Shape memory hydrogels with remodelable permanent shapes and programmable cold-induced shape recovery behavior.

Most shape memory polymers apply glass transition or crystallization of domains to fix temporary shapes and shape recovery is induced by heating, which hinders their application under heat-intolerant conditions. Moreover, the permanent shapes of polymers normally cannot be altered arbitrarily after fabrication. Herein, we present a novel shape memory hydrogel with a remodelable permanent shape and programmable cold-induced shape recovery behavior. Poly(acrylic acid) (PAA) hydrogel is prepared in the presence of diethylenetriamine (DETA) and subsequently treated with calcium acetate (Ca(Ac)2). The charge-assisted hydrogen bonding between PAA and DETA imparts the hydrogel with remodelability, while the heat-induced hydrophobic aggregation of polymer chains and acetate groups results in shape fixation by heating and shape recovery by cooling. Afterwards, programmable deformable devices are obtained by assembling hydrogel blocks with different concentrations of Ca(Ac)2. This design strategy promotes the development of shape memory polymers with diverse potential applications.

Study of the Influence of the Backplate Position on EMAT Thickness-Measurement Signals.

Nondestructive testing (NDT) is an essential method for assessing structural integrity in the oil and gas industry. Electromagnetic acoustic transducers (EMATs) have been extensively used to detect the wall-thickness reduction of plate-like structures, because they do not require direct contact. The pulse intervals of echoes are used to calculate the remnant thickness of structures. If the width of a single pulse is too large, multiple pulses will be superimposed, making it more difficult to extract the pulse interval. Thus, the width of a single pulse affects the resolution of measurements. This paper investigates the impacts of the backplate position on the pulse width and amplitude of thickness-measurement signals, using EMATs. By means of impedance modeling and measurement, it can be shown that the output impedance of the receiving coil is strongly influenced by the coil-backplate gap. With the increment in the coil-backplate gap, the signal amplitude and damping coefficient increase, while the self-resonant frequency decreases. By means of signal measurements on the specimen, it is shown that the pulse width and the signal amplitude can be significantly influenced by the backplate position. By reducing the coil-backplate gap, the pulse width can be reduced by over 80%, and by increasing the gap, the signal amplitude can be increased by over 300%. These research results can be used to optimize EMAT design, thereby suppressing the superposition of pulse echoes.

RNA-binding protein PUM2 regulates mesenchymal stem cell fate via repression of JAK2 and RUNX2 mRNAs.

The differentiation of mesenchymal stem cells (MSCs) into unwanted lineages can generate potential problems in clinical trials. Thus, understanding the molecular mechanisms, involved in this process, would help prevent unexpected complications. Regulation of gene expression, at the posttranscriptional level, is a new approach in cell therapies. PUMILIO is a conserved posttranscriptional regulator. However, the underlying mechanisms of PUMILIO, in vertebrate stem cells, remain elusive. Here, we show that depletion of PUMILIO2 (PUM2) blocks MSC adipogenesis and enhances osteogenesis. We also demonstrate that PUM2 works as a negative regulator on the 3'-untranslated regions of JAK2 and RUNX2 via direct binding. CRISPR/Cas9-mediated gene silencing of Pum2 inhibited lipid accumulation and induced excessive bone formation in zebrafish larvae. Our findings reveal novel roles of PUM2 in MSCs and provide potential therapeutic targets for related diseases.

Downregulation of nuclear progestin receptor (Pgr) and subfertility in double knockouts of progestin receptor membrane component 1 (pgrmc1) and pgrmc2 in zebrafish.

The progestin receptor membrane components (Pgrmcs) contain two paralogs, Pgrmc1 and Pgrmc2. Our previous research into single knockout of Pgrmc1 or Pgrmc2 suggests that Pgrmc1 and Pgrmc2 regulate membrane progestin receptor or steroid synthesis and therefore female fertility in zebrafish. Additional roles of Pgrmcs may not be determined in using single Pgrmc knockouts due to compensatory roles between Pgrmc1 and Pgrmc2. To address this question, we crossed single knockout pgrmc1 (pgrmc1-/-) with pgrmc2 (pgrmc2-/-), and generated double knockouts for both pgrmc1 and pgrmc2 (pgrmc1/2-/-) in a vertebrate model, zebrafish. In addition to the delayed oocyte maturation and reduced female fertility, significant reduced ovulation was found in double knockout (pgrmc1/2-/-) in vivo, though not detected in either single knockout of Pgrmc (pgrmc1-/- or pgrmc2-/-). We also found significant down regulation of nuclear progestin receptor (Pgr) protein expression only in pgrmc1/2-/-, which was most likely the cause of reduced ovulation. Lower protein expression of Pgr also resulted in reduced expression of metalloproteinase in pgrmc1/2-/-. With this study, we have provided new evidence for the physiological functions of Pgrmcs in the regulation of female fertility by regulation of ovulation, likely via regulation of Pgr, which affects regulation of metalloproteinase expression and oocyte ovulation.

