Highly stretchable strain sensors based on conducting polymer hydrogel are rapidly emerging as a promising candidate toward diverse wearable skins and sensing devices for soft machines. However, due to the intrinsic limitations of low stretchability and large hysteresis, existing strain sensors cannot fully exploit their potential when used in wearable or robotic systems. Here, a conducting polymer hydrogel strain sensor exhibiting both ultimate strain (300%) and negligible hysteresis (<1.5%) is presented. This is achieved through a unique microphase semiseparated network design by compositing poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) nanofibers with poly(vinyl alcohol) (PVA) and facile fabrication by combining 3D printing and successive freeze‐thawing. The overall superior performances of the strain sensor including stretchability, linearity, cyclic stability, and robustness against mechanical twisting and pressing are systematically characterized. The integration and application of such strain sensor with electronic skins are further demonstrated to measure various physiological signals, identify hand gestures, enable a soft gripper for objection recognition, and remote control of an industrial robot. This work may offer both promising conducting polymer hydrogels with enhanced sensing functionalities and technical platforms toward stretchable electronic skins and intelligent robotic systems.

BackgroundMuscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF‐1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation.MethodsUsing in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone.ResultsUsing cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD‐induced or dexamethasone‐induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF‐β, IL‐6 and TNFα), which are initiators of muscle‐specific ubiquitin‐E3 ligases (e.g. Atrogin‐1, MuRF‐1 and MUSA1).ConclusionsUrsolic acid improves CKD‐induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis.

The treatment for osteoporosis involves inhibiting bone resorption and osteoclastogenesis. Glycyrrhizin (GLY) is a triterpenoid saponin glycoside known to be as the most medically efficacious component of the licorice plant. It has strong anti-inflammatory, antioxidant, and antitumor properties. We investigated the effect of GLY on osteoclastogenesis, bone resorption, and intracellular oxidative stress and its molecular mechanisms. In vitro osteoclastogenesis assays were performed using bone marrow monocytes with and without glycyrrhizin. We also evaluated the effects of glycyrrhizin on the secretion of TNF-α, IL-1β, and IL-6 in LPS-stimulated RAW 264.7 cells using ELISA. The effects of glycyrrhizin on the expression of osteoclast-related genes, such as Nfatc1, c-fos, Trap, and cathepsin K (CK), were investigated by RT-PCR. Intracellular reactive oxygen species (ROS) were detected in receptor activator of nuclear factor kappa-Β ligand (RANKL)-stimulated osteoclasts in the presence and absence of glycyrrhizin. During the inhibition of osteoclastogenesis by glycyrrhizin, phosphorylation of AMPK, Nrf2, NF-κB, and MAPK was analyzed using western blotting. Our results showed that glycyrrhizin significantly inhibited RANKL-induced osteoclastogenesis, downregulated the expression of NFATc1, c-fos, TRAP, CK, DC-STAMP, and OSCAR, and inhibited p65, p38, and JNK. Glycyrrhizin was found to significantly decrease the secretion of inflammatory cytokines (TNF-α, IL-1β, and IL-6). Additionally, glycyrrhizin reduced the formation of ROS in osteoclasts by inducing AMPK phosphorylation and nuclear transfer of NRF2, resulting in an upregulation of antioxidant enzymes, such as HO-1, NQO-1, and GCLC. In summary, we found that glycyrrhizin inhibited RANKL-induced osteoclastogenesis. It was also indicated that glycyrrhizin could reduce oxidative stress by inhibiting the MAPK and NF-κB pathways and activating the AMPK/NRF2 signaling. Therefore, glycyrrhizin may be used as an effective therapeutic agent against osteoporosis and bone resorption.

