Microplastic induces mitochondrial pathway mediated cellular apoptosis in mussel (Mytilus galloprovincialis) via inhibition of the AKT and ERK signaling pathway.

Microplastics (MPs) is an escalating aquatic environmental crisis that poses significant threats to marine organisms, especially mussels. Here, we compare the cumulative toxic effects of the two most abundant morphotypes of MPs in the environment, microspheres, and microfibers, on the gill and digestive gland (DG) of Mytilus galloprovincialis in a dose-dependent (1, 10, and 100 mg/L) and time-dependent (1, 4, 7, 14, 21 days exposure) manner. DNA fragmentation assessment through TUNEL assay revealed consistency in the pattern of morphological disturbance degree and cell apoptosis proportions indicated by histopathological analysis. Upon the acute phase of exposure (day 1-4), gill and DG treated with low MPs concentration exhibited preserved morphology and low proportion of TUNEL+ cells. At higher concentrations, spherical and fibrous MP-induced structural impairments and DNA breakage occurred at distinct levels. 100 mg/L microfibers was lethal to all mussels on day 21, indicating the higher toxicity of the fibrous particles. During the chronic phase, both morphological abnormalities degree and DNA fragmentation level increased over time and with increasing concentration, but the differentials between the spherical and fibrous group was gradually reduced, particularly diminished in 10 and 100 mg/L in the last 2 weeks. Furthermore, analysis of transcriptional activities of key genes for apoptosis of 100 mg/L-day 14 groups revealed the upregulation of both intrinsic and extrinsic apoptotic induction pathway and increment in gene transcripts involving genotoxic stress and energy metabolism according to MP morphotypes. Overall, microfibers exert higher genotoxic effects on mussel. In response, mussels trigger more intense apoptotic responses together with enhanced energy metabolism to tolerate the adverse effects in a way related to the accumulation of stimuli.

Control of the growth and development of murine preantral follicles in a biomimetic ovary using a decellularized porcine scaffold.

This study aimed to derive mature oocytes from murine preantral follicles cultured in a biomimetic ovary with a porcine scaffold using decellularization technology. We evaluated the DNA content and the presence of cell and extracellular matrix (ECM) components, including collagen, elastin, and glycosaminoglycans (GAGs), in decellularized (decell) porcine ovaries. The DNA content inthe decell ovarian tissues was approximately 94 % less than that in native tissues (66 ± 9.8 ng/mg vs. 1139 ± 269 ng/mg). Furthermore, the ECM component integrity was maintained in the decell ovarian tissue. The soluble collagen concentration of native ovarian tissue (native) was 195.34 ± 15.13 µg/mg (dry wt.), which was less than 878.6 ± 8.24 µg/mg for the decell ovarian tissue due to the loss of cellular mass. Hydrogels derived from decell porcine ovaries were prepared to develop an in vitro biomimetic ovary with appropriate ECM concentration (2-6 mg/mL). Scanning electron microscope (SEM) imagining revealed that the complex fiber network and porous structure were maintained in all groups treated with varying ECM concentration (2-6 mg/mL). Furthermore, rheometer analysis indicated that mechanical strength increased with ECM concentration in a dose-dependently. The preantral follicles cultured with 4 mg/mL ECM showed high rates of antral follicle (66 %) and mature oocyte (metaphase II) development (47 %). The preantral follicles cultured in a biomimetic ovary with a decell porcine scaffold showed a higher rate of antral follicle and mature oocytes than those cultured in other biomaterials such as collagen and Matrigel. In mature oocytes derived from antral follicles, meiotic spindles and nuclei were stained using a tubulin antibody and Hoechst, respectively. Two-cell embryos were developed from MII oocytes following parthenogenetic activation. Preantral follicles were cultured in a biomimetic ovary derived from the ECM of a decell porcine ovary, and embryos were generated from MII oocytes. This biomimetic ovary could contribute to restoring fertility in infertile women with reduced ovarian function, benefit mating efforts for endangered species, and maintain animals with valuable genetic traits.

Responses of multifunctional immune complement component 1q (C1q) and apoptosis-related genes in Macrophthalmus japonicus tissues and human cells following exposure to environmental pollutants.