Subfertility and reduced progestin synthesis in Pgrmc2 knockout zebrafish.

Progestin receptor membrane component (Pgrmc1 & 2) is a heme-binding protein. Studies on Pgrmc1 have suggested possible roles in heme binding, activation of steroid-synthesizing P450s, along with binding and transferring of membrane proteins. However, the studies of Pgrmc1's paralog, Pgrmc2 are still lacking. In order to determine the physiologic function(s) of Pgrmc2, we generated a zebrafish mutant line (pgrmc2-/-). We found a reduction in both spawning frequency and the number of embryos produced in female pgrmc2-/-. This subfertility is caused by reduced oocyte maturation (germinal vesicle breakdown, GVBD) in pgrmc2-/- in vivo. Nonetheless, oocytes from pgrmc2-/- had similar sensitivity to 17α,20ß-dihydroxy-4-pregnen-3-one (DHP, a maturation induced progestin in zebrafish) compared with wildtype (wt) in vitro. Therefore, we hypothesized that oocyte maturation tardiness found in vivo, could be due to lack of progestin in pgrmc2-/-. Interestingly, we found significant reduced expression of hormones, receptors, and steroid synthesizing enzymes including lhcgr, egfra, ar, and esr2, cyp11a1 and hsd3b1. In addition, DHP levels in pgrmc2-/- ovaries showed a significant decrease compared to those in wt. In summary, we have provided a plausible molecular mechanism for the physiological functions of Pgrmc2 in the regulation of female fertility, likely via regulation of receptors and steroids in the ovary, which in turn regulates oocyte maturation in zebrafish.

Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects.

Phosphodiesterase type 4 (PDE4) inhibitors can prevent the breakdown of the second messenger cyclic adenosine monophosphate (cAMP) and improve cognitive performances in several animal models of cognition. However, the clinical development of PDE4 inhibitors has been seriously hampered by severe side effects, such as vomiting and nausea. In this study, we investigated the effect and mechanism of roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), on learning and memory abilities in the APP/PS1 mouse model of Alzheimer's disease (AD). APP/PS1 transgenic mice received 3 intragastric doses of roflumilast (0.1, 0.2 and 0.4 mg/kg) daily for 3 weeks followed by behavioral tests. Chronic administration of roflumilast significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the novel object recognition task, Morris water maze, and the step-down passive avoidance task. In addition, roflumilast increased the cAMP, phosphorylated cAMP response-element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels, and reduced the nuclear translocation of nuclear factor-kappa B (NF-κB) p65, and proinflammatory cytokine (IL-6, TNF-a and IL-1ß) levels in the hippocampus of APP/PS1 transgenic mice. In conclusion, these findings suggest that roflumilast can enhance cognitive function in APP/PS1 transgenic mice, which may be related to its stimulation of the cAMP/CREB/BDNF pathway and anti-neuroinflammatory effects.

Clinical manifestations and cerebrospinal fluid status in ocular syphilis in HIV-Negative patients.

BACKGROUND: Syphilis with ocular involvement has reemerged as a critical health problem. The aim of the present study was to explore the clinical manifestations and cerebrospinal fluid (CSF) status in ocular syphilis in human immunodeficiency virus (HIV)-negative patients. METHODS: The clinical records of patients with ocular syphilis presenting to the Shanghai Xuhui Central Hospital in the period from January 2011 to December 2012 were retrospectively reviewed. RESULTS: The median age of 25 HIV-negative patients with ocular syphilis was 53 years, 18 patients (72.0 %) were males and 7 (28.0 %) were females. None of them self-identified themselves as men who had sex with men (MSM). The ocular lesions included: uveitis (13 cases), optic neuropathy (6 cases), retinal vasculitis (5 cases), retinal detachment (3 cases), and neuroretinitis (4 cases). Serum toluidine red unheated serum test (TRUST) titer ranged from 1 to 512, with a median of 64. Overall, 18 (72.0 %) of the 25 patients had abnormal CSF results, 15 (60.0 %) CSF samples had elevated white blood cell counts, 13 (52.0 %) had elevated protein levels, and 9 (36.0 %) had reactive CSF Venereal Disease Research Laboratory (VDRL) test, respectively. Mann-Whitney U tests showed higher serum TRUST titer (>32) correlated with the abnormal CSF results. CONCLUSIONS: The demographic characteristics of patients with ocular syphilis in this study were different from previous reports. The study showed a high CSF abnormal rate in HIV-negative patients. The recommendation for CSF examination from all patients with ocular syphilis, including HIV-negative cases, is strongly supported by the present data.