In patients with CKD, muscle wasting is common and is associated with morbidity and mortality. Mechanisms leading to loss of muscle proteins include insulin resistance, which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system. However, the specific factors controlling CKDinduced suppression of Akt activity in muscle remain undefined. In mice with CKD, the reduction in Akt activity in muscle exceeded the decrease in upstream insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, suggesting that CKD activates other pathways that suppress Akt. Furthermore, a CKDinduced increase uncovered caspase-3 activity in muscle in these mice. In C2C12 muscle cells, activated caspase-3 cleaves and activates Rho-associated protein kinase 1 (ROCK1), which enhances the activity of phosphatase and tensin homolog (PTEN) and reduces Akt activity. Notably, constitutive activation of ROCK1 also led to increased caspase-3 activity in vitro. In mice with either global ROCK1 knockout or muscle-specific PTEN knockout, CKD-associated muscle proteolysis was blunted. These results suggest ROCK1 activation in CKD and perhaps in other catabolic conditions can promote loss of muscle protein via a negative feedback loop.

Aberrant Wnt signaling mediated by mutations affecting APC (adenomatous polyposis coli) or b-catenin initiates the majority of human colorectal cancers (CRC) and drives tumorigenesis through the activation of specific genes such as MYC. We report here a novel association whereby another oncogenic transcription factor, MYB/c-Myb, is necessary for intestinal adenoma development directed by activated Wnt signaling. APC Min/ þ mice in which c-myb is haploinsufficient survive longer than wildtype APC Min/ þ animals due to a delay in adenoma formation. Intestinal adenomas from APC Min/ þ mice were assessed and found to have high levels of c-myc gene expression. We explored the relationship between activated Wnt signaling and MYB in regulating MYC and found activated b-catenin in combination with MYB induces robust upregulation of MYC promoter activity, as well as endogenous MYC mRNA and protein expression, in human cells. This cooperation occurred through independent binding of MYB and b-catenin to the MYC promoter. These data highlight a cooperative function for MYB in the context of activated Wnt signaling and provide a molecular basis for the expression of MYC in CRC. Robust expression of the transcription factor MYB/c-Myb is principally restricted to immature cells in the hemopoietic system and colon epithelium. Experiments in c-myb mutant mice show that two copies of the c-myb gene are required for cell survival during emergency responses to cytotoxic damage in both these compartments.1 In addition, colonspecific loss of Myb disrupts not only colon formation in the developing mouse, but also crypt homeostasis in adults.2 Levels of MYB expression become progressively higher as human colonic epithelium undergoes transformation whereas persistent expression blocks cytodifferentiation in both mouse and human colon cells. A large number of colorectal cancer (CRC) cell lines and clinical samples show elevated levels of MYB, with altered transcriptional elongation control underpinning this increase.1 Nevertheless, in the context of CRC development, the primary focus in both mouse and human cells has been on canonical Wnt signaling through b-catenin activation.b-Catenin is normally targeted for degradation by a complex of proteins including APC, AXIN, and glycogen synthase kinase-3b.3,4 Wnt binding to its receptor disrupts this complex and leads to the cytoplasmic stabilization of de novo synthesized and non-phosphorylated b-catenin. Given that a significant proportion of CRC isolates overexpress MYB and that this likely occurs in a background of activated Wnt signaling, we considered the contribution that MYB makes to CRC development initiated by Wnt pathway activation. We report here the convergence of MYB expression with Wnt signaling in regulating intestinal adenoma formation. In vivo mouse studies showed that reduced c-myb expression positively affects survival and that c-myb expression is a necessary feature of the carcinogenic process initiated by activated Wnt signaling. Further, to understand how c-Myb is contri...

