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Rock mass quality serves as a vital index for predicting the stability and safety status of rock tunnel faces. In tunneling practice, the rock mass quality is often assessed via a combination of qualitative and quantitative parameters. However, due to the harsh on-site construction conditions, it is rather difficult to obtain some of the evaluation parameters which are essential for the rock mass quality prediction. In this study, a novel improved Swin Transformer is proposed to detect, segment, and quantify rock mass characteristic parameters such as water leakage, fractures, weak interlayers. The site experiment results demonstrate that the improved Swin Transformer achieves optimal segmentation results and achieving accuracies of 92%, 81%, and 86% for water leakage, fractures, and weak interlayers, respectively. A multi-source rock tunnel face characteristic (RTFC) dataset includes 11 parameters for predicting rock mass quality is established. Considering the limitations in predictive performance of incomplete evaluation parameters exist in this dataset, a novel tree-augmented naive Bayesian network (BN) is proposed to address the challenge of the incomplete dataset and achieved a prediction accuracy of 88%. In comparison with other commonly used Machine Learning models the proposed BN-based approach proved an improved performance on predicting the rock mass quality with the incomplete dataset. By utilizing the established BN, a further sensitivity analysis is conducted to quantitatively evaluate the importance of the various parameters, results indicate that the rock strength and fractures parameter exert the most significant influence on rock mass quality.

Summary: Multiple sampling strategies to cover different or dynamic stages of malignant continuum with organoid cultures provide a valuable platform for epithelium homeostasis, transformation, and cancer progression. Here, we present a protocol to initiate, culture, passage, and characterize organoids from normal and cancer-prone human esophageal tissues. We describe steps for multiple sampling of malignant continuum and the initiation and maintenance of multi-stage organoids. We then detail procedures for the histological characterization of organoids and co-culture systems based on organoids and stromal cells.For complete details on the use and execution of this protocol, please refer to Chen et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Objective: Investigating the effects of MYB proto-oncogene like 2 (MYBL2)-mediated regulation of Cell division cycle associated 8 (CDCA8) expression on the biological activity of cutaneous malignant melanoma cells. Methods: A375 cells with MYBL2 and CDCA8 overexpression and knockdown were evaluated using migration, invasion, and proliferation assays. Besides, cell apoptosis was quantified by flow cytometry. To investigate the tumorigenic effects of MYBL2 knockdown in vivo, A375 cells with MYBL2 knockdown were injected in BALB/C nude mice. Results: The levels of MYBL2 and CDCA8 gene expression were notably elevated in A375 cells in comparison to HaCat cells (P

Vitamin C (VC) possesses antioxidant and whitening effects. However, its effectiveness is hindered by challenges such as instability, impaired solubility, and limited bioavailability hinder. In this study, VC was encapsulated in nanoliposomes by primary emulsification and high-pressure homogenization. The VC nanoliposomes were comprehensively characterized for their microscopic morphology, particle size, polydispersity index (PDI), and encapsulation efficiency (EE). Orthogonal experiments were designed to optimize the optimal preparation process, and the antioxidant activity, whitening efficacy, transdermal absorption, and stability of VC nanoliposomes were evaluated based on this optimized process. The findings demonstrated the high reproducibility of the optimal process, with particle size, PDI, and EE values of 113.502 ± 4.360 nm, 0.104 ± 0.010, and 56.09 ± 1.01 %, respectively. Differential scanning calorimetry analysis showed effective encapsulation of VC nanoliposomes with better thermal stability than aqueous VC solution. Besides, the VC nanoliposomes demonstrated excellent antioxidant and whitening effects in efficacy experiments, stronger skin permeability in transdermal experiments and fluorescence tracking. Furthermore, storage stability tests indicated that the VC in nanoliposomes remained relatively stable after 60 days of storage. These findings highlighted the potential use of VC nanoliposomes in a wide range of applications for the cosmetic market, especially in the development of ingredients for skin care products.

To address the practical application challenges of conductive polymer composites (CPCs) in portable electronics equipment, such as their low thermal conductivity (TC) and poor electromagnetic interference (EMI) shielding effectiveness (EMI SE), it is crucial to improve their TC, electrical conductivity(σ), and EMI SE of CPCs. In this work, we present a conducting composite made of ultrahigh molecular weight polyethylene (UHMWPE) and carbon nanostructures (CNS) with a unique segregated structure. This structure is achieved through a simple high-speed mechanical mixing and compression molding process. Microscopy characteristics demonstrated that both the matrix and segregated conductive network were in-situ oriented along the compress direction of UHMWPE granules under the static hot-pressing field. CNS are compacted together at the interface between UHMWPE granules to form an oriented and interconnected conductive pathways at low CNS loading levels. The resultant UHMWPE/CNS composites with 10 wt% CNS content exhibits excellent EMI shielding performance, with EMI SE of 60.7 dB (at X-band), high conductivity of 2.42 S/cm, and acceptable thermal conductivity of 0.7217 (W/m K). High EMI shielding performance and absorption dominant mechanism are beneficial from the unique segregated structure, and individual CNS coated UHMWPE granule are similar to an electromagnetic cage. Additionally, the ultimate tensile strength of the composite remains high at 37.6 MPa even at 10.0 wt% CNS loading, and it shows effective thermal stability. These properties are attributed to the strong interfacial bonding between CNS and UHMWPE. These materials have potential applications in efficient thermal management and EMI shielding for high-performance intelligent electrical devices.

