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The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.

UnlabelledArticular destruction by invading synovial fibroblasts is a typical feature in rheumatoid arthritis (RA),. Recent data support the hypothesis that key players in this scenario are transformed-appearing synovial fibroblasts at the site of invasion into articular cartilage and bone. They maintain their aggressive phenotype toward cartilage, even when first cultured and thereafter coimplanted together with normal human cartilage into severe combined immunodeficient mice for and extended period of time. However, little is known about the upregulation of genes that leads to this aggressive fibroblast phenotype. To inhibit this progressive growth without interfering with pathways of physiological matrix remodelling, identification of pathways that operate specifically in RA synovial fibroblasts is required. In order to achieve this goal, identification of genes showing upregulation restricted to RA synovial fibroblasts is essential.AimsTo identify specifically expressed genes using RNA arbitrarily primed (RAP)-polymerase chain reaction (PCR) for differential display in patients with RA.MethodsRNA was extracted from cultured synovial fibroblasts from 10 patients with RA, four patients with osteoarthritis (OA), and one patient with psoriatic arthritis. RAP-PCR was performed using different arbitrary primers for first-strand and second-strand synthesis. First-strand and second-strand synthesis were performed using arbitrary primers: US6 (5'-GTGGTGACAG-3') for first strand, and Nuclear 1+ (5'ACGAAGAAGAG-3'), OPN28 (5'GCACCAGGGGG-3'), Kinase A2+(5'-GGTGCCTTTGG-3') and OPN24 (5'AGGGGCACCA-3') for second strand synthesis. PCR reactions were loaded onto 8 mol/l urea/6% polyacrylamide-sequencing gels and electrophoressed. Gel slices carrying the target fragment were then excised with a razor blade, eluated and reamplified. After verifying their correct size and purity on 4% agarose gels, the reamplified products derived from the single-strand confirmation polymorphism gel were cloned, and five clones per transcript were sequenced. Thereafter, a genbank analysis was performed. Quantitative reverse transcription PCRj of the segments was performed using the PCR MIMIC technique. In-situ expression of centromere kinesin-like protein-E (CENP-E) messenger (m)RNA in RA synovium was assessed using digoxigenin-labelled riboprobes, and CENP-E protein expression in fibroblasts and synovium was performed by immunogold-silver immunohistochemistry and cytochemistry. Functional analysis of CENP-E was done using different approaches (eg glucocorticoid stimulation, serum starvation and growth rate analysis of synovial fibroblasts that expressed CENP-E).ResultsIn RA, amplification of a distinct PCR product suitable for sequencing could be observed. The indicated complementary DNA fragment of 434 base pairs from RA mRNA corresponded to nucleotides 6615-7048 in the human centromere kinesin-like protein CENP-E mRNA (GenBank accession No. emb/Z15005). The isolated sequence shared greater than 99% nucleic acid (P=2.9e(-169)) identify with the human centromere kinesin-like protein CENP-E. Two base changes at positions 6624 (A to C) and 6739 (A to G) did not result in alteration in the amino acid sequence, and therefore 100% amino acid identity could be confirmed. The amplification of 10 clones of the cloned RAP product revealed the presence of CENP-E mRNA in every fibroblast culture examined, showing from 50% (271.000 +/- 54.000 phosphor imager arbitrary units) up to fivefold (961.000 +/- 145.000 phosphor image arbitrary units) upregulation when compared with OA fibroblasts. Neither therapy with disease-modifying antirheumatic drugs such as methotrexate, gold, resochine or cyclosporine A, nor therapy with oral steroids influenced CENP-E expression in the RA fibroblasts. Of the eight RA fibroblast populations from RA patients who were receiving disease-modifying antirheumatic drugs, five showed CENP-E upregulation; and of the eight fibroblast populations from RA patients receiving steroids, four showed CENP-E upregulation. Numerous synovial cells of the patients with RA showed a positive in situ signal for the isolated CENP-E gene segment confirming CENP-E mRNA production in rheumatoid synovium, whereas in OA synovial tissue CENP-E mRNA could not be detected. In addition, CENP-E expression was independent from medication. This was further confirmed by analysis of the effect of prednisolone on CENP-E expression, which revealed no alteration in CENP-E mRNA after exposure to different (physiological) concentrations of prednisolone. Serum starvation also could not suppress CENP-E mRNA completely.DiscussionSince its introduction in 1992, numerous variants of the differential display method and continuous improvements including RAP-PCR have proved to have both efficiency and reliability in examination of differentially regulated genes. The results of the present study reveal that RAP-PCR is a suitable method to identify differentially expressed genes in rheumatoid synovial fibroblasts. The mRNA, which has been found to be upregulated in rheumatoid synovial fibroblasts, codes for a kinesin-like motor protein named CENP-E, which was first characterized in 1991. It is a member of a family of centromere-associated proteins, of which six (CENP-A to CENP-F) are currently known. CENP-E itself is a kinetochore motor, which accumulates transiently at kinetochores in the G2 phase of the cell cycle before mitosis takes place, appears to modulate chromosome movement and spindle elongation,and is degraded at the end of mitosis. The presence or upregulation of CENP-E has never been associated with RA.The three-dimensional structure of CENP-E includes a coiled-coil domain. This has important functions and shows links to known pathways in RA pathophysiology. Coiled-coil domains can also be found in jun and fos oncogene products, which are frequently upregulated in RA synovial fibroblasts. They are also involved in DNA binding and transactivation processes resembling the situation in AP-1 (Jun/Fos)-dependent DNA-binding in rheumatoid synovium. Most interestingly, these coiled-coil motifs are crucial for the assembly of viral proteins, and the upregulation of CENP-E might reflect the influence of infectious agents in RA synovium. We also performed experiments showing that serum starvation decreased, but did not completely inhibit CENP-E mRNA expression. This shows that CENP-E is related to, but does not completely depend on proliferation of these cells. In addition, we determined the growth rate of CENP-E high and low expressors, showing that it was independent from the amount of CENP-E expression. supporting the statement that upregulation of CENP-E reflects an activated RA fibroblast phenotype. In summary, the results of the present study support the hypothesis that CENP-E, presumably independently from medication, may not only be upregulated, but may also be involved in RA pathophysiology.