Apoptosis is a key defense process for multiple immune system functions, playing a central role in maintaining homeostasis and cell development. The purpose of this study was to evaluate the effects of environmental pollutant exposure on immune-related apoptotic pathways in crab tissues and human cells. To do this, we characterized the multifunctional immune complement component 1q (C1q) gene and analyzed C1q expression in Macrophthalmus japonicus crabs after exposure to di(2-ethylhexyl) phthalate (DEHP) or hexabromocyclododecanes (HBCDs). Moreover, the responses of apoptotic signal-related genes were observed in M. japonicus tissues and human cell lines (HEK293T and HCT116). C1q gene expression was downregulated in the gills and hepatopancreas of M. japonicus after exposure to DEHP or HBCD. Pollutant exposure also increased antioxidant enzyme activities and altered transcription of 15 apoptotic signaling genes in M. japonicus. However, patterns in apoptotic signaling in response to these pollutants differed in human cells. HBCD exposure generated an apoptotic signal (cleaved caspase-3) and inhibited cell growth in both cell lines, whereas DEHP exposure did not produce such a response. These results suggest that exposure to environmental pollutants induced different levels of immune-related apoptosis depending on the cell or tissue type and that this induction of apoptotic signaling may trigger an initiation of carcinogenesis in M. japonicus and in humans as consumers.

Poly(l-lactide)/polycaprolactone based multifunctional coating to deliver paclitaxel/VEGF and control the degradation rate of magnesium alloy stent.

Despite significant advancements made in cardiovascular stents, restenosis, thrombosis, biocompatibility, and clinical complications remain a matter of concern. Herein, we report a biodegradable Mg alloy stent with a dual effect of the drug (Paclitaxel) and growth factor (VEGF) release. To mitigate the fast degradation of Mg alloy, inorganic and organic coatings were formed on the alloy surface. The optimized hierarchal sequence of the coating was the first layer consisting of magnesium fluoride, followed by poly(l-lactide) and hydroxyapatite coating, and finally sealed by a polycaprolactone layer (MgC). PLLA and HAp were used to increase the adhesion strength and biocompatibility of the coating. Paclitaxel and VEGF were loaded in the final PCL layer (Mg-C/PTX-VEGF). As compared to bare Mg alloy (28 % weight loss), our MgC system showed (3.1 % weight loss) successful decrease in the degradation rate. Further, the in vitro biocompatibility illustrated the highly biocompatible nature of our drug and growth factor-loaded system. The in vivo results displayed that the drug loading decreased the inflammation and neointimal hyperplasia as indicated by the α-SMA and CD-68 antibody staining. The growth factor helped in the endothelialization which was established by the FLKI and ICAM antibody staining of the tissue.

GeAs as an emerging p-type van der Waals semiconductor and its application in p-n photodiodes.

van der Waals (vdW) layered materials have shown great potential for future optoelectronic applications owing to their unique and variable properties. In particular, two-dimensional layered materials enable the creation of various circuital building blocks via vertical stacking, e.g. the vertical p-n junction as a key one. While numerous stable n-type layered materials have been discovered, p-type materials remain relatively scarce. Here, we report on the study of multilayer germanium arsenide (GeAs), another emerging p-type vdW layered material. We first verify the efficient hole transport in a multilayer GeAs field-effect transistor with Pt electrodes, which establish low contact potential barriers. Subsequently, we demonstrate a p-n photodiode featuring a vertical heterojunction of a multilayer GeAs and n-type MoS2monolayer, exhibiting a photovoltaic response. This study promotes that 2D GeAs is a promising candidate for p-type material in vdW optoelectronic devices.

Long range inter-chromosomal interaction of Oct4 distal enhancer loci regulates ESCs pluripotency.

Nuclear architecture underlies the transcriptional programs within the cell to establish cell identity. As previously demonstrated, long-range chromatin interactions of the Oct4 distal enhancer (DE) are correlated with active transcription in naïve state embryonic stem cells. Here, we identify and characterize extreme long-range interactions of the Oct4 DE through a novel CRISPR labeling technique we developed and chromosome conformation capture to identify lethal giant larvae 2 (Llgl2) and growth factor receptor-bound protein 7 (Grb7) as putative functional interacting target genes in different chromosomes. We show that the Oct4 DE directly regulates expression of Llgl2 and Grb7 in addition to Oct4. Expression of Llgl2 and Grb7 closely correlates with the pluripotent state, where knock down of either result in loss of pluripotency, and overexpression enhances somatic cell reprogramming. We demonstrated that biologically important interactions of the Oct4 DE can occur at extreme distances that are necessary for the maintenance of the pluripotent state.

