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Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8

Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.

The discovery of topological states of matter has led to a revolution in materials research. When external or intrinsic parameters break certain symmetries, global properties of topological materials change drastically. A paramount example is the emergence of Weyl nodes under broken inversion symmetry, acting like magnetic monopoles in momentum space. However, while a rich variety of non-trivial quantum phases could in principle also originate from broken time-reversal symmetry, realizing systems that combine magnetism with complex topological properties is remarkably elusive due to both considerable experimental and theoretical challenges. Here, we demonstrate that giant open Fermi arcs are created at the surface of ultrathin hybrid magnets. The Fermi-surface topology of an atomically thin ferromagnet is substantially modified by the hybridization with a heavy-metal substrate, giving rise to Fermi-surface discontinuities that are bridged by the Fermi arcs. Due to the interplay between magnetism and topology, we can control both the shape and the location of the Fermi arcs by tuning the magnetization direction. The hybridization points in the Fermi surface can be attributed to a non-trivial "mixed" topology and induce hot spots in the Berry curvature, dominating spin and charge transport as well as magneto-electric coupling effects., 14 pages, 10 figures

This paper proposes the design and implementation of an inductor with a stepped air-gap for a buck converter with improved feedback control. Typically, a power converter needs to maintain stable operation during any load transient. When designing the compensator for a converter according to the traditional method for continuous conduction mode (CCM), the same compensator is employed from light load to full load, which leads to poor response at some operating points, especially at light load. To achieve a better system response, a stepped air-gap inductor is proposed to increase the inductance at light load, which is analyzed and compared with a traditional inductor. The proposed stepped air-gap inductor reduces the influence of the magnetic flux leakage on the winding. The effect of having two different inductance values on the controller design is discussed, and the conditions for discontinuous conduction mode (DCM) at light load with the stepped air-gap inductor are outlined. A 48-V to 12-V buck converter rated for 60 W is built and tested to verify the proposed stepped air-gap inductor. With the proposed stepped air-gap inductor, experimental results show that undershoot and overshoot were improved 50% and settling time was decreased to 20% and 30% during light-to-full load transients, compared to the traditional inductor. Hence, the proposed stepped air-gap inductor can effectively improve system response.

BackgroundCD8+ tissue-resident memory T (TRM) cells, marked by CD103 (ITGAE) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.MethodsHere, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).ResultsITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.ConclusionsOur analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.

Physical review / B 104(16), L161104 (2021). doi:10.1103/PhysRevB.104.L161104, We show that the presence of a transiently excited hot electron gas in graphene leads to a substantial broadening of the C 1s line probed by time-resolved x-ray photoemission spectroscopy. The broadening is found to be caused by an exchange of energy and momentum between the photoemitted core electron and the hot electron gas, rather than by vibrational excitations. This interpretation is supported by a quantitative line-shape analysis that accounts for the presence of the excited electrons. Fitting the spectra to this model directly yields the electronic temperature of the system, in good agreement with electronic temperature values obtained from valence band data. Furthermore, we show how the momentum change of the outgoing core electrons leads to a detectable but very small change in the time-resolved photoelectron diffraction pattern and to a nearly complete elimination of the core level binding energy variation associated with the presence of a narrow �� band in the C 1s state., Published by Inst., Woodbury, NY

JuSPARC, the Jülich Short-Pulsed Particle and Radiation Center, is a laser-driven facility to enable research with short-pulsed photon and particle beams to be performed at the Forschungszentrum Jülich. The conceptual design of JuSPARC is determined by a set of state-of-the-art time-resolved instruments, which are designed to address the electronic, spin, and structural states of matter and their dynamic behaviour. From these instruments and experiments JuSPARC derives the need of operating several dedicated high pulse-power laser systems at highest possible repetition rates. They serve as core units for optimized photon up-conversion techniques generating the light pulses for the respective experiments. The applications also include experiments with spin polarized particle beams, which require the use of laser-based polarized gas targets. Thus, in its rst stage JuSPARC comprises four driving laser systems, called JuSPARC_VEGA, JuSPARC_DENEB, JuSPARC_SIRIUS and JuSPARC_MIRA, which are outlined in this article.

