathophysiology of its formation. CASE PRESENTATION: We reported a rare case of large papillary fibroelastoma in the right atrium of a young gentleman which was complicated with pulmonary embolism. Transthoracic echocardiography identified a large pedunculated mass measuring 3.4cmX3.4cmX2cm in right atrium with stalk attached to interatrial septum. The intracardiac mass was resected surgically, which revealed papillary fibroelastoma in histology examination. CONCLUSION: Differential diagnosis of intracardiac masses requires clinical information, laboratory tests and imaging modalities including echocardiography. Incidentally discovered papillary fibroelastomas are treated on the basis of their sizes, site, mobility and potential embolic complications. Due to the embolic risk inherent to intraacardiac masses, surgical resection represents an effective curative protocol in treating both symptomatic and asymptomatic right sided and left sided papillary fibroelastomas, with excellent long term postoperative prognosis.

Investigation and Improvement of Bond Performance of Synthetic Macro-Fibres in Concrete.

Strength and stiffness are the key parameters characterising the bond performance of fibres in concrete. However, a straightforward procedure for estimating the bond parameters of a synthetic macro-fibre does not exist. This study employs pull-out tests to investigate the bond behaviour of synthetic macro-fibres. Two types of macro-fibres available in the market were investigated. A gripping system was developed to protect the fibres from local damage. The experimental campaign consisted of two stages. At the first stage, 32 concrete specimens were manufactured for performing 96 pull-out tests (three fibre samples were embedded in each cube perpendicular to the top surface and two sides). Two types of macro-fibres with either 10 or 20 mm embedment length were tested. The obtained load-displacement diagrams from pull-out tests demonstrate that the bond performance (characterised by the strength and deformation modulus) of the "top" fibres is almost 20% weaker than fibres positioned to the side surfaces. At the second stage, one type of macro-fibre was chosen for further experimentation of the feasibility of improving the bond performance through the use of colloidal silica or steel micro-fibres. This investigation stage employed an additional 36 concrete specimens. The use of steel micro-fibres was found to be an efficient alternative. The success of this solution requires a suitable proportioning of the concrete.

Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators.

SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.

Fabrication of 3D PDMS Microchannels of Adjustable Cross-Sections via Versatile Gel Templates.

Flexible gel fibers with high stretchability were synthesized from physically cross-linked agar and covalently cross-linked polyacrylamide networks. Such gel material can withstand the temperature required for thermal curing of polydimethylsiloxane (PDMS), when the water in the gel was partially replaced with ethylene glycol. This gel template supported thermal replica molding of PDMS to produce high quality microchannels. Microchannels with different cross sections and representative 3D structures, including bifurcating junction, helical and weave networks, were smoothly fabricated, based on the versatile manipulation of gel templates. This gel material was confirmed as a flexible and reliable template in fabricating 3D microfluidic channels for potential devices.

Wet Spinning of Silk Fibroin-Based Core-Sheath Fibers.

In order to improve the water absorbency of natural silk and extend its applications in wider areas, silk fibroin (SF)-based fibers were prepared by coaxial wet spinning. Using a custom-made wet spinning device with coaxial spinneret, continuous core-sheath fibers were finally obtained by adjusting the core dope into iota-carrageenan/polyacrylamide hot solution and sheath dope into SF/polyurethane solution. These core-sheath fibers were characterized with respect to morphology, SF secondary structure, mechanical property, and water absorbency. Fibers fabricated from 17 wt % SF/polyurethane solution presented the most regular morphology with homogeneous and circular cross-section. Double-layered hollow structure was observed in these fibers. ß-Sheet conformation was mainly adopted by the SF in fibers as indicated in XRD analysis and FTIR spectra. The fibers demonstrated higher absorbency than the raw silk and fine incorporation of long-lasting glowing pigment, indicating potential applications in water or thermal management textile and phototherapy.

Mechanical Behavior of Steel Fiber-Reinforced Concrete Beams Bonded with External Carbon Fiber Sheets.

This study investigates the mechanical behavior of steel fiber-reinforced concrete (SFRC) beams internally reinforced with steel bars and externally bonded with carbon fiber-reinforced polymer (CFRP) sheets fixed by adhesive and hybrid jointing techniques. In particular, attention is paid to the load resistance and failure modes of composite beams. The steel fibers were used to avoiding the rip-off failure of the concrete cover. The CFRP sheets were fixed to the concrete surface by epoxy adhesive as well as combined with various configurations of small-diameter steel pins for mechanical fastening to form a hybrid connection. Such hybrid jointing techniques were found to be particularly advantageous in avoiding brittle debonding failure, by promoting progressive failure within the hybrid joints. The use of CFRP sheets was also effective in suppressing the localization of the discrete cracks. The development of the crack pattern was monitored using the digital image correlation method. As revealed from the image analyses, with an appropriate layout of the steel pins, brittle failure of the concrete-carbon fiber interface could be effectively prevented. Inverse analysis of the moment-curvature diagrams was conducted, and it was found that a simplified tension-stiffening model with a constant residual stress level at 90% of the strength of the SFRC is adequate for numerically simulating the deformation behavior of beams up to the debonding of the CFRP sheets.

Cycloaddition reactions of imines with 3-thiosuccinic anhydrides: synthesis of the tricyclic core of martinellic acid.

Arylthio-substituted succinic anhydrides undergo cycloaddition reactions with imines to produce gamma-lactams in high yield and with high diastereoselectivity. The origin of the selectivity is proposed to result from anion-pi repulsion in the transition state. The utility of this technique is demonstrated in a synthesis of the carbon framework common to the alkaloids martinellic acid and martinelline in five steps.

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma.

UNLABELLED: Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eµ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eµ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer.

Polyethylenimine coated bacterial cellulose nanofiber membrane and application as adsorbent and catalyst.

Bacterial cellulose (BC) nanofiber membranes were simply aminalized by a flush-coating and post-crosslinking method. Firstly, wet BC membranes were flushed through by an aqueous solution of polyethylenimine (PEI) and glycerol diglycidyl ether (GDE) under vacuum suction, then further heated up to 70 °C to crosslink the resultant coating on the surface of the nanofibers. The PEI coated bacterial cellulose (BC@PEI) nanofiber membrane presented excellent adsorption performance for Cu(2+) and Pb(2+) ions from aqueous solutions. Desorption of these ions was achieved using ethylene diamine tetraacetic acid treatment. This cycle of adsorption and desorption was repeated for several times with good remain adsorption performance (over 90%). Furthermore, the adsorbed Cu(2+) ions can be reduced to copper nanoparticles, and showed excellent catalytic performance for methylene blue reduction in aqueous solution. The catalytic performance can remained after several times of usage.