A Steel Wire Stress Measuring Sensor Based on the Static Magnetization by Permanent Magnets.

A new stress measuring sensor is proposed to evaluate the axial stress in steel wires. Without using excitation and induction coils, the sensor mainly consists of a static magnetization unit made of permanent magnets and a magnetic field measurement unit containing Hall element arrays. Firstly, the principle is illustrated in detail. Under the excitation of the magnetization unit, a spatially varying magnetized region in the steel wire is utilized as the measurement region. Radial and axial magnetic flux densities at different lift-offs in this region are measured by the measurement unit to calculate the differential permeability curve and magnetization curve. Feature parameters extracted from the curves are used to evaluate the axial stress. Secondly, the special stress sensor for Φ5 and Φ7 steel wires is developed accordingly. At last, the performance of the sensor is tested experimentally. Experimental results show that the sensor can measure the magnetization curve accurately with the error in the range of ±6%. Furthermore, the obtained differential permeability at working points 1200 A/m and 10000 A/m change almost linearly with the stress in steel wires, the goodness of linear fits are all higher than 0.987. Thus, the proposed steel wire stress measuring sensor is feasible.

A Longitudinal Mode Electromagnetic Acoustic Transducer (EMAT) Based on a Permanent Magnet Chain for Pipe Inspection.

A new electromagnetic acoustic transducer (EMAT) design, employing a special structure of the permanent magnet chain, is proposed to generate and receive longitudinal guided waves for pipe inspection based on the magnetostriction mechanism. Firstly, a quantitative analysis of the excitation forces shows the influence of the radial component can be ignored. Furthermore, as the axial component of the static magnetic field is dominant, a method of solenoid testing coils connected in series is adopted to increase the signal amplitude. Then, two EMAT configurations are developed to generate and receive the L(0,2) guided wave mode. The experimental results show the circumferential notch can be identified and located successfully. Finally, a detailed investigation of the performance of the proposed EMATs is given. Compared to the conventional EMAT configuration, the proposed configurations have the advantages of small volume, light weight, easy installation and portability, which is helpful to improve inspection efficiency.

L-Valine derived chiral N-sulfinamides as effective organocatalysts for the asymmetric hydrosilylation of N-alkyl and N-aryl protected ketimines.

L-Valine derived N-sulfinamides have been developed as efficient enantioselective Lewis basic organocatalysts for the asymmetric reduction of N-aryl and N-alkyl ketimines with trichlorosilane. Catalyst 3c afforded up to 99% yield and 96% ee in the reduction of N-alkyl ketimines and up to 98% yield and 98% ee in the reduction of N-aryl ketimines.

Enhancement of the excitation efficiency of a torsional wave PPM EMAT array for pipe inspection by optimizing the element number of the array based on 3-D FEM.

Electromagnetic acoustic transducers (EMATs) can generate non-dispersive T(0,1) mode guided waves in a metallic pipe for nondestructive testing (NDT) by using a periodic permanent magnet (PPM) EMAT circular array. In order to enhance the excitation efficiency of the sensor, the effects of varying the number of elements of the array on the excitation efficiency is studied in this paper. The transduction process of the PPM EMAT array is studied based on 3-D finite element method (FEM). The passing signal amplitude of the torsional wave is obtained to represent the excitation efficiency of the sensor. Models with different numbers of elements are established and the results are compared to obtain an optimal element number. The simulation result is verified by experiments. It is shown that after optimization, the amplitudes of both the passing signal and defect signal with the optimal element number are increased by 29%, which verifies the feasibility of this optimal method. The essence of the optimization is to find the best match between the static magnetic field and the eddy current field in a limited circumferential space to obtain the maximum circumferential Lorentz force.

A guided wave sensor based on the inverse magnetostrictive effect for distinguishing symmetric from asymmetric features in pipes.