Photoelectron spectroscopy is our main tool to explore the electronic structure of novel material systems, the properties of which are often determined by an intricate interplay of competing interactions. Elucidating the role of this interactions requires studies over an extensive range of energy, momentum, length, and time scales. We show that immersion lens-based momentum microscopy with spin-resolution is able to combine these seemingly divergent requirements in a unifying experimental approach. We will discuss applications to different areas in information research, for example, resistive switching and spintronics. The analysis of resistive switching phenomena in oxides requires high lateral resolution and chemical selectivity, as the processes involve local redox processes and oxygen vacancy migration. In spintronics topological phenomena are currently a hot topic, which lead to complex band structures and spin textures in reciprocal space. Spin-resolved momentum microscopy is uniquely suited to address these aspects.

Significance The ubiquitin ligase CRL4COP1/DET1 modifies specific transcription factor substrates with polyubiquitin so that they are degraded. However, the Ras–MEK–ERK signaling pathway can inactivate CRL4COP1/DET1 and thereby promote the rapid accumulation of these transcription factors. Here we show that constitutive photomorphogenesis 1 (COP1) has a critical role in mouse brain development because its deletion from neural stem cells stabilizes the transcription factors c-JUN, ETV1, ETV4, and ETV5, leading to perturbation of normal gene expression patterns; anatomic anomalies in cerebral cortex, hippocampus, and cerebellum; and perinatal lethality., The E3 ubiquitin ligase CRL4COP1/DET1 is active in the absence of ERK signaling, modifying the transcription factors ETV1, ETV4, ETV5, and c-JUN with polyubiquitin that targets them for proteasomal degradation. Here we show that this posttranslational regulatory mechanism is active in neurons, with ETV5 and c-JUN accumulating within minutes of ERK activation. Mice with constitutive photomorphogenesis 1 (Cop1) deleted in neural stem cells showed abnormally elevated expression of ETV1, ETV4, ETV5, and c-JUN in the developing brain and spinal cord. Expression of c-JUN target genes Vimentin and Gfap was increased, whereas ETV5 and c-JUN both contributed to an expanded number of cells expressing genes associated with gliogenesis, including Olig1, Olig2, and Sox10. The mice had subtle morphological abnormalities in the cerebral cortex, hippocampus, and cerebellum by embryonic day 18 and died soon after birth. Elevated c-JUN, ETV5, and ETV1 contributed to the perinatal lethality, as several Cop1-deficient mice also lacking c-Jun and Etv5, or lacking Etv5 and heterozygous for Etv1, were viable.

Background PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations. Methods A Pik3caH1047R;Trp53R270H;MMTV-Cre double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis. Results We found Pik3caH1047R and Trp53R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified S100a4 as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial–mesenchymal transition (EMT)-signature positive and S100a4-expressing cells. CRISPR/CAS9-mediated knockout of S100a4 in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for S100a4 in metastasis. Conclusions Pik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

Tissue specificity of tumor suppression It is well known that the loss of tumor suppressor genes leads to a limited subset of cancers in specific tissues. But why just those tissues? He et al. found a relatively simple explanation for how this tissue selectivity works for the tumor suppressor BAP1 using a mouse model of BAP1-induced cancer. In most cells, loss of BAP1 caused cell death or apoptosis. But in the tissues that formed tumors, differences in the regulation of genes with antiapoptotic effects allowed the cells to survive, even though BAP1 was lost. At least for this one tumor suppressor, its inactivation would normally cause a cell to die; however, this mechanism is absent in a subset of tissues, allowing the cells to proliferate and cause a tumor. Science , this issue p. 283