In this study, graded tantalum scaffolds were manufactured by electron beam powder bed fusion (EB-PBF). Compression-compression fatigue testing was conducted on the EB-PBF built graded tantalum scaffolds. The compressive fatigue behavior and compressive fatigue strength of graded tantalum scaffolds with vertical gradient (VG) and parallel gradient (PG) states were investigated. In the fatigue testing, the failure of PG graded scaffold was concentrated on the lowest strength constituent, resulting in higher cyclic ratcheting strain and fatigue damage strain. In terms of the VG graded scaffold, due to the simultaneous uniform deformation of each structure, the strain accumulation in a single cycle was small, resulting in the low cyclic ratcheting strain. In addition, the propagation of fatigue cracks in pore structure with higher strength can be retarded by the stress redistribution, resulting in the low fatigue damage strain. Therefore, the design idea of graded pore structure under identical strain condition is beneficial to obtain porous tantalum scaffold with high compressive fatigue strength.

SiC, as a representative of the third generation semiconductors, is widely investigated in power devices and sensors. However, ohmic contacts, an important component for signal output of various SiC chips, have always faced challenges with unclear formation mechanism and difficulty to withstand high temperature. To solve such problems, two sets of NPN-type SiC ohmic contact were prepared, including Ti/TaSi2/Pt and Ni/W. Experimental results show that whether ohmic contact can be formed mainly depends on the contact metal. The alloy phase with lower work function is formed after high temperature annealing, which reduces the height and width of the Schottky barrier. For the prepared SiC ohmic contacts, It was demonstrated that the invasion of oxygen atoms cause contacts failure, and incorporation of barrier layer (Ta-based layer) and effective protective layer (Pt layer) determine whether high temperatures can be tolerated. Finally, piezoresistive 4H–SiC pressure sensor chips with dimensions of 3000 μm × 3000 μm × 200 μm were fabricated using the obtained ohmic contacts. Sensor chips output resistance were monitored up to 600 °C in air to show stability of the ohmic contact. The highly stable and high temperature ohmic contact can be applied in a variety of SiC devices.

Summary: Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresistance hinders its clinical effectiveness, and the underlying mechanism remains elusive. Here, we develop patient-derived xenografts (PDXs) from 19 patients with ESCC to investigate the mechanisms driving radioresistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrichment of cancer-associated fibroblast (CAF)-derived collagen type 1 (Col1) and tumor-cell-derived CXCL1 in non-responsive PDXs. Col1 not only promotes radioresistance by augmenting DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Directly interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo. Collectively, our study provides a comprehensive understanding of the molecular mechanisms underlying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.

Sodium nitrate passivation has been developed as a new insulation technology for the production of FeSiAl soft magnetic composites (SMCs). In this work, the evolution of coating layers grown at different pH values is investigated involving analyses on their composition and microstructure. An insulation coating obtained using an acidic NaNO3 solution is found to contain Fe2O3, SiO2, Al2O3, and AlO(OH). The Fe2O3 transforms into Fe3O4 with weakened oxidizability of the NO3– at an elevated pH, whereas an alkaline NaNO3 solution leads to the production of Al2O3, AlO(OH), and SiO2. Such growth is explained from both thermodynamic and kinetic perspectives and is correlated to the soft magnetic properties of the FeSiAl SMCs. Under tuned passivation conditions, optimal performance with an effective permeability of 97.2 and a core loss of 296.4 mW∙cm−3 is achieved at 50 kHz and 100 mT.

