Yuval Nevo

Nanocellulose, a tiny fiber with huge applications

Nanocellulose is of increasing interest for a range of applications relevant to the fields of material science and biomedical engineering due to its renewable nature, anisotropic shape, excellent mechanical properties, good biocompatibility, tailorable surface chemistry, and interesting optical properties. We discuss the main areas of nanocellulose research: photonics, films and foams, surface modifications, nanocomposites, and medical devices. These tiny nanocellulose fibers have huge potential in many applications, from flexible optoelectronics to scaffolds for tissue regeneration. We hope to impart the readers with some of the excitement that currently surrounds nanocellulose research, which arises from the green nature of the particles, their fascinating physical and chemical properties, and the diversity of applications that can be impacted by this material.

p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell–specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit. Expression of p16Ink4a in beta cells induces hallmarks of senescence—including cell enlargement, and greater glucose uptake and mitochondrial activity—which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation

Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1. Inhibition of SRSF1 expression or mTOR activity abolishes the oncogenic properties of MALAT1, suggesting that SRSF1 induction and mTOR activation are essential for MALAT1-induced transformation. Our results reveal a mechanism by which lncRNA MALAT1 acts as a proto-oncogene in hepatocellular carcinoma, modulating oncogenic alternative splicing through SRSF1 upregulation. Cancer Res; 77(5); 1155-67. ©2016 AACR.

Zika Virus Infects Early- and Midgestation Human Maternal Decidual Tissues, Inducing Distinct Innate Tissue Responses in the Maternal-Fetal Interface

ABSTRACT Zika virus (ZIKV) has emerged as a cause of congenital brain anomalies and a range of placenta-related abnormalities, highlighting the need to unveil the modes of maternal-fetal transmission. The most likely route of vertical ZIKV transmission is via the placenta. The earliest events of ZIKV transmission in the maternal decidua, representing the maternal uterine aspect of the chimeric placenta, have remained unexplored. Here, we show that ZIKV replicates in first-trimester human maternal-decidual tissues grown ex vivo as three-dimensional (3D) organ cultures. An efficient viral spread in the decidual tissues was demonstrated by the rapid upsurge and continued increase of tissue-associated ZIKV load and titers of infectious cell-free virus progeny, released from the infected tissues. Notably, maternal decidual tissues obtained at midgestation remained similarly susceptible to ZIKV, whereas fetus-derived chorionic villi demonstrated reduced ZIKV replication with increasing gestational age. A genome-wide transcriptome analysis revealed that ZIKV substantially upregulated the decidual tissue innate immune responses. Further comparison of the innate tissue response patterns following parallel infections with ZIKV and human cytomegalovirus (HCMV) revealed that unlike HCMV, ZIKV did not induce immune cell activation or trafficking responses in the maternal-fetal interface but rather upregulated placental apoptosis and cell death molecular functions. The data identify the maternal uterine aspect of the human placenta as a likely site of ZIKV transmission to the fetus and further reveal distinct patterns of innate tissue responses to ZIKV. Our unique experimental model and findings could further serve to study the initial stages of congenital ZIKV transmission and pathogenesis and evaluate the effect of new therapeutic interventions. IMPORTANCE In view of the rapid spread of the current ZIKV epidemic and the severe manifestations of congenital ZIKV infection, it is crucial to learn the fundamental mechanisms of viral transmission from the mother to the fetus. Our studies of ZIKV infection in the authentic tissues of the human maternal-fetal interface unveil a route of transmission whereby virus originating from the mother could reach the fetal compartment via efficient replication within the maternal decidual aspect of the placenta, coinhabited by maternal and fetal cells. The identified distinct placental tissue innate immune responses and damage pathways could provide a mechanistic basis for some of the placental developmental abnormalities associated with ZIKV infection. The findings in the unique model of the human decidua should pave the way to future studies examining the interaction of ZIKV with decidual immune cells and to evaluation of therapeutic interventions aimed at the earliest stages of transmission.