In-vivo bone remodeling potential of Sr-d-Ca-P /PLLA-HAp coated biodegradable ZK60 alloy bone plate.

Magnesium and its alloys are widely applied biomaterials due to their biodegradability and biocompatibility. However, rapid degradation and hydrogen gas evolution hinder its applicability on a commercial scale. In this study, we developed an Mg alloy bone plate for bone remodeling and support after a fracture. We further coated the Mg alloy plate with Sr-D-Ca-P (Sr dopped Ca-P coating) and Sr-D-Ca-P/PLLA-HAp to evaluate and compare their biodegradability and biocompatibility in both in vitro and in vivo experiments. Chemical immersion and dip coating were employed for the formation of Sr-D-Ca-P and PLLA-HAp layers, respectively. In vitro evaluation depicted that both coatings delayed the degradation process and exhibited excellent biocompatibility. MC3T3-E1cells proliferation and osteogenic markers expression were also promoted. In vivo results showed that both Sr-D-Ca-P and Sr-D-Ca-P/PLLA-HAp coated bone plates had slower degradation rate as compared to Mg alloy. Remarkable bone remodeling was observed around the Sr-D-Ca-P/PLLA-HAp coated bone plate than bare Mg alloy and Sr-D-Ca-P coated bone plate. These results suggest that Sr-D-Ca-P/PLLA-HAp coated Mg alloy bone plate with lower degradation and enhanced biocompatibility can be applied as an orthopedic implant.

Germ Cell Isolation and Cryopreservation from Reproductive Organs of Brown Mealworm.

This study aimed to isolate and freeze germ cells from the superior brown mealworm. Styrofoam diet changes were observed for 20 days to determine whether mealworms were useful insects for decomposing Styrofoam. The average weight of mealworms before the Styrofoam diet was 500 mg, which decreased to 336 mg at D20 after their diet. To preserve mealworms with excellent Styrofoam-degrading ability, we first isolated the reproductive organs of mealworms, testes, ovaries, sperms, and ovarioles. Morphologically, male and female adult brown mealworms were distinguished according to the presence or absence of a protrusion at the tip of the fifth segment of the abdomen. Sperms and ovarioles were observed in anatomically isolated testes and ovaries. We compared mechanical and enzymatic (collagenase I) methods to effectively isolate ovarioles from adult female brown mealworms. For the enzymatic method, most were torn and burst as the membrane of the ovarioles was damaged by collagenase I, unlike the mechanical method. To preserve the superior genetic resources of mealworms, we cryopreserved the ovaries of female brown mealworms using slow-freezing and vitrification. Histological analysis showed that the yolk sac was completely damaged in the ovaries after slow-freezing. However, only partial damage was achieved in the vitrification group compared to the control group (no freezing). The newly developed vitrification method with alginate-encapsulated ovarioles maintained the yolk sac in the ovarioles but was evenly distributed. These results provide basic data for reproductive studies of other useful insects and contribute to the biobanking and fertility preservation of superior mealworm germ cells and endangered insects.

A Selective Adenosine A3 Receptor Antagonist, HL3501, Has Therapeutic Potential in Preclinical Liver and Renal Fibrosis Models.

BACKGROUND/AIM: Adenosine and 4 G-protein-associated membrane receptors (A1, A2A, A2B, and A3) and their derivatives regulate the central nervous, cardiovascular, peripheral, and immune system. We developed a novel selective A3 AR antagonist, HL3501, and examined its anti-fibrotic effects across various models. MATERIALS AND METHODS: The anti-fibrotic activity of HL3501 was evaluated in three cell lines (HK2, LX2, and Primary hepatic stellate cell) and a methionine-choline-deficient (MCD) model including use of mouse pharmacokinetics (PK). RESULTS: HL3501 decreased alpha-smooth muscle actin (α-SMA) and collagen 1 in TGF-ß1-induced pro-fibrotic activation in HK2 cells. HL3501 also inhibited TGF-ß1-induced HSC activation, which resulted in reduction of α-SMA and fibronectin in LX2 and human primary HSCs. In the nonalcoholic fatty liver disease activity score (NAS) analysis, HL3501 showed improved anti-steatosis and anti-inflammatory activity. The mouse PK study revealed the oral bioavailability (%F) of HL3501 at 30 mg/kg and 60 mg/kg as 92.5 and 107.2%, respectively. CONCLUSION: HL3501 presents anti-fibrotic effects in in vitro and in vivo studies. We also demonstrated that HL3501 is orally available and has a good bioavailability (BA >90%) profile from in mouse PK. HL3501, therefore, has a therapeutic potential for various fibrotic diseases, including those of liver and kidney tissues.

