LncRNA HOTAIRM1 functions in DNA double-strand break repair via its association with DNA repair and mRNA surveillance factors.

The eukaryotic exon junction complex component Y14 participates in double-strand break (DSB) repair via its RNA-dependent interaction with the non-homologous end-joining (NHEJ) complex. Using immunoprecipitation-RNA-seq, we identified a set of Y14-associated long non-coding RNAs (lncRNAs). The lncRNA HOTAIRM1 serves as a strong candidate that mediates the interaction between Y14 and the NHEJ complex. HOTAIRM1 localized to near ultraviolet laser-induced DNA damage sites. Depletion of HOTAIRM1 delayed the recruitment of DNA damage response and repair factors to DNA lesions and compromised the efficiency of NHEJ-mediated DSB repair. Identification of the HOTAIRM1 interactome revealed a large set of RNA processing factors including mRNA surveillance factors. The surveillance factors Upf1 and SMG6 localized to DNA damage sites in a HOTAIRM1-dependent manner. Depletion of Upf1 or SMG6 increased the level of DSB-induced non-coding transcripts at damaged sites, indicating a pivotal role for Upf1/SMG6-mediated RNA degradation in DNA repair. We conclude that HOTAIRM1 serves as an assembly scaffold for both DNA repair and mRNA surveillance factors that act in concert to repair DSBs.

The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia.

Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKOMK mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKOMK, indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy.

p53 Activation in Genetic Disorders: Different Routes to the Same Destination.

The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.

Engineered Bifunctional Luminescent Pillared-Layer Frameworks for Adsorption of CO2 and Sensitive Detection of Nitrobenzene in Aqueous Media.

Through a dual-ligand synthetic approach, five isoreticular primitive cubic (pcu)-type pillared-layer metal-organic frameworks (MOFs), [Zn2 (dicarboxylate)2 (NI-bpy-44)]⋅x DMF⋅y H2 O, in which dicarboxylate=1,4-bdc (1), Br-1,4-bdc (2), NH2 -1,4-bdc (3), 2,6-ndc (4), and bpdc (5), have been engineered. MOFs 1-5 feature twofold degrees of interpenetration and have open pores of 27.0, 33.6, 36.8, 52.5, and 62.1 %, respectively. Nitrogen adsorption isotherms of activated MOFs 1'-5' at 77 K all displayed type I adsorption behavior, suggesting their microporous nature. Although 1' and 3'-5' exhibited type I adsorption isotherms of CO2 at 195 K, MOF 2' showed a two-step gate-opening sorption isotherm of CO2 . Furthermore, MOF 3' also had a significant influence of amine functions on CO2 uptake at high temperature due to the CO2 -framework interactions. MOFs 1-5 revealed solvent-dependent fluorescence properties; their strong blue-light emissions in aqueous suspensions were efficiently quenched by trace amounts of nitrobenzene (NB), with limits of detection of 4.54, 5.73, 1.88, 2.30, and 2.26 µm, respectively, and Stern-Volmer quenching constants (Ksv ) of 2.93×103 , 1.79×103 , 3.78×103 , 4.04×103 , and 3.21×103 m-1 , respectively. Of particular note, the NB-included framework, NB@3, provided direct evidence of the binding sites, which showed strong host-guest π-π and hydrogen-bonding interactions beneficial for donor-acceptor electron transfer and resulting in fluorescence quenching.

From lamellar net to bilayered-lamella and to porous pillared-bilayer: reversible crystal-to-crystal transformation, CO2 adsorption, and fluorescence detection of Fe3+, Al3+, Cr3+, MnO4-, and Cr2O72- in water.