Background & Aims: Liver ischemia-reperfusion (IR) injury represents a major risk factor in both partial hepatectomy and liver transplantation. Nerve injury–induced protein 1 (Ninj1) is widely recognized as an adhesion molecule in leukocyte trafficking under inflammatory conditions, but its role in regulating sterile inflammation during liver IR injury remains unclear. Methods: Myeloid Ninj1-deficient mice were generated by bone marrow chimeric models using Ninj1 knockout mice and wild-type mice. In vivo, a liver partial warm ischemia model was applied. Liver injury and hepatic inflammation were investigated. In vitro, primary Kupffer cells (KCs) isolated from Ninj1 knockout and wild-type mice were used to explore the function and mechanism of Ninj1 in modulating KC inflammation upon lipopolysaccharide stimulation. Results: Ninj1 deficiency in KCs protected mice against liver IR injury during the later phase of reperfusion, especially in neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. This prompted ischemia-primed KCs to decrease proinflammatory cytokine production. In vitro and in vivo, using small-interfering RNA against dual-specificity phosphatase 1 (DUSP1), we found that Ninj1 deficiency diminished the inflammatory response in KCs and neutrophil infiltration through DUSP1-dependent deactivation of the c-Jun-N-terminal kinase and p38 pathways. Sivelestat, a neutrophil elastase inhibitor, functioned similarly to Ninj1 deficiency, resulting in both mitigated hepatic IR injury in mice and a more rapid recovery of liver function in patients undergoing liver resection. Conclusions: The Ninj1/Dusp1 axis contributes to liver IR injury by regulating the proinflammatory response of KCs, and influences neutrophil infiltration, partly by subsequent regulation of C-X-C motif chemokine ligand 1 (CXCL1) production after IR.

Accurate short-term load forecasting of distribution transformer in extreme weather will effectively assist power dispatching and enable safe and stable operation of power grid. Therefore, this paper proposes the Bagging–XGBoost algorithm based extreme weather identification and short-term load forecasting model, which can warn the time period and detailed value of peak load in advance. Firstly, based on Extreme Gradient Boosting (XGBoost) algorithm, the idea of Bagging is introduced to reduce the output variance and enhance the generalization ability of the algorithm. Then, the mutual information (MI) between weather influencing factors and load is analyzed to adjust the input weight of the model and improve its ability to track weather changes. Next, considering the load, weather and time factors, the extreme weather identification model is established to determine the occurrence range of peak load. Finally, the specialized training set is selected based on the weighted similarity, and high-accuracy short-term load forecasting model is established. Compared with the traditional model, the model proposed in this paper reduces the average Mean Absolute Percentage Error (MAPE) of peak load by 3% to 10%.

In this work, porous tantalum scaffolds with structures of cubic, G7 and rhombic dodecahedron with different strut angles were fabricated by electron beam powder bed fusion (EB-PBF). Uniaxial compressive testing and compression–compression fatigue testing were conducted on the EB-PBF built tantalum scaffolds. The role of pore structures on the deformation behavior and fatigue properties of the tantalum scaffolds were analyzed. The effect of buckling component in the rhombic dodecahedron structure on fatigue performance of the porous tantalum scaffolds was investigated. It was demonstrated that the G7 and cubic porous tantalum scaffolds were dominated by buckling deformation under the axial force. Due to the presence of vertical struts, the G7 scaffold showed higher fatigue strength and fatigue ratio than the dodecahedron which deformed mainly via bending, the cubic scaffold showed the highest fatigue ratio. As the strut angel increased from 35.3° to 43°, the fatigue strength and fatigue ratio of the rhombic dodecahedron tantalum scaffolds improved by 59% and 20% at 2 × 106 cycles, respectively. The ratcheting strain and fatigue damage strain during the fatigue test were both decreased with the increase of buckling component, leading to the boosting of compressive fatigue properties of tantalum scaffolds accordingly.

Identifying magmatic rock associations in a subduction zone is substantial for understanding the related geodynamic evolution. The final closure time of the Paleo-Asian Ocean and the exact subduction processes have continuously been controversial, hindering our recognition of the tectonic evolution of the Central Asian Orogenic Belt (CAOB). Here we investigated the Early Permian gabbros-granodiorites from Xi Ujimqin in the northern Inner Mongolian region. The gabbros have slightly depleted light rare-earth elements [(La/Yb)N = 0.8] and flat heavy rare earth elements (HREE) [(Gd/Yb)N = 1.1] that are comparable to those of N-MORB. They show depletion in Nb and Ta, positive whole-rock εNd(t) values of +7.7 to +8.7 and zircon εHf(t) values of +8.7 to +10.6. These mafic rocks are interpreted to be products of partial melting of depleted mantle that had been metasomatized by slab-derived fluids, with subsequent fractional crystallization and minor crustal contamination. These granodiorites chemically resemble typical adakites and have MORB-like whole-rock SrNd isotopic compositions (87Sr/86Sri = 0.7028–0.7029; εNd(t) = +8.2–+8.5) and positive zircon εHf(t) (+13.4–+15.9) values, suggesting that they originated from the subducted slab-melts and reacted with mantle wedge peridotite. UPb zircon dating shows emplacement of N-MORB-type gabbros and adakitic granodiorites at ∼297 Ma and ∼290 Ma, respectively. Our new data indicate the presence coeval slab-derived adakites and slab fluid-metasomatized asthenosphere-derived N-MORB-type rocks, indicating that subduction lasted until at least the Early Permian. Such an association along with the extension-related magmatism in northern Mongolia recorded the northward ridge subduction of the Paleo-Asian Ocean during the Late Carboniferous–Early Permian. This model is consistent with the spatial distribution and the ages of magmatic activity with positive εNd(t)–εHf(t) values from this region. Ridge subduction and induced slab windows probably played a key role in Paleozoic crustal growth of CAOB, and by inference in the other accretionary orogens throughout Earth history.

