41 research outputs found

    PRMT5 Associates With the FOXP3 Homomer and When Disabled Enhances Targeted p185erbB2/neu Tumor Immunotherapy

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    Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner

    Association of Mitochondrial DNA Variations with Lung Cancer Risk in a Han Chinese Population from Southwestern China

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    Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage and mutation due to the high rate of reactive oxygen species (ROS) production and limited DNA-repair capacity in mitochondrial. Previous studies demonstrated that the increased mtDNA copy number for compensation for damage, which was associated with cigarette smoking, has been found to be associated with lung cancer risk among heavy smokers. Given that the common and “non-pathological” mtDNA variations determine differences in oxidative phosphorylation performance and ROS production, an important determinant of lung cancer risk, we hypothesize that the mtDNA variations may play roles in lung cancer risk. To test this hypothesis, we conducted a case-control study to compare the frequencies of mtDNA haplogroups and an 822 bp mtDNA deletion between 422 lung cancer patients and 504 controls. Multivariate logistic regression analysis revealed that haplogroups D and F were related to individual lung cancer resistance (OR = 0.465, 95%CI = 0.329–0.656, p<0.001; and OR = 0.622, 95%CI = 0.425–0.909, p = 0.014, respectively), while haplogroups G and M7 might be risk factors for lung cancer (OR = 3.924, 95%CI = 1.757–6.689, p<0.001; and OR = 2.037, 95%CI = 1.253–3.312, p = 0.004, respectively). Additionally, multivariate logistic regression analysis revealed that cigarette smoking was a risk factor for the 822 bp mtDNA deletion. Furthermore, the increased frequencies of the mtDNA deletion in male cigarette smoking subjects of combined cases and controls with haplogroup D indicated that the haplogroup D might be susceptible to DNA damage from external ROS caused by heavy cigarette smoking

    Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays.

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    Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.This work is part of the ‘‘SpatioTemporal Omics Consortium’’ (STOC) paper package. A list of STOC members is available at: http://sto-consortium.org. We would like to thank the MOTIC China Group, Rongqin Ke (Huaqiao University, Xiamen, China), Jiazuan Ni (Shenzhen University, Shenzhen, China), Wei Huang (Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China), and Jonathan S. Weissman (Whitehead Institute, Boston, USA) for their help. This work was supported by the grant of Top Ten Foundamental Research Institutes of Shenzhen, the Shenzhen Key Laboratory of Single-Cell Omics (ZDSYS20190902093613831), and the Guangdong Provincial Key Laboratory of Genome Read and Write (2017B030301011); Longqi Liu was supported by the National Natural Science Foundation of China (31900466) and Miguel A. Esteban’s laboratory at the Guangzhou Institutes of Biomedicine and Health by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030502), National Natural Science Foundation of China (92068106), and the Guangdong Basic and Applied Basic Research Foundation (2021B1515120075).S