The magnetostrictive guided wave sensor with a single induced winding cannot distinguish axially symmetric from non-axially symmetric features in a pipe, because it is impossible for the sensor to detect the non-axially symmetric mode waves. When we study the effect of the change of the magnetic field in the air zone for receiving the longitudinal guided wave mode, we find that the change of the magnetic flux in the air zone is almost equivalent to the change of the flux in the pipe wall, but in opposite directions. Based on this phenomenon, we present a sensor that can detect the flexural-mode waves in pipes based on the inverse magnetostrictive effect. The sensor is composed of several coils that are arranged evenly on the outside of pipes. The coils induce a change in magnetic flux in the air to detect the flexural-mode waves. The waves can be determined by adding a phase delay to the induced signals. The symmetric and asymmetric features of a pipe can be distinguished using the sensor. A prototype sensor that can detect F(1,3) and F(2,3) mode waves is presented. The function of the sensor is verified by experiments.

Enhancement of the excitation efficiency of the non-contact magnetostrictive sensor for pipe inspection by adjusting the alternating magnetic field axial length.

The non-contact magnetostrictive sensor (MsS) has been widely used in the guided wave testing of pipes, cables, and so on. However, it has a disadvantage of low excitation efficiency. A new method for enhancing the excitation efficiency of the non-contact MsS for pipe inspection using guided waves, by adjusting the axial length of the excitation magnetic field, is proposed. A special transmitter structure, in which two copper rings are added beside the transmitter coil, is used to adjust the axial length at the expense of weakening the excitation magnetic field. An equivalent vibration model is presented to analyze the influence of the axial length variation. The final result is investigated by experiments. Results show that the excitation efficiency of the non-contact MsS is enhanced in the whole inspection frequency range of the L(0,2) mode if the axial length is adjusted to a certain value. Moreover that certain axial length is the same for pipes of different sizes but made of the same material.

Tetherless and Batteryless Soft Navigators and Grippers.

Remotely controllable soft actuators have promising potential applications in many fields including soft robotics, exploration, and invasion medical treatment. Shape memory polymers could store and release energy, resulting in shape deformation, and have been regarded as promising candidates to fabricate untethered soft robots. Herein, an untethered and battery-free soft navigator and gripper based on a shape memory hydrogel is presented. The shape memory hydrogel is obtained through hydrogen bonding between gelatin and tannic acid, and the hydrogel displays excellent shape memory properties on the basis of hydrogen bonding and the coil-triple helix transition of gelatin. Moreover, Fe3O4 nanoparticles are introduced to endow the hydrogel magnetic responsiveness and photothermal conversion capacity. Finally, the shape memory hydrogel in a stretched state is assembled with an inert hydrogel to achieve a bilayer hydrogel actuator, which could produce complex shape transformation due to the shape recovery of the shape memory layer induced by heat or light. Taking advantage of the magnetically control and light-responsive shape deformation, remotely controllable soft grippers that could navigate through tortuous paths and grasp objects from a hard-to-reach place have been accomplished. This approach will inspire the design and fabrication of novel shape memory hydrogels as remotely controllable soft robots.

Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma.

Tumor suppressor in lung cancer 1 (TSLC1) is tightly implicated in a variety of biological processes and plays critical roles in tumor development and progression. However, the roles of TSLC1 in cutaneous squamous cell carcinoma (CSCC) remain to be unraveled. Here, we reported the TSLC1 gene that was significantly downregulated in CSCC tissues and cells, and survival times of patients with TSLC1 at a low level were markedly lower than that at a high level (P = 0.0070). A stepwise investigation demonstrated that an elevated TSLC1 level evoked obvious proliferation and invasion inhibitions and arrested cell cycle at G0/G1 phase in A431 cells. Moreover, increase of caspase-3 activity mediated by elevated TSLC1 level induced cell apoptosis in A431 cells. Most notably, upregulation of TSLC1 expression reduced the numbers of colony formation and tumorigenicity. Collectively, our results presented herein suggest that TSLC1 as tumor suppressor may play prominent roles in development and progression of CSCC via regulation of different biological processes.

Deleting specific residues from the HNH linkers creates a CRISPR-SpCas9 variant with high fidelity and efficiency.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) systems are immunological defenses used in archaea and bacteria to recognize and destroy DNA from external invaders. The CRISPR-SpCas9 system harnessed from Streptococcus pyogenes (SpCas9) has become the most widely utilized genome editing tool and shows promise for clinical application. However, the off-target effect is still the major challenge for the genome editing of CRISPR-SpCas9. Based on analysis of the structure and cleavage procedures, we proposed two strategies to modify the SpCas9 structure and reduce off-target effects. Shortening the HNH or REC3 linkers (Strategy #1) aimed to move the primary position of HNH or REC3 far away from the single-guide RNA (sgRNA)/DNA hybrid (hybrid), while elongating the helix around the sgRNA (Strategy #2) aimed to strengthen the contacts between SpCas9 and the sgRNA/DNA. We designed 11 SpCas9 variants (variant No.1- variant No.11) and verified their efficiencies on the classic genome site EMX1-1, EMX1-1-OT1, and EMX1-1-OT2. The top three effective SpCas9 variants, variant No.1, variant No.2, and variant No.5, were additionally validated on other genome sites. The further selected variant No.1 was compared with two previous SpCas9 variants, HypaCas9 (a hyper-accurate Cas9 variant released in 2017) and eSpCas9 (1.1) (an "enhanced specificity" SpCas9 variant released in 2016), on two genome sites, EMX1-1 and FANCF-1. The results revealed that the deletion of Thr769 and Gly906 could substantially decrease off-target effects, while maintaining robust on-target efficiency in most of the selected genome sites.