Understanding the speciation and related influence factors of Hg in wet deposition is important to predict the fate and transport of mercury in the atmosphere. In this study, event-based samples of rainwater were collected for one year in Jinan, a northern city in eastern China. The volume-weighted mean concentration of total mercury (THg) in rainwater was 34.8 ng L−1, comparable to levels in some inland cities in China and were significantly higher than those in North America, Korea and Japan. Most of the Hg in rainwater was associated with particulates, accounted for 15.2–92.9% of THg with a mean of 66.9%, which might be attributed to the scavenging effects of high particulate-bound mercury concentrations in ambient air in urban Jinan. Dissolved mercury (DHg) accounted for 33.1% of THg, in which Hg(OH)2, HgClOH, HgCl2 and Hg(NH3)22+ are the dominant species based on the chemical equilibrium modeling simulations. THg concentrations in rainwater decreased as the rainfall amount increased owing to the dilution effect and 5 mm rainfall might be a threshold for the full wash-out capability of atmospheric Hg. For a continuous rain event, the proportion of DHg in THg could increase from 7.1% to 84.8% with the rainfall processing, especially for the species of HgClOH and HgCl2 under the influence of rainwater pH. Positive matrix factorization (PMF) analysis suggested that the major sources of Hg in rainwater were combustion emissions, marine sources, industrial emissions, as well as complexation process, which contributed to 51.4%, 24.7%, 12.2%, and 11.7% of the THg, respectively. For the specific species, the main sources varied with different Hg species, in which combustion emissions contributed one third to one half of each species sum to particulate mercury (PHg), HgClOH, HgCl2, HgBrOH and HgBrCl followed by marine sources and industrial emissions. Cluster analysis of backward trajectories revealed that polluted air masses, transported from southeast Shandong, Anhui and Jiangsu Provinces, as well as Beijing-Tianjin-Hebei region, contributed to high Hg concentration in rainwater in Jinan.

The pathological consequences leading to primary storage, autophagy impairment, impaired mitochondrial dynamics, and endoplasmic reticulum (ER) stress on neural cell dysfunction and apoptosis in metachromatic leukodystrophy (MLD) have been poorly elucidated. In the present study, we generated 2 cell lines of patient-specific-induced pluripotent stem cells (iPSCs) and modeled the progression of pathological events during the differentiation of iPSCs to motor neuron progenitors (MNPs) and mature motor neurons (MNs). The iPS cells were generated from two late-infantile MLD patient-derived skin fibroblasts using electroporation or the Sendai virus. Olig2+ MNPs were generated from both iPSC lines using a combination of small molecules in a chemically defined neural medium. Furthermore, the MNPs could be differentiated into mature MNs, which was confirmed by RT–PCR and MN markers, including SMI32 and ChAT. The population of MNs was approximately 50% under the culture conditions. Pathological observation of MLD patient-derived iPSCs revealed lysosomal accumulation and impaired autophagy. In addition, both MNPs and MNs derived from MLD-iPSCs showed increased lysosomal accumulation, dysfunctional autophagy, impaired mitophagy, endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation, and premature cellular death.

Summary: Motor control of the striated esophagus originates in the nucleus ambiguus (nAmb), a vagal motor nucleus that also contains upper airway motor neurons and parasympathetic preganglionic neurons for the heart and lungs. We disambiguate nAmb neurons based on their genome-wide expression profiles, efferent circuitry, and ability to control esophageal muscles. Our single-cell RNA sequencing analysis predicts three molecularly distinct nAmb neuron subtypes and annotates them by subtype-specific marker genes: Crhr2, Vipr2, and Adcyap1. Mapping the axon projections of the nAmb neuron subtypes reveals that Crhr2nAmb neurons innervate the esophagus, raising the possibility that they control esophageal muscle function. Accordingly, focal optogenetic stimulation of cholinergic Crhr2+ fibers in the esophagus results in contractions. Activating Crhr2nAmb neurons has no effect on heart rate, a key parasympathetic function of the nAmb, whereas activating all of the nAmb neurons robustly suppresses heart rate. Together, these results reveal a genetically defined circuit for motor control of the esophagus.