An aqua-coordinated lamellar net [Zn(5-NH2-1,3-bdc)(H2O)] (1, 5-NH2-1,3-H2bdc = 5-amino-1,3-benzenedicarboxylic acid) has been found to undergo a reversible stimuli-responsive 2D-to-2D crystal-to-crystal transformation with a water-free bilayered-lamellar net [Zn(5-NH2-1,3-bdc)] (1') upon removal and rebinding of aqua ligands, whereas a 2D porous pillared-bilayer [Zn2(5-NH2-1,3-bdc)2(NI-bpy-44)]·DMF (2, NI-bpy-44 = N-(pyridin-4-yl)-4-(pyridin-4-yl)-1,8-naphthalimide) has been tailored by introducing NI-bpy-44 to replace the coordinated aqua ligands. Pillared-bilayer 2 displayed a moderate CO2 uptake of 79.1 cm3 g-1 STP at P/P0 = 1 and 195 K with an isosteric heat of CO2 adsorption (Qst) of 37.0 kJ mol-1 at zero-loading. It is noteworthy that the water suspensions of 1 and 2 both displayed good fluorescence performances, which were effectively quenched by Fe3+, MnO4-, and Cr2O72- ions and shifted to long wavelengths by Fe3+, Al3+, and Cr3+, even with the coexistence of equal amounts of most other interfering ions. Taking the Stern-Volmer quenching constant, limit of detection, quenching efficiency, anti-interference ability, and visual observation into consideration, it is clear that both 1 and 2 are promising and excellent fluorescent sensors for highly sensitive detection of Fe3+, MnO4-, and Cr2O72-.

The RNA Processing Factor Y14 Participates in DNA Damage Response and Repair.

DNA repair deficiency leads to genome instability and hence human disease. Depletion of the RNA processing factor Y14/RBM8A in cultured cells or Rbm8a haplodeficiency in the developing mouse cortex results in the accumulation of DNA damage. Y14 depletion differentially affected the expression of DNA damage response (DDR) factors and induced R-loops, both of which threaten genomic stability. Immunoprecipitation coupled with mass spectrometry revealed DDR factors as potential Y14-interacting partners. Further results confirmed that Y14 interacts with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionated with Ku in chromatin-enriched fractions and further accumulated on chromatin upon DNA damage. Y14 knockdown delayed recruitment of DDR factors to DNA damage sites and formation of γH2AX foci and also led to Ku retention on chromatin. Accordingly, Y14 depletion compromised the efficiency of DNA end joining. Therefore Y14 likely plays a direct role in DNA damage repair via its interaction with DDR factors.

Highly Responsive PEG/Gold Nanoparticle Thin-Film Humidity Sensor via Inkjet Printing Technology.

In this study, a highly responsive humidity sensor is developed by printing gold nanoparticles (GNPs) grafted with a hygroscopic polymer. These GNPs are inkjet-printed to form a uniform thin film over an interdigitated electrode with a controllable thickness by adjusting the printing parameters. The resistance of the printed GNP thin film decreases significantly upon exposure to water vapor and exhibits a semi-log relationship with relative humidity (RH). The sensor can detect RH variations from 1.8 to 95% with large resistance changes up to 4 orders of magnitude with no hysteresis and small temperature dependence. In addition, with a small thickness, the sensor can reach absorption equilibrium quickly with response and recovery times of ≤1.2 and ≤3 s, respectively. The fast response to humidity changes also allows the GNP thin-film sensor to distinguish signals from intermittent humidification/dehumidification cycles with a frequency up to 2.5 Hz. The printed sensors on flexible substrates show little sensitivity to bending deformation and can be embedded in a mask for human respiratory detection. In summary, this study demonstrates the feasibility of applying printing technology for the fabrication of thin-film humidity sensors, and the methodology developed can be further applied to fabricate many other types of nanoparticle-based sensor devices.

Impedimetric analysis on the mass transfer properties of intact and competent E. coli cells.

Competent Escherichia coli cells are commonly used in bacterial transformation owing to its high permeability for bioorganic macromolecules like plasmid DNA. However, the mass transfer property of competent E. coli cell has not fully investigated. In the present study, mass transfer coefficients of competent and intact E. coli cells in deionized water were evaluated by impedimetric analysis of the release of cytoplasmic compounds. Because competent cells have a higher permeability after chemical treatment, the lumped mass transfer coefficient of a competent cell was approximately 6.5 times larger than that of an intact cell at room temperature. Release of cytoplasmic components was accelerated at an elevated temperature of 42 °C, which is the heat shock temperature used during bacterial transformation. At this elevated temperature, assessed lumped mass transfer coefficients of intact and competent E. coli cells were 9.28 × 10-4 min-1 and 97.10 × 10-4 min-1, respectively. Significant increase in the mass transfer coefficient of the competent cell is caused by cytolysis of cells. The double layer capacitances were also assessed from the electrochemical spectra confirming the enhanced ion release from E. coli cells and rupture of the competent cell under prolonged exposure at the elevated temperature. Impedimetric detection of the ion release with analyses using an equivalent circuit model provides a method to evaluate mass transfer properties of biomolecules.