The Genetic Program of Pancreatic β-Cell Replication In Vivo.

The molecular program underlying infrequent replication of pancreatic β-cells remains largely inaccessible. Using transgenic mice expressing green fluorescent protein in cycling cells, we sorted live, replicating β-cells and determined their transcriptome. Replicating β-cells upregulate hundreds of proliferation-related genes, along with many novel putative cell cycle components. Strikingly, genes involved in β-cell functions, namely, glucose sensing and insulin secretion, were repressed. Further studies using single-molecule RNA in situ hybridization revealed that in fact, replicating β-cells double the amount of RNA for most genes, but this upregulation excludes genes involved in β-cell function. These data suggest that the quiescence-proliferation transition involves global amplification of gene expression, except for a subset of tissue-specific genes, which are “left behind” and whose relative mRNA amount decreases. Our work provides a unique resource for the study of replicating β-cells in vivo.

Highly Modified Cellulose Nanocrystals and Formation of Epoxy-Nanocrystalline Cellulose (CNC) Nanocomposites

This work presents an environmentally friendly, iodine-catalyzed chemical modification method to generate highly hydrophobic, optically active nanocrystalline cellulose (CNC). The high degree of ester substitution (DS = 2.18), hydrophobicity, crystalline behavior, and optical activity of the generated acetylated CNC (Ac-CNC) were quantified by TEM, FTIR, solid 13C NMR, contact angle, XRD, and POM analyses. Ac-CNC possesses substantial enhancement in thermal stability (16.8%) and forms thin films with an interlayer distance of 50-150 nm, presenting cavities suitable for entrapping nano- and microparticles. Generated Ac-CNC proved to be an effective reinforcing agent in hydrophobic polymer matrices for fabricating high performance nanocomposites. When integrated at a very low weight percentage (0.5%) in an epoxy matrix, Ac-CNC provided for a 73% increase in tensile strength and a 98% increase in modulus, demonstrating its remarkable reinforcing potential and effective stress transfer behavior. The method of modification and the unique properties of the modified CNC (hydrophobicity, crystallinity, reinforcing ability, and optical activity) render them a novel bionanomaterial for a range of multipurpose applications.

Improved Adhesives Containing CNT/SP1 Nano Fillers

Carbon nanotubes (CNT) have stimulated research due to their wide range of applications. However, their existence as aggregates and the difficulty in debundling and dispersion limits the improvement of properties when used as fillers. Many techniques have been employed to obtain such dispersions including mechanical, ultrasonic, and solution mixing, resulting in limited effect. Attaching a protein moiety such as SP1 showed promising results. SP1 is a thermally stable protein, originally isolated from poplar trees, which self-assembles to an extremely stable 11-nm ring-shape dodecamer. Linkage of CNT to specific peptides on SP1 N-terminus by genetic engineering resulted in 12 CNT binding sites per ring. It was demonstrated by us that the CNT/SP1 complex prevents CNT aggregation and allows its homogenous mixing in water at rather low CNT/protein weight ratio (20:1). In order to obtain homogenous CNTs in a polymer matrix, the dehydrated complex was redispersed in epoxy resin. The CNT/SP1 is covalently bound to epoxy groups prior to polymerization with the curing agent. Dispersion and uniformity were improved by using a speed-mixer and a 3-roll mill. CNT/SP1 in epoxy resin exhibited improved mechanical properties compared with pure unfilled epoxy (EPON® 828/Versamide® 140). CNT/SP1 filler in epoxy adhesive at less than 1% wt. improved peel strength by 50% and shear strength by 24%. In addition, HR-SEM images of 0.7% wt. CNT/SP1 nano-filled epoxy adhesive fracture surfaces demonstrates efficient load transfer and crack arrest by the CNT/SP1 particles. Moreover, comparing the thermal properties of neat epoxy with those of 0.35% and 0.7% wt. CNT/SP1 filled nano-composite was tested using three methods: differential scanning calorimetry (DSC), thermomechanical analysis (TMA), and thermogravimetric analysis (TGA) showed a dramatic improvement increasing Tg by 20°C.