Ultrasound imaging is a widely used technique for fatty liver diagnosis as it is practically affordable and can be quickly deployed by using suitable devices. When it is applied to a patient, multiple images of the targeted tissues are produced. We propose a machine learning model for fatty liver diagnosis from multiple ultrasound images. The machine learning model extracts features of the ultrasound images by using a pre-trained image encoder. It further produces a summary embedding on these features by using a graph neural network. The summary embedding is used as input for a classifier on fatty liver diagnosis. We train the machine learning model on a ultrasound image dataset collected by Taiwan Biobank. We also carry out risk control on the machine learning model using conformal prediction. Under the risk control procedure, the classifier can improve the results with high probabilistic guarantees., (© 2024. The Author(s).)

The incorporation of plasmonic metal nanostructures into semiconducting chalcogenides in the form of core-shell structures provides a promising approach to enhancing the performance of photodetectors. In this study, we combined Au nanoparticles with newly developed copper-based chalcogenides Cu 2 NiSnS 4 (Au/CNTS) to achieve an ultrahigh optoelectronic response in the visible regime. The high-quality Au/CNTS core-shell nanocrystals (NCs) were synthesized by developing a unique colloidal hot-injection method, which allowed for excellent control over sizes, shapes, and elemental compositions. The as-synthesized Au/CNTS hybrid core-shell NCs exhibited enhanced optical absorption, carrier extraction efficiency, and improved photosensing performance owing to the plasmonic-induced resonance energy transfer effect of the Au core. This effect led to a significant increase in the carrier density of the Au/CNTS NCs, resulting in a measured responsivity of 1.2 × 10 3 AW -1 , a specific detectivity of 6.2 × 10 11 Jones, and an external quantum efficiency of 3.8 × 10 5 % at an incident power density of 318.5 μW cm -2 . These results enlighten a new era in the development of plasmonic core-shell nanostructure-based visible photodetectors.

Background & Aims: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood., Methods: We disrupted active DNA demethylation genes Tet1 and/or Tdg from Apc Min mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas., Results: There were increased numbers of small intestinal adenomas in Apc Min mice expressing the Tdg N151A allele, whereas Tet1-deficient and Tet1/Tdg N151A -double heterozygous Apc Min colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant Apc Min mice and hypermethylation of CpG islands in Tet1-mutant Apc Min adenomas. Up-regulation of inflammatory, immune, and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control Apc Min adenomas. This up-regulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG short hairpin RNA. A 127-gene inflammatory signature separated colonic adenocarcinomas into 4 groups, closely aligned with their microsatellite or chromosomal instability and characterized by different levels of DNA methylation and DNMT1 expression that anticorrelated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by natural killer cells., Conclusions: Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1/TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In this paper, we use terahertz combined with metamaterial technology as a powerful tool to identify analytes at different concentrations. Combined with the microfluidic chip, the experimental measurement can be performed with a small amount of analyte. In detecting the troponin antigen, surface modification is carried out by biochemical binding. Through the observation of fluorescent antibodies, the average number of fluorescent dots per unit of cruciform metamaterial is 25.60, and then, by adjusting the binding temperature and soaking time, the average number of fluorescent dots per unit of cruciform metamaterial can be increased to 181.02. Through the observation of fluorescent antibodies, it is confirmed that the antibodies can be successfully stabilized on the metamaterial and then bound to the target antigen. The minimum detectable concentration is between 0.05~0.1 μg/100 μL, and the concentration and ΔY show a positive correlation of R 2 = 0.9909.

In recent years, daily hygiene and disease control issues have received increasing attention, especially the raging epidemics caused by the spread of deadly viruses. The construction of the interface of new polymer materials is focused on, which can provide a cyclic operation process for the killing and releasing of bacteria, and perform repeated regeneration, which is of great significance for the development of advanced medical biomaterials. In order to explore the basic physical phenomena of bacterial attachment and detachment on the polymer material interface by different amine groups, this study plans to synthesize four different butyl methacrylate (BMA)-based cationic copolymers with primary, ternary, and quaternary amine groups, and compare their effects on bactericidal efficiency. Since BMA can generate strong hydrophobic interactions with the benzene ring structure, this study used a polystyrene substrate to realize a self-assembled cationic copolymer interface for controlling the counterion-induced bacterial killing/release process. Furthermore, negatively charged ions are introduced to induce changes in the hydration capability of water molecules and control the subsequent bacterial detachment function. In this study, possible directions to answer and clarify the above concepts are proposed, and there is a basic reference principle that can lead to research work in macromolecular bioscience fields., (© 2022 Wiley-VCH GmbH.)

Photo-induced electrochemical water splitting is a fascinating approach to overcome the present energy demands as well as environmental issues. To this end, near-infrared (NIR) photocatalysts stand out as promising candidates (where 53% of the solar light is NIR light) to solve the present energy crisis but the lack of NIR-activated photocatalysts has remained a great challenge for decades. Herein, for the first time, we report the synthesis of high-index faceted plasmonic Au nano-branched 12 tip nanostars, which can absorb the whole spectral region of electromagnetic radiation (UV-vis-NIR), for efficient water splitting. Moreover, the plasmonic hot spots on the Au 12 tip nanostars significantly promote the photoelectrochemical oxygen evolution reaction (OER) under NIR light (915 nm) with long-term stability. Remarkably, the Au 12 tip nanostars exhibit 250-fold enhancement of activity under 915 nm laser irradiation and 6.5-fold enhancement of activity under 532 nm laser irradiation, as compared to the Au NPs. Furthermore, the Finite-Difference Time-Domain (FDTD) study confirmed that the significant photoelectrochemical (PEC) enhancement in the NIR light region could be attributed to the hot-electron injection/plasmonic hot spot mechanism upon localized surface plasmonic resonance (LSPR) excitation. Overall, we anticipate that the present work would help to develop new NIR photoelectrocatalysts for meeting future energy demands.

Based on incredibly increasing applications in modern optoelectronic devices, the demand for securing a superior conductive transparent electrode (TCE) candidate becomes significant and urgent. However, boosting both transmittance and conductance simultaneously is an intrinsic limitation. In this work, we present silver nanoscale plasmonic wires (Ag NPWs) to function as TCEs in the visible light region by lowering their corresponding plasma frequencies. By carefully designing geometric dimensions of the Ag NPWs, we also optimize the performance for red, green, and blue colors, respectively. The demonstrated figure of merits for RGB colors appeared respectively 443.29, 459.46, and 133.78 in simulation and 302.75, 344.11, and 348.02 in experiments. Evidently, our Ag NPWs offer much greater FoMs beyond conventional TCEs that are most frequently comprised of indium tin oxide and show further advantages of flexibility and less Moire effect for the applications of flexible and high-resolution optoelectronic devices., (© 2022. The Author(s).)