CHFR is a tumor suppressor that not only recognizes poly(ADP-ribosylation) (PARylation) signals at the sites of DNA damage but also is downregulated in many types of cancer. However, the underlying mechanism linking its role in PARylation-mediated DNA damage repair and tumor suppression is unclear. Here, we examined a panel of gastric cancer cell lines as well as primary tissue samples from gastric cancer patients, and found that CHFR expression was silenced by DNA hypermethylation in gastric cancer including 38.46% of primary gastric cancers. DNMT1 was associated with aberrant methylation of CHFR, and the expression of CHFR was restored by DNMT1 inhibitor 5-aza-2-deoxycytidine (5-aza-CdR) treatment. Moreover, we found that loss of CHFR abolished DNA damage repair and sensitized gastric tumor cells to PARP inhibitor treatment. Thus, our study reveals a potential therapeutic approach for treating gastric cancer with PARP inhibitor and lacking CHFR can serve as a biomarker for predicting the efficacy of PARP inhibitor on the gastric tumor treatment in future.

In order to mitigate the spread of COVID-19, Wuhan was the first city to implement strict lockdown policy in 2020. Even though numerous researches have discussed the travel restriction between cities and provinces, few studies focus on the effect of transportation control inside the city due to the lack of the measurement and available data in Wuhan. Since the public transports have been shut down in the beginning of city lockdown, the change of traffic density is a good indicator to reflect the intracity population flow. Therefore, in this paper, we collected time-series high-resolution remote sensing images with the resolution of 1 m acquired before, during and after Wuhan lockdown by GF-2 satellite. Vehicles on the road were extracted and counted for the statistics of traffic density to reflect the changes of human transmissions in the whole period of Wuhan lockdown. Open Street Map was used to obtain observation road surfaces, and a vehicle detection method combing morphology filter and deep learning was utilized to extract vehicles with the accuracy of 62.56%. According to the experimental results, the traffic density of Wuhan dropped with the percentage higher than 80%, and even higher than 90% on main roads during city lockdown; after lockdown lift, the traffic density recovered to the normal rate. Traffic density distributions also show the obvious reduction and increase throughout the whole study area. The significant reduction and recovery of traffic density indicates that the lockdown policy in Wuhan show effectiveness in controlling human transmission inside the city, and the city returned to normal after lockdown lift.

We investigate the quasinormal modes (QNMs) of the scalar field coupled to the Einstein's tensor in the non-commutative geometry inspired black hole spacetime. It is found that the lapse function of the non-commutative black hole metric can be represented by a Kummer's confluent hypergeometric function, which can effectively solve the problem that the numerical results of the QNMs are sensitive to the model parameters and make the QNMs values more reliable. We make a careful analysis of the scalar QNM frequencies by using several numerical methods, and find that the numerical results obtained by the new WKB method (the Padé approximants) and the Mashhoon method (Pöschl-Teller potential method) are quite different from those obtained by the asymptotic iterative method (AIM) and time-domain integration method when the non-commutative parameter θ and coupling parameter η are large. The most obvious difference is that the numerical results obtained by the AIM and the time-domain integration method appear a critical value ηc with an increase of η, which leads to the dynamical instability. After carefully analyzing the numeral results, we conclude that the numerical results obtained by the AIM and the time-domain integration method are closer to the theoretical values than those obtained by the WKB method and the Mashhoon method, when the θ and η are large. Moreover, through a numerical fitting, we obtain that the functional relationship between the threshold ηc and the non-commutative parameter θ satisfies ηc=aθb+c for a fixed l approximately. We find that the stability of dynamics can be ensured in the η

Niemann−Pick disease type C (NPC) is a rare neurodegenerative disorder caused by a recessive mutation in the NPC1 or NPC2 gene, in which patients exhibit lysosomal accumulation of unesterified cholesterol and glycolipids. Most of the research on NPC has been done in patient-derived skin fibroblasts or mouse models. Therefore, we developed NPC patient neurons derived from induced pluripotent stem cells (iPSCs) to investigate the neuropathological cause of the disease. Although an accumulation of cholesterol and glycolipids, which is characteristic of NPC, was observed in both undifferentiated iPSCs and derived neural stem cells (NSCs), we could not observed the abnormalities in differentiation potential and autophagic activity in such immature cells. However, definite neuropathological features were detected in mature neuronal cells generated from NPC patient-derived iPSCs. Abnormal accumulation of cholesterol and other lipids identified by lipid droplets and number of enlarged lysosomes was more prominent in mature neuronal cells rather than in iPSCs and/or NSCs. Thin-sectioning electron microscopic analysis also demonstrated numerous typical membranous cytoplasmic bodies in mature neuronal cells. Furthermore, TUJ1-positive neurite density was significantly reduced in NPC patient-derived neuronal cells. In addition, disruption of the p62/SQSTM1−KEAP1−NRF2 axis occurred in neurons differentiated from NPC patient-derived iPSCs. These data indicate the impairment of neuronal network formation associated with neurodegeneration in mature neuronal cells derived from patients with NPC.