Self-assembling hybrid diamond–biological quantum devices

The realization of scalable arrangements of nitrogen vacancy (NV) centers in diamond remains a key challenge on the way towards efficient quantum information processing, quantum simulation and quantum sensing applications. Although technologies based on implanting NV-centers in bulk diamond crystals or hybrid device approaches have been developed, they are limited by the achievable spatial resolution and by the intricate technological complexities involved in achieving scalability. We propose and demonstrate a novel approach for creating an arrangement of NV-centers, based on the self-assembling capabilities of biological systems and their beneficial nanometer spatial resolution. Here, a self-assembled protein structure serves as a structural scaffold for surface functionalized nanodiamonds, in this way allowing for the controlled creation of NV-structures on the nanoscale and providing a new avenue towards bridging the bio–nano interface. One-, two- as well as three-dimensional structures are within the scope of biological structural assembling techniques. We realized experimentally the formation of regular structures by interconnecting nanodiamonds using biological protein scaffolds. Based on the achievable NV-center distances of 11 nm, we evaluate the expected dipolar coupling interaction with neighboring NV-centers as well as the expected decoherence time. Moreover, by exploiting these couplings, we provide a detailed theoretical analysis on the viability of multiqubit quantum operations, suggest the possibility of individual addressing based on the random distribution of the NV intrinsic symmetry axes and address the challenges posed by decoherence and imperfect couplings. We then demonstrate in the last part that our scheme allows for the high-fidelity creation of entanglement, cluster states and quantum simulation applications.

Genome-wide activation of latent donor splice sites in stress and disease

Sequences that conform to the 5′ splice site (5′SS) consensus are highly abundant in mammalian introns. Most of these sequences are preceded by at least one in-frame stop codon; thus, their use for splicing would result in pre-maturely terminated aberrant mRNAs. In normally grown cells, such intronic 5′SSs appear not to be selected for splicing. However, under heat shock conditions aberrant splicing involving such latent 5′SSs occurred in a number of specific gene transcripts. Using a splicing-sensitive microarray, we show here that stress-induced (e.g. heat shock) activation of latent splicing is widespread across the human transcriptome, thus highlighting the possibility that latent splicing may underlie certain diseases. Consistent with this notion, our analyses of data from the Gene Expression Omnibus (GEO) revealed widespread activation of latent splicing in cells grown under hypoxia and in certain cancers such as breast cancer and gliomas. These changes were found in thousands of transcripts representing a wide variety of functional groups; among them are genes involved in cell proliferation and differentiation. The GEO analysis also revealed a set of gene transcripts in oligodendroglioma, in which the level of activation of latent splicing increased with the severity of the disease.

Nano bio optically tunable composite nanocrystalline cellulose films

Plastic pollution creates major environmental damage especially when taking into account the constant increase in the use of plastic films. Therefore, increasing the use of biodegradable films and reducing non degradable plastic usage are worldwide necessities. Current biodegradable films are not transparent or strong enough for most applications. In this work we utilize nanocellulose and semiconductor nanocrystals to reinforce and functionalize a biodegradable transparent film to create a transparent, strong and optically tunable plastic film. Nanocrystalline cellulose is produced from cellulose fibers, the main component of plant cell walls. The nanocrystalline cellulose particles are 5–20 nm in diameter, a few hundreds of nanometers in length, and have superb mechanical properties. The optical properties are controlled by introducing nanocrystals within the nanocellulose layers. The hybrid nanocellulose/nanocrystals film reinforcement will enable the reduction in the amount of plastic polymer in most polymeric materials while maintaining mechanical integrity with additional optical properties.