PTPN3 acts as a tumor suppressor and boosts TGF-ß signaling independent of its phosphatase activity.

TGF-ß controls a variety of cellular functions during development. Abnormal TGF-ß responses are commonly found in human diseases such as cancer, suggesting that TGF-ß signaling must be tightly regulated. Here, we report that protein tyrosine phosphatase non-receptor 3 (PTPN3) profoundly potentiates TGF-ß signaling independent of its phosphatase activity. PTPN3 stabilizes TGF-ß type I receptor (TßRI) through attenuating the interaction between Smurf2 and TßRI. Consequently, PTPN3 facilitates TGF-ß-induced R-Smad phosphorylation, transcriptional responses, and subsequent physiological responses. Importantly, the leucine-to-arginine substitution at amino acid residue 232 (L232R) of PTPN3, a frequent mutation found in intrahepatic cholangiocarcinoma (ICC), disables its role in enhancing TGF-ß signaling and abolishes its tumor-suppressive function. Our findings have revealed a vital role of PTPN3 in regulating TGF-ß signaling during normal physiology and pathogenesis.

Smad7 enables STAT3 activation and promotes pluripotency independent of TGF-ß signaling.

Smad7 is a negative feedback product of TGF-ß superfamily signaling and fine tunes a plethora of pleiotropic responses induced by TGF-ß ligands. However, its noncanonical functions independent of TGF-ß signaling remain to be elucidated. Here, we show that Smad7 activates signal transducers and activators of transcription 3 (STAT3) signaling in maintaining mouse embryonic stem cell pluripotency in a manner independent of the TGF-ß receptors, yet dependent on the leukemia inhibitory factor (LIF) coreceptor glycoprotein 130 (gp130). Smad7 directly binds to the intracellular domain of gp130 and disrupts the SHP2-gp130 or SOCS3-gp130 complex, thereby amplifying STAT3 activation. Consequently, Smad7 facilitates LIF-mediated self-renewal of mouse ESCs and is also critical for induced pluripotent stem cell reprogramming. This finding illustrates an uncovered role of the Smad7-STAT3 interplay in maintaining cell pluripotency and also implicates a mechanism involving Smad7 underlying cytokine-dependent regulation of cancer and inflammation.

High-performance flexible thin-film transistors exfoliated from bulk wafer.

Mechanically flexible integrated circuits (ICs) have gained increasing attention in recent years with emerging markets in portable electronics. Although a number of thin-film-transistor (TFT) IC solutions have been reported, challenges still remain for the fabrication of inexpensive, high-performance flexible devices. We report a simple and straightforward solution: mechanically exfoliating a thin Si film containing ICs. Transistors and circuits can be prefabricated on bulk silicon wafer with the conventional complementary metal-oxide-semiconductor (CMOS) process flow without additional temperature or process limitations. The short channel MOSFETs exhibit similar electrical performance before and after exfoliation. This exfoliation process also provides a fast and economical approach to producing thinned silicon wafers, which is a key enabler for three-dimensional (3D) silicon integration based on Through Silicon Vias (TSVs).

[Electroacupuncture intervention improves lipid metabolism and promotes browning of white adipose tissue by activating AMPK/Sirt1 pathway and up-regulating Nrg4 content in middle-aged and aged obese rats].