Fabrication of Strain Gauges via Contact Printing: A Simple Route to Healthcare Sensors Based on Cross-Linked Gold Nanoparticles.

In this study, we developed a novel and efficient process for the fabrication of resistive strain gauges for healthcare-related applications. First, 1,9-nonanedithiol cross-linked gold nanoparticle (GNP) films were prepared via layer-by-layer (LbL) spin-coating and subsequently transferred onto flexible polyimide foil by contact printing. Four-point bending tests revealed linear response characteristics with gauge factors of ∼14 for 4 nm GNPs and ∼26 for 7 nm GNPs. This dependency of strain sensitivity is attributed to the perturbation of charge carrier tunneling between neighboring GNPs, which becomes more efficient with increasing particle size. Fatigue tests revealed that the strain-resistance performance remained nearly the same after 10.000 strain/relaxation cycles. We demonstrate that these sensors are well suited to monitor muscle movements. Furthermore, we fabricated all-printed strain sensors by directly transferring cross-linked GNP films onto soft PDMS sheets equipped with interdigitated electrodes. Due to the low elastic modulus of poly(dimethylsiloxane) (PDMS), these sensors are easily deformed and, therefore, they respond sensitively to faint forces. When taped onto the skin above the radial artery, they enable the well-resolved and robust recording of pulse waves with diagnostically relevant details.

Alternative Splicing in Neurogenesis and Brain Development.

Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

Highly Deformable Origami Paper Photodetector Arrays.

Flexible electronics will form the basis of many next-generation technologies, such as wearable devices, biomedical sensors, the Internet of things, and more. However, most flexible devices can bear strains of less than 300% as a result of stretching. In this work, we demonstrate a simple and low-cost paper-based photodetector array featuring superior deformability using printable ZnO nanowires, carbon electrodes, and origami-based techniques. With a folded Miura structure, the paper photodetector array can be oriented in four different directions via tessellated parallelograms to provide the device with excellent omnidirectional light harvesting capabilities. Additionally, we demonstrate that the device can be repeatedly stretched (up to 1000% strain), bent (bending angle ±30°), and twisted (up to 360°) without degrading performance as a result of the paper folding technique, which enables the ZnO nanowire layers to remain rigid even as the device is deformed. The origami-based strategy described herein suggests avenues for the development of next-generation deformable optoelectronic applications.

Printed Combinatorial Sensors for Simultaneous Detection of Ascorbic Acid, Uric Acid, Dopamine, and Nitrite.

In this study, an effective and simple direct printing method was developed to create sensing devices on screen-printed carbon electrodes (SPCEs) to detect multiple species simultaneously. Two sensing materials, graphene oxide nanoribbons (GONRs) and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), were printed on one SPCE for detection of multiple biochemical substances. Printed layers of the GONRs and PEDOT:PSS mixture (GONRs & PEDOT:PSS) on SPCE showed embedment of GONRs in the PEDOT:PSS layer and diminished the electrochemical activity of GONRs. In contrast, by printing the GONRs and PEDOT:PSS at separate locations (GONRs + PEDOT:PSS) on the same SPCE, the electrochemical activities of both GONRs and PEDOT:PSS can be preserved. Thus, without synthesizing new materials, the modified electrode is able to simultaneously detect ascorbic acid (AA), uric acid (UA), dopamine (DA), and nitrite (NO2-), with high anodic oxidation currents and well-separated voltammetric peaks, in differential pulse voltammetry measurements. The detection limits for the four analytes are 41 nM (AA), 30 nM (DA), 11 nM (UA), and 18 nM (NO2-), respectively. The electrode can either detect single species separately or simultaneously determine specific concentrations of the four species in aqueous mixtures, and this can be further extended for many other electrochemical sensing applications.