Based on the method of computing the curl of vector, axial-vector and the tensor current operator equations, the possible quantum anomaly for the transverse Ward–Takahashi relations in QED3 and QED2 theories is studied. The absence of transverse anomalies for both axial-vector current in QED2 theory and vector (tensor) current in QED3 theory are verified respectively. Further, it is found that when we ignore the contribution of the three integral-term involving the vertex function in the Wilson line, we can get a set of closed coupled integral Dyson–Schwinger equations in QED3. Keywords: Transverse Ward–Takahashi, Vector, Tensor, QED3, Dyson–Schwinger

In addition to its use in the conventional textile industry, Bombyx Mori silk has attracted significant attention in the materials science and biomedical engineering disciplines. Recently, the possibility of drawing silk fibers with superior toughness has gained particular research interest. Cellulose nanofiber (CNF) is widely studied as a reinforcement material owing to its excellent mechanical properties combined with relatively low density and promising biocompatibility. This paper reports silkworm silk fibers dispersed with CNF that present outstanding tensile properties compared with conventional silk fibers. The silkworm diet was modified by including CNFs, and tensile tests were carried out for the drawn silk fibers. Tensile testing of the drawn silk showed improved Young's modulus and tensile strength when the diet included CNFs at 5 wt% concentration. Fourier transform infrared spectroscopy and atomic force microscopy studies were also conducted to determine the reason for the observed improvement in properties. Morphological studies revealed that the individual fibrils or fibril bundles are aligned in the longitudinal direction of the silk fibers and are uniformly dispersed. Moreover, finite element analysis was performed to estimate the volume fraction of CNF in the silkworm silk fiber. This work opens the door for development of renewable and sustainable bio-composites.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

We investigate the massless scalar quasinormal modes (QNMs) of the noncommutative D-dimensional Schwarzschild-Tangherlini black hole spacetime in this paper. By using the Wentzel-Kramers-Brillouin (WKB) approximation method, the asymptotic iterative method (AIM) and the inverted potential method (IPM), we made a detail analysis of the massless scalar QNM frequencies by varying the general smeared matter distribution and the allowable characteristic parameters (k and θ) corresponding to different dimensions. It is found that the nonconvergence of the high order WKB approximation exists in the QNMs frequencies of scalar perturbation around the noncommutative D-dimensional Schwarzschild black holes. We conclude that the 3rd WKB result should be more reliable than those of the high order WKB method since our numerical results are also verified by the AIM method and the IPM method. In the dimensional range of 4≤D≤7, the scalar QNMs as a function of the different parameters (the noncommutative parameter θ, the smeared matter distribution parameter k, the multipole number l and the main node number n) are obtained. Moreover, we study the dynamical evolution of a scalar field in the background of the noncommutative high dimensional Schwarzschild-Tangherlini black hole.

MicroRNA-645 (miR-645) has been implicated in numerous types of human cancers including colon cancer. However, the effects and mechanisms of action of miR-645 dysregulation on the growth and malignancy of colorectal cancer (CRC) remain unclear. In this study, we demonstrated that miR-645 knockdown significantly diminished CRC cell migration and invasion and repressed epithelial–mesenchymal transition (EMT). Conversely, miR-645 overexpression enhanced CRC cell migration, invasion, and EMT. In vivo assays confirmed that miR-645 knockdown substantially reduced CRC growth and metastasis. Regarding the mechanism, ephrin-A5 (EFNA5) was identified as a direct target gene of miR-645. MiR-645 specifically targeted the 3′-untranslated region of EFNA5 mRNA and hindered its expression. EFNA5 knockdown attenuated the effects of miR-645 knockdown on CRC cell migration and invasion. Additionally, we noted a statistically significant inverse correlation between EFNA5 mRNA and miR-645 levels in tumors from 28 patients with CRC. Hence, miR-645 acts as an oncogenic miRNA that may increase CRC cell migration, invasiveness, and metastasis by targeting EFNA5.

GALNT14 is a member of N-acetylgalactosaminyltransferase enzyme family and mediates breast cancer cell development. Here, we find that GALNT14 regulates multidrug resistance (MDR) in breast cancer. The expression of GALNT14 is associated with MDR in breast cancer. Higher level of GALNT14 facilitates MCF-7 cells to resist Adriamycin, whereas knockdown of GALNT14 sensitizes cells to Adriamycin. Moreover, the expression of GALNT14 associates with the expression of P-gp, the efflux pump localized on the cell membrane, which could be the underlying mechanism of how GALNT14 induces MDR. In-depth analysis shows that GALNT14 regulates the stability of P-gp. Finally, GALNT14 associates with higher level of P-gp in chemotherapy-resistant human breast cancer tissues. Taken together, our studies reveal a molecular mechanism in breast cancer MDR.