OBJECTIVE: To investigate the mechanism of electroacupuncture （EA） in promoting the browning of white adipose tissue in middle-aged and aged obese rats induced by high fat by regulating AMP-activated protein kinase （AMPK） /silence-information regulatory factor 1 （Sirt1） pathway and neuregulin 4 （Nrg4）. METHODS: Twenty-four male SD rats were randomized into blank control, model and EA groups （n=8 per group）. The obesity model was established by feeding the rats with high-fat diet for 6 weeks. For the EA group, EA （2 Hz/15 Hz, 1.5 mA） was applied to "Guanyuan" （CV4） and bilateral "Shenshu" （BL23）, "Fenglong" （ST40） and "Tianshu" （ST25） for 20 min, once a day, 5 days a week for 6 weeks. Rats of the blank control and model groups were also restrained for 20 min. The body mass and food intake were measured every week, and the Lee's index, epididymal fat, perirenal fat and brown adipose tissue were weighed. The contents of serum total cholesterol （TC）, triglyceride （TG）, high density lipoprotein cholesterol （HDL-C）, low density lipoprotein cholesterol （LDL-C） and norepinephrine （NE） were determined by ELISA. H.E. staining was used to observe the morphological changes of white and brown adipose tissue. The mRNA expression levels of mitochondrial uncoupling protein 1 （UCP1）, peroxisome proliferator activated receptor γ co-activator 1α （PGC-1α）, PR-domain protein 16 （PRDM16）, peroxisome proliferator activated receptor γ （PPARγ） and Nrg4 in the adipose tissue were detected by quantitative real time PCR, and the protein expression levels of Nrg4, AMPKα, Sirt1 and interleukin-6 （IL-6） in the white and brown adipose tissue were detected by Western blot. RESULTS: Compared with the blank control group, the body mass, food intake, the Lee's index, epididymal fat and perirenal fat mass, and serum TG, TC and LDL-C contents and the expression level of IL-6 protein were significantly increased （P<0.01, P<0.05, P<0.001）, and the brown adipose mass, serum HDL-C and NE contents, the expression levels of UCP1, PGC-1α, PRDM16, PPARγ and Nrg4 mRNAs, and the protein expression levels of AMPKα, Sirt1 and Nrg4 proteins in both white and brown adipose tissues were significantly decreased in the model group （P<0.01, P<0.05）. After EA intervention, the increased levels of body mass, food intake, Lee's index, epididymal fat and perirenal fat mass, serum TG, TC and LDL-C contents, and the expression of IL-6 protein, and the decreased levels of brown adipose mass, serum HDL-C and NE contents, expression levels of UCP1, PGC-1α, PRDM16, PPARγ and Nrg4 mRNAs, and those of AMPKα, Sirt1 and Nrg4 proteins in both white and brown adipose tissues were apparently reversed（P<0.05, P<0.01, P<0.001）. H.E. staining showed an increase of the volume and content of intracellular vacuoles of both white and brown adipose tissues, disordered arrangement of cells with vague boundary in the model group, which was relatively milder including a decrease of volume and content of vacuoles of both white and brown adipose, neat arrangement of cells with clear boundary. CONCLUSION: EA intervention can improve lipid metabolism and promote white adipose tissue browning in middle-aged and aged obese rats, which is possibly associated with its functions in activating AMPK/Sirt1 signaling pathway and up-regulating the level of Nrg4.

Behavioral responses of two captive bottlenose dolphins (Tursiops truncatus) to a continuous 50 kHz tone.

At present, the fundamental frequencies of signals of most commercially available acoustic alarms to deter small cetaceans are below 20 kHz, but it is not well ascertained whether higher frequencies have a deterrent effect on bottlenose dolphins (Tursiops truncatus). Two captive bottlenose dolphins housed in a floating pen were subjected to a continuous pure tone at 50 kHz with a source level of 160 ± 2 dB (re 1 µPa, rms). The behavioral responses of dolphins were judged by comparing surfacing distance relative to the sound source, number of surfacings, and number of echolocation clicks produced, during forty 15 min baseline periods with forty 15 min test periods (four sessions per day, 40 sessions in total). On all 10 study days, surfacing distance and the number of surfacings increased while click production decreased during broadcasts of test sound. The avoidance threshold sound pressure level for a continuous 50 kHz tone for the bottlenose dolphins, in the context of this study, was estimated to be 144 ± 2 dB (re 1 µPa, rms). The results indicated that a continuous 50 kHz tonal signal can deter bottlenose dolphins from an area.

Protein tyrosine phosphatase PTPN2 regulates TGF-ß signaling through Smad4 dephosphorylation.

Transforming Growth Factor beta (TGF-ß) is a multifunctional cytokine that regulates cell proliferation, differentiation, and apoptosis. Dysregulation of the TGF-ß signaling is one of the major mechanisms underlying tumor progression. We have previously reported that anaplastic lymphoma kinase (ALK) phosphorylates Smad4 at Tyr95, which compromises the DNA-binding ability of Smad4 and thus renders ALK-positive cancer cells resistant to TGF-ß tumor-suppressive action. In this study, we demonstrated that tyrosine phosphatase PTPN2 positively regulated TGF-ß signaling through dephosphorylating Smad4 at the Tyr95 site. Both in vitro and cell-based assays revealed that PTPN2 bound to and dephosphorylated Smad4, thereby preserving the DNA-binding ability of Smad4. Furthermore, overexpression of PTPN2 restored TGF-ß transcriptional and growth inhibitory responses in ALK-positive cancer cells. Consistently, Spermidine, an activator of PTPN2, also promoted TGF-ß-induced gene expression, apoptosis, and anti-proliferation effect. Taken together, we revealed that PTPN2 functioned as a tumor suppressor to antagonize the inhibitory effect of tyrosine phosphorylation of Smad4 and to ensure the proper TGF-ß growth inhibitory signaling in cancer cells.