Additional file 1: Figure S1. Frequency of TP53 and PIK3CA mutations in human breast cancer samples. A. TP53 and PIK3CA are the two most frequently altered genes in breast cancers. B. Frequency of PIK3CA and TP53 double mutant breast cancer samples. C. Frequency of TP53 mutations in breast cancer samples with PIK3CA mutations. Figure S2. Expression of Pik3caH1047R (A) and Trp53R270H (B) alleles in a Pik3caH1047R/+;Trp53R270H/+;MMTV-Cre tumor as assessed by RNA-seq. Figure S3. Tumor progression in Pik3caH1047R;Trp53R270H;MMTV-Cre mice, Pik3caH1047R;MMTV-Cre mice and Trp53R270H;MMTV-Cre mice. Figure S4. Lower magnification of the panels in Fig. 2 in the same order. Figure S5. Histology of Trp53R270H;MMTV-Cre primary mammary tumors. A. adenocarcinoma, B. adenosquamous carcinoma, C. sarcomatoid (spindle cell) carcinoma, D. invasive poorly differentiated carcinoma on bone (arrow indicates bone tissue), E. poorly differentiated carcinoma, and F. metastatic lymph node (from the same animal bearing primary tumor in panel E). Figure S6. Immunofluorescence staining of a poorly differentiated Pik3caH1047R;Trp53R270H;MMTV-Cre carcinoma with focal sarcomatoid features (A-C) or sarcomatoid Pik3caH1047R;Trp53R270H;MMTV-Cre (D-E) adenocarcinoma or sarcomatoid Trp53R270H;MMTV-Cre carcinoma (F). Staining for Krt18 (green), Krt5 (red), Vimentin (green), progesterone receptor (Pgr, green) and estrogen receptor(Esr, red) are shown. DAPI is shown in blue. Figure S7. Cellular heterogeneity of Pik3caH1047R;Trp53R270H;MMTV-Cre tumors. A. Same as Fig. 3B-D. EMT signature positive (B) and S100a4 positive (C) for cells in panel A. The numbers indicate the percentages of cell types (A), percentage of EMT positive cells (B) and S100a4 positive cells (C). Figure S8. Expression level of S100a4 in breast cancer TCGA data set (www.cbioportal.org). RSEM*: RNA-Seq by Expectation Maximization (BMC Bioinformatics 2011, 12:323). Figure S9. S100a4 protein levels in CRISPR/Cas9 knockout lines assessed by Western blotting. Figure S10. Log2 RPKM heatmap comparing RNA-seq based expression of select genes in the S100a4 knockout, parental and vector control cell lines. Table S1. Summary of allelic frequency, in the S100a4 knockout lines.

A stable BiI3 monosheet has been grown for the first time on the (0001) surface of the topological insulator Bi2Se3 as confirmed by scanning tunnelling microscopy, surface X-ray diffraction, and X-ray photoemision spectroscopy. BiI3 is deposited by molecular beam epitaxy from the crystalline BiTeI precursor that undergoes decomposition sublimation. The key fragment of the bulk BiI3 structure, a 2 [I—Bi—I] layer of edge-sharing BiI6 octahedra, is preserved in the ultra-thin film limit, but exhibits large atomic relaxations. The stacking sequence of the trilayers and alternations of the Bi—I distances in the monosheet are the same as in the bulk BiI3 structure. Momentum resolved photoemission spectroscopy indicates a direct band gap of 1.2 eV. The Dirac surface state is completely destroyed and a new flat band appears in the band gap of the BiI3 film that could be interpreted as an interface state., This work is supported by the DFG through SPP 1666 (Topological Insulators) and ERANET Chemistry program. The authors thank Arthur Ernst for providing the DFT calculations of the relaxed BiI3 double-layer film. We thank F. Weiss for technical support. The authors thank the staff of the ESRF and Elettra for their help and hospitality during their visit in Grenoble and Trieste, and G. Zamborlini, M. Jugovac and V. Feyer (PGI-6) for assistance, in using the NanoESCA beamline.

Hemispherical deflection analyzers are the most widely used energy filters for state-of-the-art electron spectroscopy. Due to the high spherical symmetry, they are also well suited as imaging energy filters for electron microscopy. Here, we review the imaging properties of hemispherical deflection analyzers with emphasis on the application for cathode lens microscopy. In particular, it turns out that aberrations, in general limiting the image resolution, cancel out at the entrance and exit of the analyzer. This finding allows more compact imaging energy filters for momentum microscopy or photoelectron emission microscopy. For instance, high resolution imaging is possible, using only a single hemisphere. Conversely, a double pass hemispherical analyzer can double the energy dispersion, which means it can double the energy resolution at certain transmission, or can multiply the transmission at certain energy resolution.