N-Acetylgalactosaminyltransferase-14 (GALNT14) is a member of acetylgalactosaminyltransferases family. We have shown that GALNT14 could promote breast cancer cell invasion. However, the underlying molecular mechanism is unclear. Here, using yeast two hybrid, we find that EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) interacts with GALNT14. Both in vitro and in vivo binding assays show that EFEMP2 is associated with GALNT14. Moreover, we find that GALNT14 mediates glycosylation of EFEMP2. EFEMP2 significantly increased the invasion ability of breast cancer cells including MCF-7 and MBA-MD-231 cells, and this phenomenon is suppressed by knockdown expression of GALNT14. In addition, the GALNT14-dependent O-glycosylation of EFEMP-2 regulates the stability of EFEMP-2 protein in breast cancer cells. Taken together, our results demonstrate a novel molecular mechanism underlying breast cancer invasion.

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A), leading to the progressive accumulation of glycosphingolipids. Classical hemizygous males usually present symptoms, including pain and paresthesia in the extremities, angiokeratoma, hypo- or anhidrosis, abdominal pain, cornea verticillata, early stroke, tinnitus, and/or hearing loss, during early childhood or adolescence. Moreover, proteinuria, renal impairment, and cardiac hypertrophy can appear with age. Enzyme replacement is the most common therapy for Fabry disease at present which has been approved in Japan since 2004. We report a case involving a 27-year-old male with extreme terminal pain, anhidrosis, abdominal pain, tinnitus, hearing impairment, cornea verticillata, and recurrent huge ulcers in the lower extremities. At the age of 16 years, he was diagnosed with Fabry disease with a positive family history and very low α-gal A activity. He then received enzyme replacement therapy (ERT) with recombinant human agalsidase beta at 1 mg/kg every 2 weeks for 10 years. Throughout the course of ERT, his leg ulcers recurred, and massive excretion of urinary globotriaosylceramide and plasma globotriaosylsphingosine was observed. Electron microscopy of the venous tissue in the regions of the ulcer showed massive typical zebra bodies in the vascular wall smooth muscle cells.

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease that results in the accumulation of very long chain fatty acids (VLCFA) in plasma and all tissues. Recent studies regarding cerebral X-ALD (CALD) treatment emphasize the importance of its early diagnosis. 26:0 lysophosphatidylcholine (LysoPC) is a sensitive biomarker for newborn screening of X-ALD, while its application for Japanese DBS is unclear. Therefore, we evaluated the feasibility of 20:0 LysoPC and 24:0 LysoPC along with 26:0 LysoPC for diagnosing X-ALD in a cohort of newborns (n = 604), healthy adults (n = 50) and patients (n = 4). Results indicated that 26:0 LysoPC had strong significance for discrimination of patients by the amounts of 2.0 to 4.0 and 0.1 to 1.9 pmol/punch for patients and newborns/healthy adults, respectively. Based on these values, we recommend that further diagnostic confirmation is essential if the amount of 26:0 LysoPC in DBS is above 1.7 pmol/punch.

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A). The clinical variability of the phenotypes of Fabry disease in females is still poorly understood. The degree of aberrant methylation of non-mutated alleles is thought to have significant effects on X-chromosome inactivation (XCI). We previously reported that one heterozygous Fabry female showing classical phenotypes had complete methylation of the non-mutated allele of the GLA gene. In this report, we summarized 36 heterozygous females with a clinical severity score based on the FAbry STabilization indEX (FASTEX). We measured their α-gal A activity and plasma/ serum globotriaosylsphingosine (lyso-Gb3) accumulation and performed electron microscopy of skin biopsies. We analyzed the methylation-sensitive restriction enzyme sites throughout the GLA gene, including the 5’UTR, and found a single SacII site and multiple HhaI and HpaII sites aggregated in exon 1 and the 5’UTR. One HpaII sequence in exon 7 was also detected as a methylation-sensitive site. With methylation-sensitive restriction enzymes, methylated and non-methylated alleles could be separated, and the ratio of the methylation was quantified. We found a clear correlation between the severity of the phenotype and lyso-Gb3 accumulation for heterozygous Fabry disease in females. Methylation of the non-mutated allele was also proportionately correlated to the clinical severity score measured by FASTEX. Keywords: Heterozygous Fabry females, Fabry stabilization indEX, Methylation, X-chromosome inactivation