Background: Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the clinical features and molecular defects of BWS patients in China. Methods: Thirty-one patients with clinical suspicion of BWS were retrospectively recruited to the study from Shanghai Children's Hospital between January 2014 and December 2017. Clinical data, including demographics, clinical features, and molecular testing results were extracted and systematically analyzed. Results: Twenty-one patients with a BWS score ≥ 4 (6, IQR 4, 7) were clinically diagnosed with BWS, and 10 children with a BWS score ≥ 2 and < 4 (2, IQR 2, 3) were clinically suspected BWS patients. The most common cardinal feature of clinically diagnosed patients was macroglossia (71.4%) followed by lateralized overgrowth (33.3%) and exomphalos (14.3%), and the major suggestive features were umbilical hernia and/or diastasis recti (65.0%) and ear creases or pits (61.9%). Among 10 clinically suspected BWS patients, macroglossia and lateralized overgrowth were observed in 3 (30%) and 2 (20%) patients, and umbilical hernia and/or diastasis recti occurred in 7 (70.0%) patients. Seven (33.3%) clinically diagnosed patients and 3 (30%) suspected patients were identified with loss of methylation at KCNQ1OT1:TSS differentially methylated region (DMR; IC2 LOM), 5 (23.8%) clinically diagnosed BWS patients were identified with gain of methylation at H19/IGF2:IG-DMR (IC1 GOM), and 1 (4.8%) clinically diagnosed BWS patients was identified with paternal uniparental isodisomy 11 (pUPD11). The phenotype-genotype correlation analysis showed no significant difference among patients with IC2 LOM, IC1 GOM, and pUPD11. Conclusions: The current study presents the first cohort study of BWS patients in mainland China. The clinical and molecular features of the patients are similar to those of other reported BWS patients in the Chinese population.

Chronic kidney disease (CKD) and related inflammatory responses stimulate protein-energy wasting, a complication causing loss of muscle mass. Primarily, muscle wasting results from accelerated protein degradation via autophagic/lysosomal and proteasomal pathways, but mechanisms regulating these proteolysis pathways remain unclear. Since dephosphorylation of FoxOs regulates ubiquitin/proteasome protein metabolism, we tested whether a novel nuclear phosphatase, the small C-terminal domain phosphatase (SCP) 4, regulates FoxOs signaling and, in turn, muscle wasting. In cultured mouse myoblast cells, SCP4 overexpression stimulated proteolysis while knockdown of SCP4 prevented the proteolysis stimulated by inflammatory cytokines. SCP4 overexpression led to nuclear accumulation of FoxO1/3a followed by increased expression of catabolic factors including myostatin, Atrogin-1 and MuRF-1, and induction of lysosomal-mediated proteolysis. Treatment of C2C12 myotubes with proinflammatory cytokines stimulated SCP4 expression in an NF-κB-dependent manner. In skeletal muscle of mice with CKD, SCP4 expression was up-regulated. Similarly, in skeletal muscle of patients with CKD, SCP4 expression was significantly increased. Knockdown of SCP4 significantly suppressed FoxO1/3a-mediated expression of Atrogin-1 and MuRF-1 and prevented muscle wasting in mice with CKD. Thus, SCP4 is a novel regulator of FoxO transcription factors and promotes cellular proteolysis. Hence, targeting SCP4 may prevent muscle wasting in CKD and possibly other catabolic conditions.

Context, Covert severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections could be seeding new outbreaks. How to identify asymptomatic SARS-CoV-2 infections early has become a global focus. Objective, To explore the roles of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies detection, nucleic acid tests and computed tomography (CT) scanning to identify asymptomatic SARS-CoV-2 infection. Design, The clinical data of 389 individuals with close contacts including in general characteristics, SARS-CoV-2 etiology, serum-specific IgM and IgG antibody detection and CT imaging results, were systematically analyzed. Results, The present study showed that only 89 of the 389 individuals with close contacts were positive after the first nucleic acid test, while 300 individuals were still negative after two nucleic acid tests. Among the 300 individuals, 75 did not have pneumonia, and the other 225 individuals had pulmonary imaging changes. A total of 143 individuals were eventually diagnosed as having asymptomatic infection through IgM antibody and IgG antibody detection. The sensitivity, specificity and false-negative rate of IgM and IgG antibody detection were approximately 97.1% (347/357), 95.3% (204/214) and 4.67% (10/214), respectively. It also indicated that over approximately 2 weeks, most individuals were both IgM positive and IgG positive, accounting for 68.57% (72/105). Over approximately 3 weeks, the proportion of IgM-positive and IgG-positive individuals decreased to 8.57% (9/105), and the proportion of IgM-negative and IgG-positive individuals increased to 76.19% (80/105). Conclusions, There are highlighted prospects of IgM/IgG antibody detection as a preferred method in identifying the individuals with asymptomatic SARS CoV-2 infection, especially combined with nucleic acid tests and pulmonary CT scanning.