Dietary Efficacy Evaluation by Applying a Prediction Model Using Clinical Fecal Microbiome Data of Colorectal Disease to a Controlled Animal Model from an Obesity Perspective.

Obesity associated with a Western diet such as a high-fat diet (HFD) is a known risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this study, we aimed to develop fecal microbiome data-based deep learning algorithms for the risk assessment of colorectal diseases. The effects of a HFD and a candidate food (Nypa fruticans, NF) on IBD and CRC risk reduction were also evaluated. Fecal microbiome data were obtained from 109 IBD patients, 111 CRC patients, and 395 healthy control (HC) subjects by 16S rDNA amplicon sequencing. IBD and CRC risk assessment prediction models were then constructed by deep learning algorithms. Dietary effects were evaluated based on fecal microbiome data from rats fed on a regular chow diet (RCD), HFD, and HFD plus ethanol extracts or water extracts of NF. There were significant differences in taxa when IBD and CRC were compared with HC. The diagnostic performance (area under curve, AUC) of the deep learning algorithm was 0.84 for IBD and 0.80 for CRC prediction. Based on the rat fecal microbiome data, IBD and CRC risks were increased in HFD-fed rats versus RCD-fed rats. Interestingly, in the HFD-induced obesity model, the IBD and CRC risk scores were significantly lowered by the administration of ethanol extracts of NF, but not by the administration of water extracts of NF. In conclusion, changes in the fecal microbiome of obesity by Western diet could be important risk factors for the development of IBD and CRC. The risk prediction model developed in this study could be used to evaluate dietary efficacy.

Discovery of GSK3ß Inhibitors through In Silico Prediction-and-Experiment Cycling Strategy, and Biological Evaluation.

Direct inhibitors of glycogen synthase kinase 3ß (GSK3ß) have been investigated and reported for the past 20 years. In the search for novel scaffold inhibitors, 3000 compounds were selected through structure-based virtual screening (SBVS), and then high-throughput enzyme screening was performed. Among the active hit compounds, pyrazolo [1,5-a]pyrimidin-7-amine derivatives showed strong inhibitory potencies on the GSK3ß enzyme and markedly activated Wnt signaling. The result of the molecular dynamics (MD) simulation, enhanced by the upper-wall restraint, was used as an advanced structural query for the SBVS. In this study, strong inhibitors designed to inhibit the GSK3ß enzyme were discovered through SBVS. Our study provides structural insights into the binding mode of the inhibitors for further lead optimization.

A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer.

Cancer stem cells (CSCs) are a tumor cell subpopulation that drives tumor progression and metastasis, leading to a poor overall survival of patients. In colorectal cancer (CRC), the hyper-activation of Wnt/ß-catenin signaling by a mutation of both adenomatous polyposis coli (APC) and K-Ras increases the size of the CSC population. We previously showed that CPD0857 inactivates Wnt/ß-catenin signaling by promoting the ubiquitin-dependent proteasomal degradation of ß-catenin and Ras proteins, thereby decreasing proliferation and increasing the apoptosis of CRC lines. CPD0857 also decreased the growth and invasiveness of CRC cells harboring mutant K-Ras resistant to EGFR mAb therapy. Here, we show that CPD0857 treatment decreases proliferation and increases the neuronal differentiation of neural progenitor cells (NPCs). CDP0857 effectively reduced the expression of CSC markers and suppressed self-renewal capacity. CPD0857 treatment also inhibited the proliferation and expression of CSC markers in D-K-Ras MT cells carrying K-Ras, APC and PI3K mutations, indicating the inhibition of PI3K/AKT signaling. Moreover, CPD0857-treated xenograft mice showed a regression of tumor growth and decreased numbers of CSCs in tumors. We conclude that CPD0857 could serve as the basis of a drug development strategy targeting CSCs activated through Wnt/ß-catenin-Ras MAPK-PI3K/AKT signaling in CRCs.