We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

Summary: Age-related macular degeneration (AMD) is a leading cause of vision loss. To better understand disease pathogenesis and identify causal genes in GWAS loci for AMD risk, we present a comprehensive database of human retina and retinal pigment epithelium (RPE). Our database comprises macular and non-macular RNA sequencing (RNA-seq) profiles from 129 donors, a genome-wide expression quantitative trait loci (eQTL) dataset that includes macula-specific retina and RPE/choroid, and single-nucleus RNA-seq (NucSeq) from human retina and RPE with subtype resolution from more than 100,000 cells. Using NucSeq, we find enriched expression of AMD candidate genes in RPE cells. We identify 15 putative causal genes for AMD on the basis of co-localization of genetic association signals for AMD risk and eye eQTL, including the genes TSPAN10 and TRPM1. These results demonstrate the value of our human eye database for elucidating genetic pathways and potential therapeutic targets for ocular diseases. : To find genes underlying risk for age-related macular degeneration, Orozco et al. analyze human ocular transcriptomes in conjunction with genotypes and build a single-nucleus atlas. They identify 15 putative causal genes, of which TSPAN10 and TRPM1 were enriched in retinal pigment epithelium, the site of early disease pathology. Keywords: eQTL, NucSeq, single cell, RNA-seq, age-related macular degeneration, AMD, retinal pigment epithelium, retina, GWAS

The co-sensitization is an effective way to enhance the spectral responses of the dye-sensitized solar cells (DSSCs) by using multiple dyes to absorb different parts of the solar spectrum. The organic sensitizers of the triphenylamine derivatives, W3 and W4 dyes, are synthesized with complementary light absorption spectra to that of the commercially available N719 dye. The main absorption peaks are at 400–500 nm and 500–600 nm for the triphenylamine derivatives and the N719 dye, respectively. Owing to the outstanding cell performance and the higher absorption coefficient, the W4 dye was applied to co-sensitize with the N719 dye. A wide absorption wavelength (400–700 nm) for light harvesting is obtained for the co-sensitized ZnO film soaking in the N719 dye for 2 h and subsequently in the W4 dye for 1.5 h, and thereby an light-to-electricity conversion efficiency ( η ) value of 4.34% is achieved for the pertinent DSSC, which is higher than those of the cells sensitized with individual W4 dye (3.38%) and N719 dye (3.76%). The co-sensitized ZnO film cannot only possess wider light absorption range but also better sensitizer coverage since the small size of the organic dye (W4) can adsorb on the gaps between the three dimensional N719 dye on the ZnO surface. The electrochemical impedance spectroscopy (EIS) and the incident photo-to-current conversion efficiency (IPCE) are utilized to analyse the interfacial resistance and the wavelength-dependent light-to-electricity efficiency for the DSSCs, respectively.

To enhance the spectral responses of the dye-sensitized solar cells (DSSCs), utilizing two or more dyes with complementary absorption spectra is a feasible way to absorb light in various regions of the solar spectrum. The organic dye, J1 dye, is self-synthesized for the first time, which shows a high absorption coefficient of 38,500 M −1 cm −1 and an absorption spectrum ranged from 400 to 600 nm. By co-sensitizing the J1 dye with the commercial N719 dye, the absorption region of the J1/N719 dyes can be extended to 700 nm, which nearly covers all the visible region of the solar spectrum. A light-to-electricity conversion efficiency ( η ) of 4.67% is achieved for the co-sensitized DSSC, which is higher than those of the cells sensitized with individual J1 dye (3.26%) or N719 dye (3.27%), probably due to the enhanced light absorption and more complete coverage of the small organic J1 dye on the ZnO surfaces for the co-sensitized DSSC. The ultraviolet-visible (UV-vis) absorption spectra and the incident photon-to-current conversion efficiency (IPCE) measurement are also utilized to analyse the wavelength-dependent light-to-electricity efficiency of the DSSCs.