Terahertz (THz) radiation has attracted wide attention in recent years due to its non-destructive properties and ability to sense molecular structures. In applications combining terahertz radiation with metamaterial technology, the interaction between the terahertz radiation and the metamaterials causes resonance reactions; different analytes have different resonance performances in the frequency domain. In addition, a microfluidic system is able to provide low volume reagents for detection, reduce noise from the environment, and concentrate the sample on the detection area. Through simulation, a cruciform metamaterial pattern was designed; the proportion, periodicity, and width of the metamaterial were adjusted to improve the sensing capability of the chip. In the experiments, the sensing capabilities of Type A, B, and C chips were compared. The Type C chip had the most significant resonant effect; its maximum shift could be increased to 89 GHz. In the probiotic experiment, the cruciform chip could have a 0.72 GHz shift at a concentration of 0.025 mg/50 μL, confirming that terahertz radiation combined with a metamaterial microfluidic chip can perform low-concentration detection.

Background: People's quality of life diverges on their demographics, socioeconomic status, and social connections., Objective: By taking both demographic and socioeconomic features into account, we investigated how quality of life varied on social networks using data from both longitudinal surveys and contact diaries in a year-long (2015-2016) study., Methods: Our 4-wave, repeated measures of quality of life followed the brief version of the World Health Organization Quality of Life scale (WHOQOL-BREF). In our regression analysis, we integrated these survey measures with key time-varying and multilevel network indices based on contact diaries., Results: People's quality of life may decrease if their daily contacts contain high proportions of weak ties. In addition, people tend to perceive a better quality of life when their daily contacts are face-to-face or initiated by others or when they contact someone who is in a good mood or someone with whom they can discuss important life issues., Conclusions: Our findings imply that both functional and structural aspects of the social network play important but different roles in shaping people's quality of life., (©Tso-Jung Yen, Ta-Chien Chan, Yang-Chih Fu, Jing-Shiang Hwang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 28.01.2022.)

High-performance p-type thin-film transistors (pTFTs) are crucial for realizing low-power display-on-panel and monolithic three-dimensional integrated circuits. Unfortunately, it is difficult to achieve a high hole mobility of greater than 10 cm 2 /V·s, even for SnO TFTs with a unique single-hole band and a small hole effective mass. In this paper, we demonstrate a high-performance GeSn pTFT with a high field-effect hole mobility (μ FE ), of 41.8 cm 2 /V·s; a sharp turn-on subthreshold slope ( SS ), of 311 mV/dec, for low-voltage operation; and a large on-current/off-current (I ON /I OFF ) value, of 8.9 × 10 6 . This remarkably high I ON /I OFF is achieved using an ultra-thin nanosheet GeSn, with a thickness of only 7 nm. Although an even higher hole mobility (103.8 cm 2 /V·s) was obtained with a thicker GeSn channel, the I OFF increased rapidly and the poor I ON /I OFF (75) was unsuitable for transistor applications. The high mobility is due to the small hole effective mass of GeSn, which is supported by first-principles electronic structure calculations.

In life science, rapid mutation detection in oligonucleotides is in a great demand for genomic and medical screening. To satisfy this demand, surface-enhanced resonance Raman spectroscopy (SERRS) in the deep-UV (DUV) regime offers a promising solution due to its merits of label-free nature, strong electromagnetic confinement, and charge transfer effect. Here, we demonstrate an epitaxial aluminum (Al) DUV-SERRS substrate that resonates effectively with the incident Raman laser and the ss-DNA at 266 nm, yielding significant SERRS signals of the detected analytes. For the first time, to the best of our knowledge, we obtaine SERRS spectra for all bases of oligonucleotides, not only revealing maximum characteristic Raman peaks but also recording the highest enhancement factor of up to 10 6 for a 1 nm thick adenine monomer. Moreover, our epitaxial Al DUV-SERRS substrate is able to enhance the Raman signal of all four bases of 12-mer ss-DNA and to further linearly quantify the single-base mutation in the 12-mer ss-DNA.

Antifouling materials are indispensable in the biomedical field, but their high hydrophilicity and surface free energy provoke contamination on surfaces under atmospheric conditions, thus limiting their applicability in medical devices. This study proposes a new zwitterionic structure, 4-vinylpyridine carboxybetaine (4VPCB), that results in lower surface free energy and increases biological inertness. In the design of 4VPCB, one to three carbon atoms are inserted between the positive charge and negative charge (carbon space length, CSL) of the pyridyl-containing side chain to adjust hydration with water molecules. The pyridine in the 4VPCB structure provides the hydrophobicity of the zwitterionic functional group, and thus it can have a lower free energy in the gas phase but maintain higher hydrophilicity in the liquid phase environment. Surface plasmon resonance and confocal microscopy were used to analyze the antiprotein adsorption and anti-blood cell adhesion properties of the P4VPCB brush surface. The results showed that the CSL in the P4VPCB structure affected the biological inertness of the surface. The protein adsorption on the surface of P4VPCB2 (CSL= 2) is lower than that on the surfaces of P4VPCB1 (CSL = 1) and P4VPCB3 (CSL = 3), and the optimal resistance to protein adsorption can be reduced to 7.5 ng cm -2 . The surface of P4VPCB2 can also exhibit excellent blood-inert function in the adhesion test with various human blood cells, offering a potential possibility for the future design of a new generation of blood-inert medical materials.

In this work, we integrated a periodic seed layer and oblique deposition method to fabricate a stochastically-distributed oblique-flat-sheet metamaterial perfect absorber (MPA). Such design could increase its absorption bandwidth and tolerance to high angle-incidence due to the fact that various oblique flat sheets offer different resonance conditions while even a single oblique flat sheet could provide different optical paths for resonance. On the other hand, a seed layer could reduce uncertainty regarding to direct oblique deposition and provide abilities to manipulate the bandwidth of the MPA. We also setup a simulation model in the aids of Visual Basic Application and examined the absorption behavior of the MPA under TM and TE oblique incidence that could achieve high absorbance under 80° and 60° incidence, respectively. Finally, in measurement, the fabricated sample owns 65% absorbance within 80-250 THz and over 90% absorbance within 250-320 THz at x-polarization normal incidence; as for the y-polarization normal incidence, we could achieve overall 70% absorbance within 80-300 THz. The measured results reveal similar tendency compared to the simulated ones., (© 2021. The Author(s).)