HL3501, a Novel Selective A3 Adenosine Receptor Antagonist, Lowers Intraocular Pressure (IOP) in Animal Glaucoma Models.

PURPOSE: The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects. METHODS: For the rabbit model, intraocular pressure (IOP) was increased by laser photocoagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining. RESULTS: HL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and α-smooth muscle actin expression induced by Dex treatment. CONCLUSIONS: HL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma. TRANSLATIONAL RELEVANCE: HL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.

Azathioprine antagonizes aberrantly elevated lipid metabolism and induces apoptosis in glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with poor survival rate. Temozolomide (TMZ) is used as standard chemotherapy to treat GBM, but a large number of patients either respond poorly and/or develop resistance after long-term use, emphasizing the need to develop potent drugs with novel mechanisms of action. Here, using high-throughput compound screening (HTS), we found that azathioprine, an immunosuppressant, is a promising therapeutic agent to treat TMZ-resistant GBM. Through integrative genome-wide analysis and global proteomic analysis, we found that elevated lipid metabolism likely due to hyperactive EGFR/AKT/SREBP-1 signaling was inhibited by azathioprine. Azathioprine also promoted ER stress-induced apoptosis. Analysis of orthotopic xenograft models injected with patient-derived GBM cells revealed reduced tumor volume and increased apoptosis after azathioprine and TMZ co-treatment. These data indicate that azathioprine could be a powerful therapeutic option for TMZ-resistant GBM patients.

Small Molecule Destabilizer of ß-Catenin and Ras Proteins Antagonizes Growth of K-Ras Mutation-Driven Colorectal Cancers Resistant to EGFR Inhibitors.

BACKGROUND: Oncogenic K-Ras mutations in colorectal cancer (CRC) combined with APC mutations worsen CRC prognosis and lower drug effectiveness. Thus, inhibition of both Wnt/ß-catenin and Ras-MAPK signaling may be a rational strategy to improve the treatment of this cancer. OBJECTIVE: To identify a novel compound inhibiting both Wnt/ß-catenin and Ras-MAPK signaling in CRC. METHODS AND PATIENTS: We developed a two-part screening system consisting of analysis of TOP flash reporter cells and then potential toxicity effects on primary neural stem cells (NSCs). We then screened 2000 chemical compounds and tested efficacy of candidates against isogenic colon cancer cells harboring wild-type or mutant K-Ras. We employed immunohistochemistry and immunocytochemistry to determine marker signatures associated with development of disease phenotypes. RESULTS: We identified CPD0857, a compound that inactivates Wnt/ß-catenin signaling and promotes ubiquitin-dependent proteasomal degradation of ß-catenin and Ras proteins. CPD0857 effectively decreased proliferation and increased apoptosis of CRC cell lines, and overcame resistance of CRC harboring APC and K-Ras mutations to treatment with an EGFR monoclonal antibody (mAb). Moreover, CPD0857 attenuated invasiveness of highly migratory CRC cells in vitro. Accordingly, xenograft mice treated with CPD0857 showed slower tumor growth and significant decreases in both ß-catenin and Ras protein expression. CONCLUSIONS: CPD0857 may be a potential drug for treating aggressive CRC carrying mutations that aberrantly activate Wnt/ß-catenin and Ras-ERK pathways.

Epigenetic modulator inhibition overcomes temozolomide chemoresistance and antagonizes tumor recurrence of glioblastoma.

Glioblastoma multiforme (GBM) heterogeneity causes a greater number of deaths than any other brain tumor, despite the availability of alkylating chemotherapy. GBM stem-like cells (GSCs) contribute to GBM complexity and chemoresistance, but it remains challenging to identify and target GSCs or factors that control their activity. Here, we identified a specific GSC subset and show that activity of these cells is positively regulated by stabilization of methyl CpG binding domain 3 (MBD3) protein. MBD3 binds to CK1A and to BTRCP E3 ubiquitin ligase, triggering MBD3 degradation, suggesting that modulating this circuit could antagonize GBM recurrence. Accordingly, xenograft mice treated with the CK1A activator pyrvinium pamoate (Pyr-Pam) showed enhanced MBD3 degradation in cells expressing high levels of O6-methylguanine-DNA methyltransferase (MGMT) and in GSCs, overcoming temozolomide chemoresistance. Pyr-Pam blocked recruitment of MBD3 and the repressive nucleosome remodeling and deacetylase (NuRD) complex to neurogenesis-associated gene loci and increased acetyl-histone H3 activity and GSC differentiation. We conclude that CK1A/BTRCP/MBD3/NuRD signaling modulates GSC activation and malignancy, and that targeting this signaling could suppress GSC proliferation and GBM recurrence.