MicroRNA-575 (miR-575) is oncogene in many tumors. However, the role of miR-575 in the progression of gastric cancer (GC) is still unknown. The aim of this study was to identify whether miR-575 play a role in the development of GC. We obtained GC cell lines, GC tissues from 40 patients to measure the levels of miR-575 and its predicted target PTEN by using RT‑PCR, immunohistochemistry or western blot analysis. MGC-803 cells were transfected with miR-575 inhibitor, and cells viability and apoptosis were measured. miR-575 aberrantly up-regulated in GC tissues and GC cell lines compared with corresponding control. In cell lines, MGC‑803 expressed highest level of miR-575 among the tested cells. The level of miR-575 was correlated with the tumor size, AJCC stage and prognosis, but not with the other clinical parameters. Knockdown of miR-575 inhibited proliferation and promoted apoptotic death of MGC-803 cells both in vitro and vivo. PTEN levels (both mRNA and protein) were remarkably decreased in cancer tissues compared with the paired-adjacent tissues, and negatively correlated with miR-575 in the tissues. By using luciferase reporter assay, we found PTEN was a direct downstream target of miR-575, and negatively regulated by miR-575 via targeting its 3′UTR. Knockdown or overexpression of miR-575 in MGC-803 cells negatively regulated PTEN expression. Finally, silencing PTEN partially impaired anti-proliferative effects of miR-575 inhibitor. miRNA-575 serves a pivotal role in GC as a cancer promoter gene by targeting PTEN to regulate proliferation and apoptosis of the cancer cells.

Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons (MNs). To date, its underlying mechanisms have yet to be clarified completely, and there are no truly effective treatments. Here, we show that MAP4K4, a MAP kinase family member, regulates MN death, with its suppression not only promoting survival but preventing neurite degeneration and decreasing mutant SOD1 levels through autophagy activation. Moreover, we report that MAP4K4 signaling specifically modulates MN viability via phosphorylated JNK3 and activation of the canonical c-Jun apoptotic pathway. Finally, we show the feasibility of MAP4K4 as a drug target by using an available MAP4K4-specific inhibitor, which improves survival of ESC and/or iPSC-derived MNs and MNs cultured from mouse spinal cords. In summary, our studies highlight a MAP4K4-initiated signaling cascade that induces MN degeneration, shedding light on the mechanism underlying MN degeneration and providing a druggable target for ALS therapeutics. : Wu et al. identify MAP4K4 as a key regulator of motor neuron degeneration in ALS. Reduction of MAP4K4 promotes motor neuron survival and neurite integrity under conditions of exogenous or endogenous stress both by directly attenuating c-Jun-mediated apoptosis and by activating autophagy, thereby reducing protein aggregation. Keywords: pluripotent stem cells, human motor neurons, amyotrophic, lateral sclerosis, MAP4K4, JNK, apoptosis, autophagy, FoxO1, therapeutics

Summary: We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3−/− mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total β-tubulin levels in Tubb3−/− and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins. : Latremoliere et al. show that the neuronal-specific tubulin isoform TUBB3 is not required for normal development and function of the nervous system. Lack of TUBB3 decreases the dynamics of microtubules in growth cones, and this reduces axonal growth after peripheral nerve injury and strongly delays functional recovery. Keywords: tubulin, TUBB3, development, mouse, axonal growth, microtubule dynamics, sensory recovery, spot culture, post-translational modifications, diffusion tensor imaging

Purpose: To determine the effect of socioeconomic factors and variables related to delay to treatment on Chinese women with urinary incontinence (UI). Methods: We conducted a cross-sectional survey involving 346 incontinent women living in three urban communities. We enrolled a representative subsample of 196 women who sought treatment for UI within the next six months in the study. Socioeconomic and clinical characteristic data were collected using a self-administered questionnaire and the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form. Results: Of the 196 women (age [mean and standard deviation] 51.58 ± 7.91 years), the delay ranged 1–15 years; 64 women (32.7%) reported a >3-year delay. Age (odds ratio [OR] = 1.98, 95% confidence interval [CI]: 1.31–3.00), lower UI severity (subjective) (OR = 2.32, 95%CI: 1.38–3.87), and non-mixed UI (stress or urgency UI alone, OR = 1.60, 95%CI: 1.11–2.32) were risk factors for longer delay. Conclusion: Women who were older, had lower subjective UI severity, and who reported only stress or urgency UI tended to delay treatment longer; such patients should be targeted for health education and intervention regarding UI in urban communities.

Purpose: To investigate the bothersomeness of female urinary incontinence (UI) and analyse its influencing factors. Methods: A purposive sample of 506 women with UI from three communities in Jinan was studied using the International Consultation on Incontinence Questionnaire–Urinary Incontinence Short Form, modified Social Impact Scale, and a coping efficacy questionnaire. The influencing factors of bothersomeness were identified using one-way analysis of variance, χ2 test, and logistic regression. Results: Of the participants, 33.4% were bothered by UI symptoms; logistic regression indicated that severity of UI, stigma, coping efficacy, and duration of symptoms were independent factors of bothersomeness, which clarified 49.8% of the variation. Conclusion: UI patients should receive individualised intervention. Healthcare workers can provide targeted intervention to patients bothered by UI to alleviate symptoms, decrease the sense of stigma, and increase confidence in coping with symptoms to decrease bothersomeness.