miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway.

Background: miR-29c has been associated with the progression of many cancers. However, the function and mechanism of miR-29c have not been well investigated in breast cancers. Methods: Real-time quantitative PCR was used to assess expression of miR-29c and DNMT3B mRNA. Western blot and immunochemistry were used to examine the expression of DNA methyltransferase 3B (DNMT3B) protein in breast cancer cells and tissues. The functional roles of miR-29c in breast cancer cells such as proliferation, migration, invasion, colony formation, and 3D growth were evaluated using MTT, transwell chambers, soft agar, and 3D Matrigel culture, respectively. In addition, the luciferase reporter assay was used to check if miR-29c binds the 3\u27UTR of DNMT3B. The effects of miR-29c on the DNMT3B/TIMP3/STAT1/FOXO1 pathway were also examined using Western blot and methyl-specific qPCR. The specific inhibitor of STAT1, fludarabine, was used to further check the mechanism of miR-29c function in breast cancer cells. Studies on cell functions were carried out in DNMT3B siRNA cell lines. Results: The expression of miR-29c was decreased with the progression of breast cancers and was closely associated with an overall survival rate of patients. Overexpression of miR-29c inhibited the proliferation, migration, invasion, colony formation, and growth in 3D Matrigel while knockdown of miR-29c promoted these processes in breast cancer cells. In addition, miR-29c was found to bind 3\u27UTR of DNMT3B and inhibits the expression of DNMT3B, which was elevated in breast cancers. Moreover, the protein level of TIMP3 was reduced whereas methylation of TIMP3 was increased in miR-29c knockdown cells compared to control. On the contrary, the protein level of TIMP3 was increased whereas methylation of TIMP3 was reduced in miR-29c-overexpressing cells compared to control. Knockdown of DNMT3B reduced the proliferation, migration, and invasion of breast cancer cell lines. Finally, our results showed that miR-29c exerted its function in breast cancers by regulating the TIMP3/STAT1/FOXO1 pathway. Conclusion: The results suggest that miR-29c plays a significant role in suppressing the progression of breast cancers and that miR-29c may be used as a biomarker of breast cancers

Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD

EMPRESS. VI. Outflows Investigated in Low-Mass Galaxies with M∗=104−107 M⊙M_*=10^4-10^7~M_\odot: Weak Feedback in Low-Mass Galaxies?

We study emission line profiles of 21 nearby low-mass ($M_*=10^4-10^7~M_\odot$) galaxies in deep medium-high resolution spectra taken with Magellan/MagE. These low-mass galaxies are actively star-forming systems with high specific star-formation rates of $\mathrm{sSFR}\sim100-1000~\mathrm{Gyr}^{-1}$ that are well above the star-formation main sequence and its extrapolation. We identify broad-line components of H$\alpha$ and [OIII]$\lambda 5007$ emission in 14 out of the 21 galaxies that cannot be explained by the MagE instrumental profile or the natural broadening of line emission. We conduct double Gaussian profile fitting to the emission of the 14 galaxies, and find that the broad-line components have line widths significantly larger than those of the narrow-line components, indicative of galactic outflows. The board-line components have moderately large line widths of $\sim 100$ km s$^{-1}$. We estimate the maximum outflow velocities $v_\mathrm{max}$ and obtain values of $\simeq 60-200$ km s$^{-1}$, which are found to be comparable to or slightly larger than the escape velocities. Positive correlations of $v_\mathrm{max}$ with star-formation rates, stellar masses, and circular velocities, extend down into this low-mass regime. Broad- to narrow-line flux ratios BNRs are generally found to be smaller than those of massive galaxies. The small $v_\mathrm{max}$ and BNRs suggest that the mass loading factors $\eta$ can be as small as 0.1 - 1 or below, in contrast to the large $\eta$ of energy-driven outflows predicted by numerical simulations.Comment: 22 pages, 11 figures, Accepted for publication by Ap

The Life-Cycle of Operons

Operons are a major feature of all prokaryotic genomes, but how and why operon structures vary is not well understood. To elucidate the life-cycle of operons, we compared gene order between Escherichia coli K12 and its relatives and identified the recently formed and destroyed operons in E. coli. This allowed us to determine how operons form, how they become closely spaced, and how they die. Our findings suggest that operon evolution may be driven by selection on gene expression patterns. First, both operon creation and operon destruction lead to large changes in gene expression patterns. For example, the removal of lysA and ruvA from ancestral operons that contained essential genes allowed their expression to respond to lysine levels and DNA damage, respectively. Second, some operons have undergone accelerated evolution, with multiple new genes being added during a brief period. Third, although genes within operons are usually closely spaced because of a neutral bias toward deletion and because of selection against large overlaps, genes in highly expressed operons tend to be widely spaced because of regulatory fine-tuning by intervening sequences. Although operon evolution may be adaptive, it need not be optimal: new operons often comprise functionally unrelated genes that were already in proximity before the operon formed