Well-to-well variation in the number of reads and detected transcripts for Ba/F3 cells. (a) Number of mapped reads plotted against number of sequenced reads for each well. (b) Number of detected transcripts plotted against number of sequenced reads for each well. (PDF 237Â kb)

Hierarchical clustering of (a) human and (b) mouse cell lines based on 100 most variable genes. (PDF 1272Â kb)

Heatmaps illustrating the total number of detected transcripts for each well selected for downstream processing. Data are for three microchips, each with 5184 wells arranged in a 72Â Ă Â 72 square layout. Microchips 72,618 and 72,598 were used for profiling human and mouse cell lines (names of cell lines indicated in the plot). Microchip 72,625 was used for profiling pancreatic islets. For microchips with multiple dispensed samples, the dispense area for each sample is indicated. (PDF 93Â kb)

Checkerboard assay. (a) Image of a microchip where the right half contains negative control master mix (NTC wells, n = 2520) and the left half contains lambda DNA master mix master (Positive wells, n = 1024) and negative control master mix (Test wells, n = 1496) in a checkerboard pattern. (b) Number of Test wells with signal, number of NTC wells with signal, and calculated misalignment rate for 11 MSNDs and 19 microchips. (PDF 1288 kb)

Percentage of mitochondrial transcripts plotted against total number of detected transcripts for mouse Ba/F3 cells (a), human cell lines (b), mouse cell lines (c), and pancreatic islets (d). Dashed lines indicate the minimum number of detected transcripts required as a cell QC filter for each data set. (PDF 409Â kb)

Effect of requiring a minimum number of reads per UMI on single-cell purity. Shown are data for the species-mixing experiment when considering UMIs supported by a minimum of 1, 2 or 3 reads. Single-cell purity estimates are shown in each panel. Otherwise as Fig. 3. (PDF 94Â kb)

Unsupervised principal component analysis (PCA) for mouse pancreatic islet cells based on the 500 most variable genes. Circles correspond to cells and are colored by (a) microchip (n = 116 for 72574, n = 352 for 72625) and (b) transcript counts of cell type markers (Ins1, Gcg, Ppy, and Sst). (PDF 139 kb)

Overview of single-cell RNA-seq workflow on the ICELL8 system with detailed information on each processing step, including the time required for completion. (PDF 80Â kb)

Cell-to-cell variability and comparison of single-cell ensemble versus bulk expression. (a) Scatter plot of per-gene transcript counts for two Ba/F3 cells. (b) Scatter plot of per-gene read counts for two Ba/F3 cells shown in (a). (c) Scatter plot of per-gene transcript counts for bulk cells versus ensemble of single cells. (PDF 272Â kb)

Simulation and experiment are performed to investigate the influence of onion states with different-helicity pair vortices on the magnetization reversal process. It is found that for the onion state that has pair vortices with the same helicity, flux-closure state occurs in the reversal process; for the onion state that has pair vortices with opposite helicity, flux-closure state does not occur in the reversal process, and the onion state transforms directly to the reverse onion state. In addition, notches at the same side and diagonal notches with respect to the field direction are designed on the permalloy rings to induce onion states with same-helicity pair vortices and opposite-helicity pair vortices, respectively, for the control of the three-step and two-step magnetization reversal processes.

An actuator with single-domain magnetic thin films is designed to investigate the actuation in the application of a magnetic field. The single-domain magnetic thin film used in this study has high shape anisotropy, and the single-domain magnetization is observed using magnetic force microscope. The hysteresis in the planar deflection of the cantilever beam is found, and the magnetic switching behavior of the single-domain magnetic thin films is also observed in the actuation.

Magnetization reversals in permalloy rings controlled by nucleation sites using triangular fins at the same side and diagonal with respect to the field direction are demonstrated by magnetoresistance measurement and micromagnetic simulation. In the ring with triangular fins at the same side, there exists two-step reversal from onion to flux-closure state (or vortex state) and then from flux-closure (or vortex state) to reverse onion state; in the ring with diagonal triangular fins, one-step reversal occurs directly from onion to reverse onion state. The reversal processes are repeatable and controllable in contrast to an ideal ring without triangular fins where one-step and two-step reversals occur randomly in sweep-up and sweep-down processes.