Large device variation is a fundamental challenge for resistive random access memory (RRAM) array circuit. Improved device-to-device distributions of set and reset voltages in a SiN x RRAM device is realized via arsenic ion (As + ) implantation. Besides, the As + -implanted SiN x RRAM device exhibits much tighter cycle-to-cycle distribution than the nonimplanted device. The As + -implanted SiN x device further exhibits excellent performance, which shows high stability and a large 1.73 × 10 3 resistance window at 85 °C retention for 10 4 s, and a large 10 3 resistance window after 10 5 cycles of the pulsed endurance test. The current-voltage characteristics of high- and low-resistance states were both analyzed as space-charge-limited conduction mechanism. From the simulated defect distribution in the SiN x layer, a microscopic model was established, and the formation and rupture of defect-conductive paths were proposed for the resistance switching behavior. Therefore, the reason for such high device performance can be attributed to the sufficient defects created by As + implantation that leads to low forming and operation power.

Monolayer transition metal dichalcogenides (TMDs), direct bandgap materials with an atomically thin nature, are promising materials for electronics and photonics, especially at highly scaled lateral dimensions. However, the characteristically low total absorption of photons in the monolayer TMD has become a challenge in the access to and realization of monolayer TMD-based high-performance optoelectronic functionalities and devices. Here, we demonstrate gate-tunable plasmonic phototransistors (photoFETs) that consist of monolayer molybdenum disulfide (MoS 2 ) photoFETs integrated with the two-dimensional plasmonic crystals. The plasmonic photoFET has an ultrahigh photoresponsivity of 2.7 × 10 4 AW -1 , achieving a 7.2-fold enhancement in the photocurrent compared to pristine photoFETs. This benefits predominately from the combination of the enhancement of the photon-absorption-rate via the strongly localized-electromagnetic-field and the gate-tunable plasmon-induced photocarrier-generation-rate in the monolayer MoS 2 . These results demonstrate a systematic methodology for designing ultrathin plasmon-enhanced photodetectors based on monolayer TMDs for next-generation ultracompact optoelectronic devices in the trans-Moore era.

Perfect absorbers (PAs) at near infrared allow various applications such as biosensors, nonlinear optics, color filters, thermal emitters and so on. These PAs, enabled by plasmonic resonance, are typically powerful and compact, but confront inherent challenges of narrow bandwidth, polarization dependence, and limited incident angles as well as requires using expensive lithographic process, which limit their practical applications and mass production. In this work, we demonstrate a non-resonant PA that is comprised of six continuous layers of magnesium fluoride (MgF 2 ) and chromium (Cr) in turns. Our device absorbs more than 90% of light in a broad range of 900-1900 nm. In addition, such a planar design is lithography-free, certainly independent with polarization, and presents a further advantage of wide incidence up to 70°. The measured performance of our optimized PA agrees well with analytical calculations of transfer matrix method (TMM) and numerical simulations of finite element method, and can be readily implemented for practical applications.

Atomically thin transition metal dichalcogenides (TMDC) have received much attention due to their wide variety of optical and electronic properties. Among various TMDC materials, molybdenum disulfide (MoS 2 ) has been intensely studied owing to its potential applications in nanoelectronics and optoelectronics. However, two-dimensional MoS 2 photodetectors suffer from low responsivity due to low optical cross section. Combining MoS 2 with plasmonic nanostructures can drastically increase scattering cross section and enhance local light-matter interaction. Moreover, suspended MoS 2 has been shown to exhibit higher photoluminescence intensity and strong photogating effect, which can be employed in photodetectors. Herein, we propose an approach to utilize plasmonic nanostructures and physical suspension for 2D MoS 2 photosensing enhancement by hybridizing 2D bilayer MoS 2 , 1D silicon nanowires, and 0D silver nanoparticles. The hybrid structure shows a gateless responsivity of 402.4 A/W at a wavelength of 532 nm, which represents the highest value among the ever reported gateless plasmonic MoS 2 photodetector. The great responsivity and large active area results in an exceptional detectivity of 2.34 × 10 12 Jones. This study provides a new approach for designing high-performance 2D TMDC-based optoelectronic devices.

Implementing high-performance n- and p-type thin-film transistors (TFTs) for monolithic three-dimensional (3D) integrated circuit (IC) and low-DC-power display is crucial. To achieve these goals, a top-gate transistor is preferred to a conventional bottom-gate structure. However, achieving high-performance top-gate p-TFT with good hole field-effect mobility ( μ FE ) and large on-current/off-current (I ON /I OFF ) is challenging. In this report, coplanar top-gate nanosheet SnO p-TFT with high μ FE of 4.4 cm 2 /Vs, large I ON /I OFF of 1.2 × 10 5 , and sharp transistor's turn-on subthreshold slopes ( SS ) of 526 mV/decade were achieved simultaneously. Secondary ion mass spectrometry analysis revealed that the excellent device integrity was strongly related to process temperature, because the HfO 2 /SnO interface and related μ FE were degraded by Sn and Hf inter-diffusion at an elevated temperature due to weak Sn-O bond enthalpy. Oxygen content during process is also crucial because the hole-conductive p-type SnO channel is oxidized into oxygen-rich n-type SnO 2 to demote the device performance. The hole μ FE , I ON /I OFF , and SS values obtained in this study are the best-reported data to date for top-gate p-TFT device, thus facilitating the development of monolithic 3D ICs on the backend dielectric of IC chips.

DNA methylation is a critical process in the regulation of gene expression with dramatic effects in development and continually expanding roles in oncogenesis. 5-Methylcytosine was once considered to be an inherited and stably repressive epigenetic mark, which can be only removed by passive dilution during multiple rounds of DNA replication. However, in the past two decades, physiologically controlled DNA demethylation and deamination processes have been identified, thereby revealing the function of cytosine methylation as a highly regulated and complex state-not simply a static, inherited signature or binary on-off switch. Alongside these fundamental discoveries, clinical studies over the past decade have revealed the dramatic consequences of aberrant DNA demethylation. In this review we discuss DNA demethylation and deamination in the context of 5-methylcytosine as critical processes for physiological and physiopathological transitions within three states-development, immune maturation, and oncogenic transformation; and we describe the expanding role of DNA demethylating drugs as therapeutic agents in cancer., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Advanced Genetics published by Wiley Periodicals LLC.)