Predicting cell types and genetic variations contributing to disease by combining GWAS and epigenetic data

Genome-wide association studies (GWASs) identify single nucleotide polymorphisms (SNPs) that are enriched in individuals suffering from a given disease. Most disease-associated SNPs fall into non-coding regions, so that it is not straightforward to infer phenotype or function; moreover, many SNPs are in tight genetic linkage, so that a SNP identified as associated with a particular disease may not itself be causal, but rather signify the presence of a linked SNP that is functionally relevant to disease pathogenesis. Here, we present an analysis method that takes advantage of the recent rapid accumulation of epigenomics data to address these problems for some SNPs. Using asthma as a prototypic example; we show that non-coding disease-associated SNPs are enriched in genomic regions that function as regulators of transcription, such as enhancers and promoters. Identifying enhancers based on the presence of the histone modification marks such as H3K4me1 in different cell types, we show that the location of enhancers is highly cell-type specific. We use these findings to predict which SNPs are likely to be directly contributing to disease based on their presence in regulatory regions, and in which cell types their effect is expected to be detectable. Moreover, we can also predict which cell types contribute to a disease based on overlap of the disease-associated SNPs with the locations of enhancers present in a given cell type. Finally, we suggest that it will be possible to re-analyze GWAS studies with much higher power by limiting the SNPs considered to those in coding or regulatory regions of cell types relevant to a given disease

An Integrated-Photonics Optical-Frequency Synthesizer

Integrated-photonics microchips now enable a range of advanced functionalities for high-coherence applications such as data transmission, highly optimized physical sensors, and harnessing quantum states, but with cost, efficiency, and portability much beyond tabletop experiments. Through high-volume semiconductor processing built around advanced materials there exists an opportunity for integrated devices to impact applications cutting across disciplines of basic science and technology. Here we show how to synthesize the absolute frequency of a lightwave signal, using integrated photonics to implement lasers, system interconnects, and nonlinear frequency comb generation. The laser frequency output of our synthesizer is programmed by a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and traceability to the SI second. This is accomplished with a heterogeneously integrated III/V-Si tunable laser, which is guided by dual dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through out-of-loop measurements of the phase-coherent, microwave-to-optical link, we verify that the fractional-frequency instability of the integrated photonics synthesizer matches the $7.0*10^{-13}$ reference-clock instability for a 1 second acquisition, and constrain any synthesis error to $7.7*10^{-15}$ while stepping the synthesizer across the telecommunication C band. Any application of an optical frequency source would be enabled by the precision optical synthesis presented here. Building on the ubiquitous capability in the microwave domain, our results demonstrate a first path to synthesis with integrated photonics, leveraging low-cost, low-power, and compact features that will be critical for its widespread use.Comment: 10 pages, 6 figure

The Microscopic Origin of Residual Stress for Flat Self-Actuating Piezoelectric Cantilevers

In this study, flat piezoelectric microcantilevers were fabricated under low-stress Pb(Zr0.52Ti0.48)O3 (PZT) film conditions. They were analyzed using the Raman spectrum and wafer curvature methods. Based on the residual stress analysis, we found that a thickness of 1 μm was critical, since stress relaxation starts to occur at greater thicknesses, due to surface roughening. The (111) preferred orientation started to decrease when the film thickness was greater than 1 μm. The d33 value was closely related to the stress relaxation associated with the preferred orientation changes. We examined the harmonic response at different PZT cantilever lengths and obtained a 9.4-μm tip displacement at 3 Vp-p at 1 kHz. These analyses can provide a platform for the reliable operation of piezoelectric microdevices, potentially nanodevice when one needs to have simultaneous control of the residual stress and the piezoelectric properties

Observation of new magnetic ground state in frustrated quantum antiferromagnet spin-liquid system Cs2CuCl4

Cs2CuCl4 is known to possess a quantum spin-liquid phase with antiferromagnetic interaction below 2.8 K. We report the observation of a new metastable magnetic phase of the triangular frustrated quantum spin system Cs2CuCl4 induced by the application of hydrostatic pressure. We measured the magnetic properties of Cs2CuCl4 following the application and release of pressure after 3 days. We observed a previously unknown ordered magnetic phase with a transition temperature of 9 K. Furthermore, the recovered sample with new magnetic ground state possesses an equivalent crystal structure to the uncompressed one with antiferromagnetic quantum spinliquid phase

A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer

<p>Abstract</p> <p>Background</p> <p>Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy.</p> <p>Methods</p> <p>The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival.</p> <p>Results</p> <p>At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61–0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52–0.83) were independent negative prognostic factors for overall survival.</p> <p>Conclusion</p> <p>Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC.</p