    Bandgap Engineering of Lead-Free Halide Double Perovskites

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    Lead-free halide double perovskites (HDPs, A2BIBIIIX6) with attractive optical and electronic features are regarded as one of the most promising alternatives to overcome the toxicity and stability issues of lead halide perovskites. They provide a wide range of possible combinations and rich substitutional chemistry with interesting properties for various optoelectronic devices. However, the performance of state-of-the-art lead-free HDPs is not yet comparable to that of lead halide perovskites, especially in the photovoltaic field. One of the main reasons for this is that HDPs usually have large and/or indirect bandgaps, which limit their optical and optoelectronic properties in the visible and infrared region. In this thesis, we attempt to modify the bandgap and optical properties of HDPs using metal doping/alloying and crystallization control, as well as provide detailed understanding of the alloying at the atomic level. We also observe significant changes of the bandgap of HDPs at different temperatures (i.e., thermochromism) and uncover the reasons behind it.  We first adopt the metal doping/alloying strategy to alter the absorption properties of benchmark HDPs Cs2AgBiBr6. By introducing Cu as the dopant in Cs2AgBiBr6, we significantly broaden the absorption edge from around 610 nm to around 860 nm. Systematic characterizations indicate that Cu doping introduces defect states (sub-bandgap states) in the bandgap, without changing the bandgap of Cs2AgBiBr6. Interestingly, these sub-bandgaps can generate considerable amount of band carriers upon optical excitation, making these double perovskites promising for near-infrared light detection.  In parallel with the material modification using the metal doping/alloying strategy, the fundamental understanding of these doped/alloyed double perovskite is also of critical importance. In the second paper, we reveal the atomic-level structure of alloyed double perovskites by presenting a series of double perovskite alloys with the chemical formula Cs2AgIn1-xFexCl6 (x = 0-1) showing tunable bandgaps in the range of 2.8-1.6 eV. Our results show that Fe3+ substitutes In3+ in the lattice with the formation of [FeCl6]3−·[AgCl6]5− domains, which grow larger gradually as the Fe3+ concentration increases. It is noted that these domains could be further connected to form microscopically segregated Fe3+-rich phases in the double perovskite alloys.  To narrow the bandgap of Cs2AgBiBr6, we also develop a crystallization control approach, where high temperature is employed to assist the single crystal growth. By simply increasing the crystal growth temperature from 60 oC to 150 oC, the bandgap of Cs2AgBiBr6 crystals can be reduced from 1.98 eV to 1.72 eV, which is the lowest reported bandgap for Cs2AgBiBr6 at ambient conditions. The underlying reason is hypothesized to be related to the increased level of Ag–Bi disorder in the crystal structure.  Lastly, we observe an interesting reversible thermochromic behavior in HDPs Cs2NaFeCl6. Specifically, the optical bandgap of Cs2NaFeCl6 is reduced from 2.06 eV to 1.86 eV when the temperature increases from RT to 150 oC and turns back to its original value after cooling. Meanwhile, we observe lattice expansion during the heating/ cooling process without phase transition. Our first-principles calculation indicates that the underlying mechanism for the thermochromic phenomenon in Cs2NaFeCl6 is mainly related to the electron-phonon coupling.  Although the development of HDPs is in its early stages, we believe that HDPs with impressive optical and electronic properties and rich substitutional chemistry have a bright future in optoelectronic and multifunctional applications. Our findings shed new light to the absorption and bandgap modulation of HDPs and provide new insights into the atomic-level structures of DPAs, which can help to develop efficient optoelectronic devices. Blyfria halid-dubbelperovskiter (HDP:er, A2BIBIIIX6) med attraktiva optiska och elektroniska egenskaper betraktas som ett av de mest lovande alternativen för att övervinna de toxicitets- och stabilitetsproblem som bly-halidperovskiter för optoelektriska tillämpningar har. HDP:er ger upphov till en bredd av möjliga kombinationer och en rik möjlighet till substitutionskemi med intressanta egenskaper för olika optoelektriska komponenter. Prestandan hos vetenskapens bästa blyfria HDP:er är dock ännu inte jämförbar med bly-halidperovskiters, särskilt inte inom solcellsfältet. En av de främsta orsakerna till detta, är att HDP:er vanligtvis har stora och/eller indirekta bandgap, vilket begränsar deras optiska och optoelektroniska egenskaper i det synliga och infraröda området. I denna avhandling försöker vi modifiera bandgap och optiska egenskaper hos HDP:er med hjälp av metalldopning/legering och kristalliseringskontroll, så väl som ge en detaljerad förståelse för legeringen på atomnivå. Vi observerar även betydande förändringar av bandgap hos HDP:er vid olika temperaturer (dvs. Termokromism) och visar på orsakerna bakom detta.  Vi antar först metalldopning-/legeringsstrategin för att ändra absorptionsegenskaperna hos HDP-utgångsmaterialet Cs2AgBiBr6. Genom att introducera Cu som dopämne i Cs2AgBiBr6 breddar vi absorptionskanten avsevärt, från cirka 610 nm till cirka 860 nm. Systematiska karakteriseringar indikerar att Cu-dopning introducerar defekttillstånd (sub-bandgap-tillstånd) i bandgapet, utan att ändra bandgapet för Cs2AgBiBr6. Intressant nog kan dessa subbandgap generera en betydande mängd bandbärare via optisk excitation, vilket gör dessa dubbelperovskiter lovande för ljusdetektering i det nära-infraröda området.  Parallellt med materialmodifieringen med hjälp av metalldopnings- /legeringsstrategin är den grundläggande förståelsen av dessa dopade/legerade dubbelperovskiter också av avgörande betydelse. I den andra artikeln undersöker vi atomnivåstrukturen hos dopade dubbelperovskiter genom att presentera en serie dubbelperovskitlegeringar med den kemiska formeln Cs2AgIn1-xFexCl6 (x = 0–1) som visar ett justerbart bandgap i intervallet 2.8–1.6 eV. Våra resultat visar att Fe3+ ersätter In3+ i gitteret och bildar [FeCl6]3−·[AgCl6]5−domäner som gradvis växer sig större när Fe3+ koncentrationen ökar. Det är observerat att dessa domäner kan sammanföras ytterligare för att bilda mikroskopiskt segregerade Fe3+-rika faser i dubbelperovskitlegeringarna.  För att minska Cs2AgBiBr6-HDP:ernas bandgap utvecklade vi även en kristalliseringskontrollmetod, där hög temperatur används för att främja enkristallin tillväxt. Genom att öka kristalltillväxttemperaturen från 60 oC till 150 oC kan bandgapet för Cs2AgBiBr6 minskas från 1.98 eV till 1.72 eV, vilket är det minsta bandgap som har rapporterats för Cs2AgBiBr6 i rumsförhållanden. Den underliggande orsaken antas vara relaterad till den ökade nivån av Ag-Bi-oordning i kristallstrukturen.  Slutligen har vi observerat ett intressant reversibelt termokromatiskt beteende i Cs2NaFeCl6-HDP:er. Mer specifikt, reduceras det optiska bandgapet för Cs2NaFeCl6 från 2.06 eV till 1.86 eV när temperaturen ökar från RT till 150 oC och återgår till sitt ursprungliga värde efter kylning. Under tiden observerar vi gitterexpansion under uppvärmnings-/kylprocessen utan fasövergång. Vår första-princip-beräkning visar att den underliggande mekanismen för det termokromatiska fenomenet i Cs2NaFeCl6 främst är relaterade till elektron-fonon-koppling.  Även om utvecklingen av HDP:er är i ett tidigt skede, tror vi att HDP:er med imponerande optiska och elektroniska egenskaper och rik substitutionskemi har en ljus framtid inom optoelektroniska och multifunktionella applikationer. Våra resultat kastar nytt ljus över absorption- och bandgapmoduleringen av HDP:er och ger nya insikter gällande atomnivåstrukturer av dubbelperovskitlegeringar, vilket kan bidra till utvecklingen av effektiva optoelektroniska komponenter.  Funding agencies: China Scholarship Council (CSC)</p