Plasmonics have been well investigated on photodetectors, particularly in IR and visible regimes. However, for a wide range of ultraviolet (UV) applications, plasmonics remain unavailable mainly because of the constrained optical properties of applicable plasmonic materials in the UV regime. Therefore, an epitaxial single-crystalline aluminum (Al) film, an abundant metal with high plasma frequency and low intrinsic loss is fabricated, on a wide bandgap semiconductive gallium nitride (GaN) to form a UV photodetector. By deliberately designing a periodic nanohole array in this Al film, localized surface plasmon resonance and extraordinary transmission are enabled; hence, the maximum responsivity (670 A W -1 ) and highest detectivity (1.48 × 10 15  cm Hz 1/2 W -1 ) is obtained at the resonance wavelength of 355 nm. In addition, owing to coupling among nanoholes, the bandwidth expands substantially, encompassing the entire UV range. Finally, a Schottky contact is formed between the single-crystalline Al nanohole array and the GaN substrate, resulting in a fast temporal response with a rise time of 51 ms and a fall time of 197 ms. To the best knowledge, the presented detectivity is the highest compared with those of other reported GaN photodetectors., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)

Metal-oxide thin-film transistors (TFTs) have been implanted for a display panel, but further mobility improvement is required for future applications. In this study, excellent performance was observed for top-gate coplanar binary SnO 2 TFTs, with a high field-effect mobility ( μ FE ) of 136 cm 2 /Vs, a large on-current/off-current (I ON /I OFF ) of 1.5 × 10 8 , and steep subthreshold slopes of 108 mV/dec. Here, μ FE represents the maximum among the top-gate TFTs made on an amorphous SiO 2 substrate, with a maximum process temperature of ≤ 400 °C. In contrast to a bottom-gate device, a top-gate device is the standard structure for monolithic integrated circuits (ICs). Such a superb device integrity was achieved by using an ultra-thin SnO 2 channel layer of 4.5 nm and an HfO 2 gate dielectric with a 3 nm SiO 2 interfacial layer between the SnO 2 and HfO 2 . The inserted SiO 2 layer is crucial for decreasing the charged defect scattering in the HfO 2 and HfO 2 /SnO 2 interfaces to increase the mobility. Such high μ FE , large I ON , and low I OFF top-gate SnO 2 devices with a coplanar structure are important for display, dynamic random-access memory, and monolithic three-dimensional ICs.

Lead halide perovskite materials have recently received considerable attention for achieving an economic and tunable laser owing to their solution-processable feature and promising optical properties. However, most reported perovskite-based lasers operate with a large lasing-mode volume, resulting in a high lasing threshold due to the inefficient coupling between the optical gain medium and cavity. Here, we demonstrate a continuous-wave nanolasing from a single lead halide perovskite (CsPbBr 3 ) quantum dot (PQD) in a plasmonic gap-mode nanocavity with an ultralow threshold of 1.9 Wcm -2 under 120 K. The calculated ultrasmall mode volume (∼0.002 λ 3 ) with a z -polarized dipole and the significantly large Purcell enhancement at the corner of the nanocavity inside the gap dramatically enhance the light-matter interaction in the nanocavity, thus facilitating lasing. The demonstration of PQD nanolasing with an ultralow-threshold provides an approach for realizing on-chip electrically driven lasing and integration into on-chip plasmonic circuitry for ultrafast optical communication and quantum information processing.

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive technique to identify vibrational fingerprints of trace analytes. However, present SERS techniques suffer from the lack of uniform, reproducible, and stable substrates to control the plasmonic hotspots in a wide spectral range. Here, we report the promising application of epitaxial aluminum films as a scalable plasmonic platform for SERS applications. To assess the uniformity of aluminum substrates, atomically thin transition metal dichalcogenide monolayers are used as the benchmark analyte due to their inherent two-dimensional homogeneity. Besides the distinctive spectral capability of aluminum in the ultraviolet (325 nm), we demonstrate that the aluminum substrates can even perform comparably with the silver counterparts made from single-crystalline colloidal silver crystals using the same SERS substrate design in the visible range (532 nm). This is unexpected from the prediction solely based on optical dielectric functions and illustrate the superior surface and interface properties of epitaxial aluminum SERS substrates.

Constrained by the diffraction limit, a lens can only resolve features larger than half of the incident wavelength owing to the decaying nature of evanescent waves. Several novel devices have been proposed, for example, superlenses and hyperlenses to break this limit. In this work, we present a flat hyperlens composed of silver nanowires embedded in a modified anodic aluminum oxide (AAO) template to demonstrate subwavelength imaging. Measurement conducted by the near-field scanning optical microscope at 633 nm suggests that our proposed flat hyperlens can indeed achieve sub-wavelength imaging with a resolution down to 0.34λ and 0.25λ along two orthogonal directions. Furthermore, to confirm the resolution limit of the flat hyperlens, numerical simulations were performed at the incident wavelengths of 633 and 365 nm, and the corresponding resolution were 0.19λ and 0.3λ, respectively, thus paving a route for sub-wavelength photolithography.

All-nonmetal resistive random access memory (RRAM) with a N + -Si/SiN x /P + -Si structure was investigated in this study. The device performance of SiN x developed using physical vapor deposition (PVD) was significantly better than that of a device fabricated using plasma-enhanced chemical vapor deposition (PECVD). The SiN x RRAM device developed using PVD has a large resistance window that is larger than 10 4 and exhibits good endurance to 10 5 cycles under switching pulses of 1 μs and a retention time of 10 4 s at 85 °C. Moreover, the SiN x RRAM device developed using PVD had tighter device-to-device distribution of set and reset voltages than those developed using PECVD. Such tight distribution is crucial to realise a large-size cross-point array and integrate with complementary metal-oxide-semiconductor technology to realise electronic neurons. The high performance of the SiN x RRAM device developed using PVD is attributed to the abundant defects in the PVD dielectric that was supported by the analysed conduction mechanisms obtained from the measured current-voltage characteristics.