Co 50 Fe 50 films with thickness varying from 100 to 500 A were deposited on a glass substrate by sputtering process, respectively. Two kinds of CoFe films were studied: one was the as-deposited film, and the other the annealed film. The annealing procedure was to keep the films at 400 °C for 5 h in a vacuum of 5×10 −6 mbar. From the X-ray study, we find that the as-deposited film prefers the CoFe(1 1 0) orientation. Moreover, the body-centered cubic (bcc) CoFe(1 1 0) line is split into two peaks: one corresponding to the ordered body-centered tetragonal (bct) phase, and the other, the disordered bcc phase. After annealing, the peak intensity of the ordered bct phase becomes much stronger, while that of the disordered bcc phase disappears. The annealing has also caused the ordered CoFe(2 0 0) line to appear. When the amount of the ordered bct phase in Co 50 Fe 50 is increased, the saturation magnetization ( M s ) and coercivity ( H c ) become larger, but the electrical resistivity ( ρ ) decreases. From the temperature coefficient of resistance (TCR) measurement, we learn that the bct grains in the CoFe film start to grow at temperature 82 °C.

An increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to ≈2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism/20 kb over 1.5 Mb) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-Mb locus that are likely to harbor candidate schizophrenia susceptibility genes.

In this study, we tested humidity s effect on the conductivity of transparent polyaniline thin films over a period of time. After creating three environments of different humidity levels (high, medium, and low) for storing our polyaniline thin film samples, we used a multimeter to measure the electrical resistance and observed the changes in electrical resistance of the samples over time. We discovered that the electrical resistance of the three samples all increased over time, with the electrical resistance of those in high and medium humidity environments increasing at a significantly greater rate than the electrical resistance of the sample in the low humidity environment. The results suggest that an environment with less water vapor could better preserve the conductivity of polyaniline thin films.

To further understand the molecular distinctions between kidney cancer subtypes, we analyzed exome, transcriptome and copy number alteration data from 167 primary human tumors that included renal oncocytomas and non-clear cell renal cell carcinomas (nccRCCs), consisting of papillary (pRCC), chromophobe (chRCC) and translocation (tRCC) subtypes. We identified ten significantly mutated genes in pRCC, including MET, NF2, SLC5A3, PNKD and CPQ. MET mutations occurred in 15% (10/65) of pRCC samples and included previously unreported recurrent activating mutations. In chRCC, we found TP53, PTEN, FAAH2, PDHB, PDXDC1 and ZNF765 to be significantly mutated. Gene expression analysis identified a five-gene set that enabled the molecular classification of chRCC, renal oncocytoma and pRCC. Using RNA sequencing, we identified previously unreported gene fusions, including ACTG1-MITF fusion. Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes. Finally, we observed upregulation of the anti-apoptotic factor BIRC7 in MiTF-high RCC tumors, suggesting a potential therapeutic role for BIRC7 inhibitors.

In migrating adherent cells such as fibroblasts and endothelial cells, the microtubule-organizing center (MTOC) reorients toward the leading edge [1–3]. MTOC reorientation repositions the Golgi toward the front of the cell [1] and contributes to directional migration [4]. The mechanism of MTOC reorientation and its relation to the formation of stabilized microtubules (MTs) in the leading edge, which occurs concomitantly with MTOC reorientation [3], is unknown. We show that serum and the serum lipid, lysophosphatidic acid (LPA), increased Cdc42 GTP levels and triggered MTOC reorientation in serum-starved wounded monolayers of 3T3 fibroblasts. Cdc42, but not Rho or Rac, was both sufficient and necessary for LPA-stimulated MTOC reorientation. MTOC reorientation was independent of Cdc42-induced changes in actin and was not blocked by cytochalasin D. Inhibition of dynein or dynactin blocked LPA- and Cdc42-stimulated MTOC reorientation. LPA also stimulates a Rho/mDia pathway that selectively stabilizes MTs in the leading edge [5, 6]; however, activators and inhibitors of MTOC reorientation and MT stabilization showed that each response was regulated independently. These results establish an LPA/Cdc42 signaling pathway that regulates MTOC reorientation in a dynein-dependent manner. MTOC reorientation and MT stabilization both act to polarize the MT array in migrating cells, yet these processes act independently and are regulated by separate Rho family GTPase-signaling pathways.

Field evolution of two types of mixed states made of four vortex cores and two anti-vortex cores are investigated numerically. The two types of mixed states both consist of one rhombic domain and one or two cross-tie walls. The two mixed states are found to exhibit different magnetization processes. As the field is applied along the long side direction, both mixed states exhibit two steps in magnetization curves; as the field is applied in parallel or antiparallel to the magnetization direction of the rhombic domain, however, it may exhibit two-step or three-step characteristic depending on its magnetization configuration.