Gochujang prepared using rice and wheat koji partially alleviates high-fat diet-induced obesity in rats.

The aim of this study was to compare whether gochujang products prepared using giant embryo rice koji (rice gochujang, RG) and wheat koji (wheat gochujang, WG) have anti-obesity effects on rats fed a high-fat diet (HFD), who served as a model for obesity. The nutritional composition of RG and WG including proximate constituents, amino acid and fatty acid compositions were investigated. Consequently, the secondary fermented metabolites were analyzed in RG and WG by ultrahigh-performance liquid chromatography and mass spectrometry. Rats were fed a HFD containing 10% RG powder (HFD-RG) or 10% WG powder (HFD-WG) for 8 weeks. Body weight gain, weights of liver, epididymal, retroperitoneal, perirenal, and total white fat pads, and levels of serum triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, and leptin were lower in all gochujang groups than in the HFD group. Furthermore, RG and WG treatment decreased the hepatic TG content and lipid accumulation and significantly reduced the size of epididymal adipocytes. These effects are probably mediated through inhibition of hepatic fatty acid synthase, acetyl CoA carboxylase, malic enzyme, and adipose tissue lipoprotein lipase activities. The anti-obesity effect was slightly greater in the HFD-RG group than in the HFD-WG group. This effect may be attributed to secondary metabolites, such as capsaicin, genistein, daidzein, soyasaponin, and lysophosphatidylcholines, contained in gochujang prepared using giant embryo rice or wheat koji.

Thickness effect on low-power driving of MoS2 transistors in balanced double-gate fields.

In field-effect transistors (FETs), when the thickness of the semiconducting transition metal dichalcogenides (TMDs) channel exceeds the maximum depletion depth, the entire region cannot be completely controlled by a single-gate electric field. The layer-to-layer carrier transitions between the van der Waals interacted TMD layers result in the extraordinary anisotropic carrier transport in the in-plane and out-of-plane directions. The performance of the TMD FETs can be largely enhanced by optimizing the thickness of the TMD channel as well as increasing the effective channel area through which the gate field is delivered. In this study, we investigated the carrier behavior and device performance in double-gate FETs fabricated using a 57 nm thick MoS2, which is thicker than the maximum depletion depth of about 50 nm, and a much thinner 4 nm thick MoS2. The results showed that in the thick MoS2, the gate voltages at both ends formed two independent channels which had no synergistic effect on the device performance owing to the inefficient delivery of the vertical electric field. On the other hand, in the thin MoS2 channel, the double-gate voltages effectively controlled one channel, resulting in twice the carrier mobility and operation in a low electric field region, i.e. below 0.2 MV cm-1.

Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo-cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.This article is highlighted in the In This Issue feature, p. 1.

Edge Contact for Carrier Injection and Transport in MoS2 Field-Effect Transistors.

The contact properties of van der Waals layered semiconducting materials are not adequately understood, particularly for edge contact. Edge contact is extremely helpful in the case of graphene, for producing efficient contacts to vertical heterostructures, and for improving the contact resistance through strong covalent bonding. Herein, we report on edge contacts to MoS2 of various thicknesses. The carrier-type conversion is robustly controlled by changing the flake thickness and metal work functions. Regarding the ambipolar behavior, we suggest that the carrier injection is segregated in a relatively thick MoS2 channel; that is, electrons are in the uppermost layers, and holes are in the inner layers. Calculations reveal that the strength of the Fermi-level pinning (FLP) varies layer-by-layer, owing to the inhomogeneous carrier concentration, and particularly, there is negligible FLP in the inner layer, supporting the hole injection. The contact resistance is large despite the significantly reduced contact resistivity normalized by the contact area, which is attributed to the current-crowding effect arising from the narrow contact area.