Terahertz (THz) radiation has attracted wide attention for its ability to sense molecular structure and chemical matter because of a label-free molecular fingerprint and nondestructive properties. When it comes to molecular recognition with terahertz radiation, our attention goes first towards the absorption spectrum, which is beyond the far infrared region. To enhance the sensitivity for similar species, however, it is necessary to apply an artificially designed metamaterial sensor for detection, which confines an electromagnetic field in an extremely sub-wavelength space and hence receives an electromagnetic response through resonance. Once the resonance is caused through the interaction between the THz radiation and the metamaterial, a minute variation might be observed in the frequency domain. For a geometric structure of a metamaterial, a novel design called an X-shaped plasmonic sensor (XPS) can create a quadrupole resonance and lead to sensitivity greater than in the dipole mode. A microfluidic system is able to consume reagents in small volumes for detection, to diminish noise from the environment, and to concentrate the sample into detection spots. A microfluidic device integrated with an X-shaped plasmonic sensor might thus achieve an effective and highly sensitive detection cartridge. Our tests involved not only measurements of liquid samples, but also the performance of a dry bio-sample coated on an XPS., Competing Interests: The authors declare no conflict of interest.

We present experimental and theoretical studies of a metamaterial-based plasmonic structure to build a plasmonic-molecular coupling detection system. High molecular sensitivity is realized only when molecules are located in the vicinity of the enhanced field (hot spot region); thus, introducing target molecules in the hot spot region to maximize plasmonic-molecular coupling is crucial to developing the sensing technology. We design a metamaterial consisting of a vertically oriented metal insulator metal (MIM) structure with a 25 nm channel sandwiched between two metal films, which enables the delivery of molecules into the large ravinelike hot spot region, offering an ultrasensitive platform for molecular sensing. This metamaterial is applied to carbon dioxide and butane detection. We design the structure to exhibit resonances at 4033 and 2945 cm -1 , which overlap with the C═O and -CH 2 vibration modes, respectively. The mutual coupling of these two resonance modes creates a Fano resonance, and their distinct peaks are clearly observed in the corresponding transmission dips. In addition, owing to its small footprint, such a vertical-oriented MIM structure enables us to increase the integration density and allows the detection of a 20 ppm concentration with negligible background noise and high selectivity in the mid-infrared region.

Introduction: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia., Methods: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays., Results: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson r = 0.5770, p = 0.0001) and relapse (Pearson r = 0.8919; p = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells., Conclusion: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL.

The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively. MBD4 is also involved in DNA damage response and transcriptional regulation. The interaction with other proteins is likely critical for understanding MBD4 functions. To identify novel proteins that interact with MBD4, we used tandem affinity purification (TAP) from HEK-293 cells. The MBD4-TAP fusion and its co-associated proteins were purified sequentially on IgG and calmodulin affinity columns; the final eluate was shown to contain MLH1 by western blotting, and MBD4-associated proteins were identified by mass spectrometry. Bands with molecular weight higher than that expected for MBD4 (˜66 kD) yielded peptides corresponding to MBD4 itself and the small ubiquitin-like molecule-1 (SUMO1), suggesting that MBD4 is sumoylated in vivo. MBD4 sumoylation was validated by co-immunoprecipitation in HEK-293 and MCF7 cells, and by an in vitrosumoylation assay. Sequence and mutation analysis identified three main sumoylation sites: MBD4 is sumoylated preferentially on K137, with additional sumoylation at K215 and K377. Patterns of MBD4 sumoylation were altered, in a DNA damage-specific way, by the anti-metabolite 5-fluorouracil, the alkylating agent N-Methyl-N-nitrosourea and the crosslinking agent cisplatin. MCF7 extract expressing sumoylated MBD4 displays higher thymine glycosylase activity than the unmodified species. Of the 67 MBD4 missense mutations reported in The Cancer Genome Atlas, 14 (20.9%) map near sumoylation sites. These results indicate that MBD4 is sumoylated in vivo in a DNA damage-specific manner, and suggest that sumoylation serves to regulate its repair activity and could be compromised in cancer. This study expands the role played by sumoylation in fine-tuning DNA damage response and repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Enhancing the efficiency of antibody protein immobilized on a silicon nanowire-based chip for their antigens detection is reported. An external electric field (EEF) is applied to direct the orientation of antibodies during their immobilization on a chip. Atomic force microscopy (AFM) is used to measure the binding forces between immobilized antibody and targeting antigen under the influence of EEF at different angles. The maximum binding force under a specific angle (optimal angle; oa) of EEF ( max EEF oa ) implies the optimal orientation of the antibodies on the chip. In this report, two different cancer carcinoembryonic antigen (CEA)-related cell adhesion molecules 5 (CEACAM5) & 1 (CEACAM1) were used for the examples of disease antigen detection. max EEF oa of anti-CEACAM5 or anti-CEACAM1 immobilized on a general chip was firstly determined. Spectroscopy of AFM revealed that both binding forces were the largest ones with their antigens when max EEF oa was applied as compared with no or other angles of EEF. These antibody proteins accompanied with the application of EEF were secondly immobilized on silicon-nanowires (n = 1000) and the field effects were measured (∆I) as their target antigens were approached. Results showed that ∆I was the largest ones when max EEF oa s (225°/270° and 135°/180° for anti-CEACAM5 and anti-CEACAM1, respectively) were applied as compared with other angles of EEF. These observations imply that the silicon nanowires together with the application of max EEF oa as detection tools could be applied for the cancer diagnostics in the future., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Lysine acetyltransferases (KATs) are exquisitely fine-tuned to target specific lysine residues on many proteins, including histones, with aberrant acetylation at distinct lysines implicated in different pathologies. However, researchers face a lack of molecular tools to probe the importance of site-specific acetylation events in vivo. Because of this, there can be a disconnect between the predicted in silico or in vitro effects of a drug and the actual observable in vivo response. We have previously reported on how an in vitro biochemical analysis of the site-specific effects of the compound C646 in combination with the KAT p300 can accurately predict changes in histone acetylation induced by the same compound in cells. Here, we build on this effort by further analyzing a number of reported p300 modulators, while also extending the analysis to correlate the effects of these drugs to developmental and phenotypical changes, utilizing cellular and zebrafish model systems. While this study demonstrates the utility of biochemical models as a starting point for predicting in vivo activity of multi-site targeting KATs, it also highlights the need for the development of new enzyme inhibitors that are more specific to the regulation of KAT activity in vivo., Competing Interests: The author(s) declare no competing interests.