    Challenges and Progress in Lead-Free Halide Double Perovskite Solar Cells

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    Lead-free halide double perovskites (HDPs) with a chemical formula of A(2)B(+)B(3+)X(6) are booming as attractive alternatives to solve the toxicity issue of lead-based halide perovskites (APbX(3)). HDPs show excellent stability, a wide range of possible combinations, and attractive optoelectronic features. Although a number of novel HDPs have been studied, the power conversion efficiency of the state-of-the-art double perovskite solar cell is still far inferior to that of the dominant Pb-based ones. Understanding the fundamental challenges is essential for further increasing device efficiency. In this review, HDPs with attractive electronic and optical properties are focused on, and current challenges in material properties and device fabrication that limit high-efficiency photovoltaics are analyzed. Finally, the promising approaches and views to overcome these bottlenecks are highlighted.Funding Agencies|Swedish Research Council [2018-04809]; Carl Tryggers Stiftelse; Olle Engkvist Byggmastare Stiftelse; STINT grant [CH2018-7655]; Jiangsu Key Laboratory for Carbon-Based Functional Materials &amp; Devices (Soochow University); aforsk [21-32]</p

    Dependence of Macro- and Micro-Properties on α Plates in Ti-6Al-2Zr-1Mo-1V Alloy with Tri-Modal Microstructure

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    Tri-modal microstructure is often the target microstructure of titanium alloy components. In this study, the parameters, such as volume fraction, size of primary equiaxed &alpha; (&alpha;p), secondary lamellar &alpha; (&alpha;s) and thin &alpha; plates (&alpha;t) in tri-modal microstructure of Ti-6Al-2Zr-1Mo-1V alloy are adjusted by double heat treatment procedures. The properties of these constituent phases and their effect on the macro-properties are then investigated. The results show that the hardness of primary &alpha; (&alpha;p) varies slightly with heat treatment routes. The hardness of &alpha; plates region including &alpha;s and &alpha;t increases with increasing &alpha;t volume fraction and not with decreasing thickness of &alpha;s and &alpha;t. Using volume average of the thickness of &alpha;s and &alpha;t as effective thickness (teff), the hardness of &alpha; plates region and teff follow the Hall-Petch relationship. Meanwhile, as &alpha;t volume fraction increases, colony structure of &alpha;s is gradually destroyed, which makes each &alpha;s have large deformation degree by multiple directions slip. When volume fraction ratio of &alpha;p, &alpha;s and &alpha;t is about 1:1:1, &alpha;p and &alpha;s can undergo relatively large deformation and &alpha;t can contribute relatively large strength to the alloy and therefore the alloy has both good strength and ductility

    Deep-Like Hashing-in-Hash for Visual Retrieval: An Embarrassingly Simple Method

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    Effect of Ni-Coated Carbon Nanotubes Additions on the Eutectic Sn-0.7Cu Lead-Free Composite Solder

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    Sn-0.7Cu-based (all in wt.% unless specified otherwise) composite solders functionalized with Ni-coated carbon nanotubes (CNTs) with various weight proportions ranging from 0.01 to 0.2 wt.% were successfully produced. The Ni-coated CNTs were synthesized with discontinuous nickel coating by an improved electroless nickel plating technique. The microstructural, melting and wetting properties of Sn-0.7Cu-based composite solders were evaluated as a function of different amounts of Ni-coated CNTs addition. Compared to Sn-0.7Cu, it was observed that the microstructure of the composite solder added to the Ni-coated CNTs was still composed of the intermetallic compound Cu6Sn5 in a &beta;-Sn matrix, but the micromorphology changed greatly. When 0.05 wt.% Ni-coated CNTs were added, the rod-shaped Cu6Sn5 particles disappeared, and all appeared in a form of dot-shaped Cu6Sn5 particles. DSC results showed only a slight decrease in the melting behavior of the composite solder. Experimental results unveiled that the addition of Ni-coated CNTs to Sn-0.7Cu solder could improve the wettability. With the addition of 0.05 wt.% Ni-coated CNTs, the wetting angle decreased by 13.35%, and an optimum wetting angle of 25.44&deg; was achieved
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