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M.

RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxia-induced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.

Metal-Organic Framework Colloids: Disassembly and Deaggregation.

We demonstrate a high-resolution method as an efficient tool to in situ characterize partially reversible assembly and aggregation of metal-organic framework (MOF) colloids. Based on the gas-phase electrophoresis, the primary size and the degree of aggregation of the MOF-525 crystals are tunable by pH adjustment and mobility selection. These findings allow for the further size control of MOF colloids and prove the capability of semiquantitative analysis for the MOF-based platforms in a variety of aqueous formulations (e.g., biomedical applications).

Inkjet-Printed Porous Silver Thin Film as a Cathode for a Low-Temperature Solid Oxide Fuel Cell.

In this work we report a porous silver thin film cathode that was fabricated by a simple inkjet printing process for low-temperature solid oxide fuel cell applications. The electrochemical performance of the inkjet-printed silver cathode was studied at 300-450 °C and was compared with that of silver cathodes that were fabricated by the typical sputtering method. Inkjet-printed silver cathodes showed lower electrochemical impedance due to their porous structure, which facilitated oxygen gaseous diffusion and oxygen surface adsorption-dissociation reactions. A typical sputtered nanoporous silver cathode became essentially dense after the operation and showed high impedance due to a lack of oxygen supply. The results of long-term fuel cell operation show that the cell with an inkjet-printed cathode had a more stable current output for more than 45 h at 400 °C. A porous silver cathode is required for high fuel cell performance, and the simple inkjet printing technique offers an alternative method of fabrication for such a desirable porous structure with the required thermal-morphological stability.

Synthesis of short graphene oxide nanoribbons for improved biomarker detection of Parkinson's disease.

We demonstrate the microwave-assisted synthesis of short graphene oxide nanoribbons (GONRs) through unzipping cut multiwalled carbon nanotubes (MWCNTs). Transmission electron microscopy and dynamic light scattering spectroscopy were used to examine the length, size, and morphology, i. e. unzipping level, of our various products. The nanotube core and nanoribbon shell can be observed from short GONRs via a modified unzipping recipe. Then the short GONRs were adopted to modify the glassy carbon electrode for the electrochemical detection of ascorbic acid (AA), uric acid (UA), and dopamine (DA). Compared to other nanomaterials, cyclic voltammograms of short GONRs show higher anodic oxidation currents for AA, UA, and DA. The detection limits of three analytes are 26, 98, and 24 nM, respectively, in amperometric current-time measurements. Especially, the sensitivity for DA is improved to be 40.86 µA µM(-1) cm(-2). The improved detection signals are due to the increased active sites of the open ends of short GONRs. Moreover, the width side of short GONRs could be more active than their length side. All above-mentioned results reveal that the short GONRs can provide a novel platform for electrochemically biomarker detection of Parkinson's disease.

RBM4 promotes pancreas cell differentiation and insulin expression.

The RNA-binding protein RNA-binding motif protein 4 (RBM4) modulates alternative splicing of muscle-specific mRNA isoforms during muscle cell differentiation. To better understand the physiological function of RBM4, we exploited a gene knockout strategy in the present study. Mice with targeted disruption of one of the two Rbm4 genes exhibited hyperglycemia coincident with reduced levels of serum insulin and reduced size of pancreatic islets. The embryonic pancreases of Rbm4-deficient mice showed reduced expression or aberrant splicing of many transcripts encoding factors required for pancreas cell differentiation and function. Using pancreatic acinar AR42J cells, we demonstrated that RBM4 promoted insulin gene expression by altering the isoform balance of the transcription factors Isl1 and Pax4 via alternative splicing control. RBM4 overexpression was sufficient to convert AR42J cells into insulin-producing cells. Moreover, RBM4 may mediate glucose-induced insulin expression and insulin receptor isoform switches. These results suggest that RBM4 may have role in promoting pancreas cell differentiation and endocrine function, essentially via alternative splicing regulation.