Dinoflagelates and cyanobacteria produce saxitoxin (STX), a lethal bis-guanidinium neurotoxin causing paralytic shellfish poisoning. A number of metazoans have soluble STX-binding proteins that may prevent STX intoxication. However, their STX molecular recognition mechanisms remain unknown. Here, we present structures of saxiphilin (Sxph), a bullfrog high-affinity STX-binding protein, alone and bound to STX. The structures reveal a novel high-affinity STX-binding site built from a "proto-pocket" on a transferrin scaffold that also bears thyroglobulin domain protease inhibitor repeats. Comparison of Sxph and voltage-gated sodium channel STX-binding sites reveals a convergent toxin recognition strategy comprising a largely rigid binding site where acidic side chains and a cation-π interaction engage STX. These studies reveal molecular rules for STX recognition, outline how a toxin-binding site can be built on a naïve scaffold, and open a path to developing protein sensors for environmental STX monitoring and new biologics for STX intoxication mitigation.

BUB-related 1 (BubR1) encoded by Budding Uninhibited by Benzimidazole 1B (BUB1B) is a crucial mitotic checkpoint protein ensuring proper segregation of chromosomes during mitosis. Mutations of BUB1B are responsible for mosaic variegated aneuploidy (MVA), a human congenital disorder characterized by extensive abnormalities in chromosome number. Although microcephaly is a prominent feature of MVA carrying the BUB1B mutation, how BubR1 deficiency disturbs neural progenitor proliferation and neuronal output and leads to microcephaly is unknown. Here we show that conditional loss of BubR1 in mouse cerebral cortex recapitulates microcephaly. BubR1-deficient cortex includes a strikingly reduced number of late-born, but not of early-born, neurons, although BubR1 expression is substantially reduced from an early stage. Importantly, absence of BubR1 decreases the proportion of neural progenitors in mitosis, specifically in metaphase, suggesting shortened mitosis owing to premature chromosome segregation. In the BubR1 mutant, massive apoptotic cell death, which is likely due to the compromised genomic integrity that results from aberrant mitosis, depletes progenitors and neurons during neurogenesis. There is no apparent alteration in centrosome number, spindle formation or primary cilia, suggesting that the major effect of BubR1 deficiency on neural progenitors is to impair the mitotic checkpoint. This finding highlights the importance of the mitotic checkpoint in the pathogenesis of microcephaly. Furthermore, the ependymal cell layer does not form in the conditional knockout, revealing an unrecognized role of BubR1 in assuring the integrity of the ventricular system, which may account for the presence of hydrocephalus in some patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

An eco-friendly electrochemical approach, including base and acid treatments, and anodization, has been developed for preparation of defect-rich porous aluminum electrodes for efficient hydrogen evolution. A small Tafel slope value of 43 mV dec-1 reveals improved reaction kinetics through the micropores, 3D channels, and zig-zag edges of the aluminum electrode. It exhibits an onset potential of 460 mV and an overpotential of 580 mV at the current density of 10 mA cm-2 due to the porous and edge structures that enhance the charge transfer and mass transport.

Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and treatment. In addition to conventional therapy, melanoma treatment is currently based on targeting the BRAF/MEK/ERK signaling pathway and immune checkpoints. As drug resistance remains a major obstacle to treatment success, advanced therapeutic approaches based on novel targets are still urgently needed. We reasoned that the base excision repair enzyme thymine DNA glycosylase (TDG) could be such a target for its dual role in safeguarding the genome and the epigenome, by performing the last of the multiple steps in DNA demethylation. Here we show that TDG knockdown in melanoma cell lines causes cell cycle arrest, senescence, and death by mitotic alterations; alters the transcriptome and methylome; and impairs xenograft tumor formation. Importantly, untransformed melanocytes are minimally affected by TDG knockdown, and adult mice with conditional knockout of Tdg are viable. Candidate TDG inhibitors, identified through a high-throughput fluorescence-based screen, reduced viability and clonogenic capacity of melanoma cell lines and increased cellular levels of 5-carboxylcytosine, the last intermediate in DNA demethylation, indicating successful on-target activity. These findings suggest that TDG may provide critical functions specific to cancer cells that make it a highly suitable anti-melanoma drug target. By potentially disrupting both DNA repair and the epigenetic state, targeting TDG may represent a completely new approach to melanoma therapy.

Traditional Resistive Random Access Memory (RRAM) is a metal-insulator-metal (MIM) structure, in which metal oxide is usually used as an insulator. The charge transport mechanism of traditional RRAM is attributed to a metallic filament inside the RRAM. In this paper, we demonstrated a novel RRAM device with no metal inside. The N + -Si/SiO x /P + -Si combination forms a N + IP + diode structure that is different from traditional MIM RRAM. A large high-resistance/low-resistance window of 1.9 × 10 4 was measured at room temperature. A favorable retention memory window of 1.2 × 10 3 was attained for 10 4  s at 85 °C. The charge transport mechanism of virgin, high- and low-resistance states can be well modeled by the single Shklovskii-Efros percolation mechanism rather than the charge transport in metallic filament. X-ray photoelectron spectroscopy demonstrated that the value of x in SiO x was 0.62, which provided sufficient oxygen vacancies for set/reset RRAM functions.

We design an all-dielectric taper and then excite its surface modes by illuminating a plane wave upon the taper to achieve broadband light trapping spanning from 20 to 100 GHz. Via Lewin's theory, such excitation of surface modes could be analogous to "trapped rainbow", i.e., activation of negative Goos-Hänchen effect within a negative refractive waveguide. To further reinforce this statement, the corresponding power flow distributions within the all-dielectric taper are recorded in finite-integration time domain simulation and suggest that a chromatic incident pulse is indeed trapped at different critical thicknesses of the taper, a character of the negative refractive waveguide. Finally, the transmittance is measured and compared to the simulated ones. The two followed the similar trend.