Kaposi's sarcoma-associated herpesvirus viral protein kinase augments cell survival.

Oncogenic viruses have developed various strategies to antagonize cell death and maintain lifelong persistence in their host, a relationship that may contribute to cancer development. Understanding how viruses inhibit cell death is essential for understanding viral oncogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with three different cancers in the human population, including Kaposi's sarcoma (KS), the most common cancer in HIV patients. Previous studies have indicated that the KSHV-encoded viral protein kinase (vPK) impacts many processes dysregulated in tumorigenesis. Here, we report that vPK protects cells from apoptosis mediated by Caspase-3. Human umbilical vein endothelial cells (HUVECs) expressing vPK (HUVEC-vPK) have a survival advantage over control HUVEC under conditions of extrinsic- and intrinsic-mediated apoptosis. Abolishing the catalytic activity of vPK attenuated this survival advantage. We found that KSHV vPK-expressing HUVECs exhibited increased activation of cellular AKT kinase, a cell survival kinase, compared to control cells without vPK. In addition, we report that vPK directly binds the pleckstrin homology (PH) domain of AKT1 but not AKT2 or AKT3. Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. Furthermore, vPK expression activated VEGF/VEGFR2 in HUVECs and promoted angiogenesis through the AKT pathway. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK's ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers.

A magnetic flux leakage and magnetostrictive guided wave hybrid transducer for detecting bridge cables.

Condition assessment of cables has gained considerable attention for the bridge safety. A magnetic flux leakage and magnetostrictive guided wave hybrid transducer is provided to inspect bridge cables. The similarities and differences between the two methods are investigated. The hybrid transducer for bridge cables consists of an aluminum framework, climbing modules, embedded magnetizers and a ribbon coil. The static axial magnetic field provided by the magnetizers meets the needs of the magnetic flux leakage testing and the magnetostrictive guided wave testing. The magnetizers also provide the attraction for the climbing modules. In the magnetic flux leakage testing for the free length of cable, the coil induces the axial leakage magnetic field. In the magnetostrictive guided wave testing for the anchorage zone, the coil provides a pulse high power variational magnetic field for generating guided waves; the coil induces the magnetic field variation for receiving guided waves. The experimental results show that the transducer with the corresponding inspection system could be applied to detect the broken wires in the free length and in the anchorage zone of bridge cables.

Oncogenic viruses, cancer biology, and innate immunity.

Malignancies that arise as a result of viral infection account for roughly 15% of cancer cases worldwide. The innate immune system is the body's first line of defense against oncogenic viral infection and is also involved in the response against viral-driven tumors. In this review, we discuss research advances made over the last five years elucidating how the innate immune system recognizes and responds to oncogenic viruses, how these viruses have evolved to escape this immune pressure, and ways that innate immunity can inform the development of novel therapeutics against oncogenic viral infection and their associated cancers.

Reduced Vitellogenesis and Female Fertility in Gper Knockout Zebrafish.

The role G-protein coupled estrogen receptor (GPER) plays in vertebrate reproduction remains controversial. To investigate GPER's reproductive role, we generated a gper zebrafish mutant line (gper-/- ) using TALENs. Gper mutant females exhibited reduced fertility with a 40.85% decrease in embryo production which was associated with a significant decrease in the number of Stage V (730-750 µm) ovulated oocytes. Correspondingly, the number of early vitellogenic follicles (Stage III, 400-450 µm) in gper-/- ovaries was greater than that in wildtypes (wt), suggesting that subsequent follicle development was retarded in the gper-/- fish. Moreover, plasma vitellogenin levels were decreased in gper-/- females, and epidermal growth factor receptor (Egfr) expression was lower in Stage III vitellogenic oocytes than in wt counterparts. However, hepatic nuclear estrogen receptor levels were not altered, and estrogen levels were elevated in ovarian follicles. These results suggest that Gper is involved in the control of ovarian follicle development via regulation of vitellogenesis and Egfr expression in zebrafish.