Mechanical probing of icelike water monolayers.

Direct measurements of the normal force interactions between a mica-tungsten contact pair at various humidity levels reveal the presence of repulsive forces at about 0.5 nm before intimate contact. Such repulsive interactions begin to appear above 20% RH and are fully developed in the range of 38-45% RH. Using the DMT model of contact, a reduced elastic modulus of approximately 6.7 GPa is extracted from these repulsive interactions and attributed to the presence of icelike water on mica at room temperature. The collapse of such structures was also inferred from the measurements.

On scale dependence in friction: transition from intimate to monolayer-lubricated contact.

Scale dependence in friction is studied in the present paper using the newly developed mesoscale friction tester (MFT). A transition in frictional shear strength from several hundreds of MPa to several tens of MPa was observed over a very limited range of contact radii (20-30 nm) in both ambient and dry environments. Thus, a single apparatus has been able to establish these two limits which are consistent with the values previously obtained from friction experiments using atomic force microscopy (AFM) and the surface force apparatus (SFA), respectively. Consequently, it is hypothesized here that a shear strength in the hundreds of MPa results from intimate contact (solid-solid) and a shear strength in the tens of MPa results from a monolayer-lubricated contact. Furthermore, both the probe size and the normal pressure govern the interfacial conditions in the contact zone and it is these conditions, rather than the nominal environment, which in turn determine the resulting shear strengths. A continuum analysis based on the Lifshitz theory for van der Waals interactions is used to explain the quantized shear strengths which were obtained from our experiments and previous AFM and SFA friction experiments. This quantized friction behavior [J.N. Israelachvili, P.M. McGuiggan, A.M. Homola, Science 240 (1988) 189] results from the discrete separation due to the different interfacial conditions that can arise between two sliding surfaces. The consistency between the analysis and the experimental results shows that this analysis is applicable for nonwear friction with single asperity contact.

On the modified Tabor parameter for the JKR-DMT transition in the presence of a liquid meniscus.

The JKR, DMT, Maugis models and Tabor parameter for contact under normal loading have been developed based mainly on solid-solid (van der Waals) interactions. In this case, the characteristic length scale for the adhesive forces in the Tabor parameter is the equilibrium interatomic spacing. However, for contact in humid environments, where a liquid meniscus may be present, capillary forces with a longer force range related to the Kelvin radius dominate. Fogden and White [J. Colloid Interface Sci. 138 (1990) 414] introduced a parameter that includes the Kelvin radius for the JKR-DMT transition. This topic was also addressed by Maugis and Gauthier-Manuel [J. Adhes. Sci. Technol. 8 (1994) 1311] who included capillary effects within the frame work that Maugis had previously established. The parameters introduced by Fogden and White and Maugis and Gauthier-Manuel can be viewed as a modified Tabor parameter for the JKR-DMT transition. In the present work, the Kelvin equation linking the Kelvin radius and the relative humidity was explicitly included in the modified Tabor parameter. This provided a quantitative description of the JKR-DMT transition in terms of the relative humidity. This parameter was examined via load and contact radius measurements, where the latter were obtained from Bowden and Tabor's assumption that the friction force f=tauA. The friction experiments were conducted at two different humidity levels using a newly-developed mesoscale friction tester (MFT), which provides a very wide range of contact radii. The modified Tabor parameter was used to reexamine data from pull-off experiments in water and cyclohexane vapor environments [L.R. Fisher, J.N. Israelachvili, Colloids Surf. 3 (1981) 303 and H.K. Christenson, J. Colloid Interface Sci. 121 (1988) 170]. Finally, guidelines are presented for the appropriate choice of contact mechanics models to be used in interpreting data from SFA and AFM experiments in humid environments.

Mesoscale scanning probe tips with subnanometer rms roughness.

Surface smoothness of probe tips is critical for applications, such as measuring surface tension of various liquids, oscillatory hydration forces, and interfacial shear strengths from friction experiments. In this study we establish conditions for fabricating tips with smooth surfaces by controlling the electrochemical polishing process throughout the tip evolution rather than following the current practice of producing tips by the drop-off method. Polishing is conducted under a constant voltage, with the wire immersed below the nominal air/electrolyte interface by no more than one-half of the wire diameter and stopping the etching at different current levels. This process provides a tip radius range of approximately 100 nm to 5 microm for a tungsten wire with a 0.2 mm diameter. Alternatively, the wire can be placed above the nominal air/electrolyte interface but within the meniscus until the current drops to zero. In this case, the tip radii range from 5 to 50 microm. In both cases, atomic force microscopy scans of these tips show that the surface rms roughness is about 0.3 nm.