We utilized size-tunable gold nanoparticles (Au NPs) to investigate the toxicogenomic responses of the model organism Caenorhabditis elegans. We demonstrated that the nematode C. elegans can uptake Au NPs coated with or without 11-mercaptoundecanoic acid (MUA), and Au NPs are detectable in worm intestines using X-ray microscopy and confocal optical microscopy. After Au NP exposure, C. elegans neurons grew shorter axons, which may have been related to the impeded worm locomotion behavior detected. Furthermore, we determined that MUA to Au ratios of 0.5, 1 and 3 reduced the worm population by more than 50% within 72 hours. In addition, these MUA to Au ratios reduced the worm body size, thrashing frequency (worm mobility) and brood size. MTT assays were employed to analyze the viability of cultured C. elegans primary neurons exposed to MUA-Au NPs. Increasing the MUA to Au ratios increasingly reduced neuronal survival. To understand how developmental changes (after MUA-Au NP treatment) are related to changes in gene expression, we employed DNA microarray assays and identified changes in gene expression (e.g., clec-174 (involved in cellular defense), cut-3 and fil-1 (both involved in body morphogenesis), dpy-14 (expressed in embryonic neurons), and mtl-1 (functions in metal detoxification and homeostasis)).

We developed an osseocompatible β-type Ti-28Nb-11Ta-8Zr (TNTZ) alloy that displays the excellent elastic modulus, cellular response, corrosion resistance and antibacterial capability demanded for bone-mimetic materials. The TNTZ alloy exhibited an elastic modulus of 49 GPa, which approximates that of human bones and prevent stress shielding effects. A further anodic oxidation and subsequent post-annealing modification formed a crystalline nanoporous TNTZ oxide layer (NPTNTZO(c)) on the alloy surface, potentially promoting interlocking with the extracellular matrix of bone cells and cell proliferation. Osteoblast viability tests also verified that NPTNTZO(c) enhanced cell growth more significantly than that of flat TNTZ. In addition, potentiodynamic polarization tests in Hanks' balanced salt solution (HBSS) revealed that both TNTZ and NPTNTZO(c) exhibited better corrosion resistance than commercial pure titanium. Finally, NPTNTZO(c) reinforced with silver nanoparticles (NPTNTZO, ((c)/AgNPs) intensified the antibacterial efficiency against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli for 8 h with antibacterial efficiencies of 87.82%, 97.68%, and 93.90%, respectively, facilitating infection prevention during surgery and recovery stages.)

While biophysical stimuli from polymeric matrices are known to significantly affect the fates of human mesenchymal stem cells (hMSCs), the stimulatory effects of nano-sized silicon-based matrices on hMSCs have not been thoroughly investigated. We previously demonstrated that vertically aligned, single-crystalline silicon nanowires (SiNWs) can control the osteogenicity of hMSCs via controllable spring constants from SiNWs matrix. However, other possible differentiation fates of hMSCs on SiNWs have not been explored. We hypothesize that tunable spring constant from artificial SiNWs matrices can direct different types of hMSC differentiations. The spring constants of tunable SiNW matrices can be consistently controlled by tuning the SiNW length. The results of gene expression and cell stiffness suggest that hMSCs differentiations are sensitive to our distinguishable spring constants from the SiNWs groups, and simultaneously conduct osteogenicity and adipogenicity. These findings suggest that SiNW matrices can regulate the fates of hMSCs when the SiNW characteristics are carefully tuned.

Background: Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study., Methods: The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts., Results: We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation., Conclusions: Our data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.

Objectives: This paper examines how people express personal mood concurrently with those connected with them by one or two degrees of separation., Design: Participatory cohort study., Setting: Online contact diary., Participants: 133 participants kept online diaries for 7 months in 2014, which included 127 455 contacts with 12 070 persons., Main Outcome Measures: Diary keepers rated a contacted person's mood during each specific contact, as well as the strength of ties between any pairs of such contacted persons. Such rich information about ties and contacts enable us to construct a complete contact network for each diary keeper, along with the network members' mood and tie strength. We calculate one's overall mood by that person's average mood score during the study period and take the shortest path between any given pair of contacted persons as the degree of separation. We further assume that two connecting persons in a contact network have made contact with each other during the study period, which allows us to examine whether and how personal moods occur concurrently within these contact networks., Results: Using mixed-effects models while controlling for covariates at individual, tie and contact levels, we show that personal mood score positively and significantly correlates with the average mood among those directly tied to the person. The same effect remains positive and significant for those connected to the person by two degrees, although the effect size is reduced by about one-half. The mood of anyone separated by more than two degrees is statistically irrelevant., Conclusions: Applying network perspectives and rich data at both tie and contact levels to inquiries about subjective well-being, the current study sheds new light on how an improved diary approach can help explain the sophisticated ways in which individuals express their personal moods concurrently during social interactions in everyday life, contact by contact., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We employ model organism Caenorhabditis elegans to effectively study the toxicology of anatase and rutile phase titanium dioxide (TiO 2 ) nanoparticles (NPs). The experimental results show that nematode C. elegans can take up fluorescein isothiocyanate-labeled TiO 2 NPs and that both anatase and rutile TiO 2 NPs can be detected in the cytoplasm of cultured primary neurons imaged by transmission electron microscopy. After TiO 2 NP exposure, these neurons also grow shorter axons, which may be related to the detected impeded worm locomotion behavior. Furthermore, anatase TiO 2 NPs did not affect the worm's body length; however, we determined that a concentration of 500 μg/mL of anatase TiO 2 NPs reduced the worm population by 50% within 72 h. Notably, rutile TiO 2 NPs negatively affect both the body size and worm population. Worms unable to enter the L4 larval stage explain a severe reduction in the worm population at TiO 2 NPs LC 50 /3d. To obtain a better understanding of the cellular mechanisms involved in TiO 2 NP intoxication, DNA microarray assays were employed to determine changes in gene expression in the presence or absence of TiO 2 NP exposure. Our data reveal that three genes (with significant changes in expression levels) were related to metal binding or metal detoxification (mtl-2, C45B2.2, and nhr-247), six genes were involved in fertility and reproduction (mtl-2, F26F2.3, ZK970.7, clec-70, K08C9.7, and C38C3.7), four genes were involved in worm growth and body morphogenesis (mtl-2, F26F2.3, C38C3.7, and nhr-247), and five genes were involved in neuronal function (C41G6.13, C45B2.2, srr-6, K08C9.7, and C38C3.7).