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For reservoirs with complex non-Gaussian geological characteristics, such as carbonate reservoirs or reservoirs with sedimentary facies distribution, it is difficult to implement history matching directly, especially for the ensemble-based data assimilation methods. In this paper, we propose a multi-source information fused generative adversarial network (MSIGAN) model, which is used for parameterization of the complex geologies. In MSIGAN, various information such as facies distribution, microseismic, and inter-well connectivity, can be integrated to learn the geological features. And two major generative models in deep learning, variational autoencoder (VAE) and generative adversarial network (GAN) are combined in our model. Then the proposed MSIGAN model is integrated into the ensemble smoother with multiple data assimilation (ESMDA) method to conduct history matching. We tested the proposed method on two reservoir models with fluvial facies. The experimental results show that the proposed MSIGAN model can effectively learn the complex geological features, which can promote the accuracy of history matching.

The TMC genes encode a set of homologous transmembrane proteins whose functions are not well understood. Biallelic mutations in either TMC6 or TMC8 are detected in more than half of cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV). It is controversial whether EV induced by mutations in TMC6 or TMC8 originates from keratinocyte or lymphocyte defects. Quantification of TMC6 and TMC8 RNA levels in various organs revealed that lymphoid tissues have the highest levels of expression of both genes, and custom antibodies confirmed protein expression in mouse lymphocytes. To study the function of these proteins we generated mice with targeted deletion mutant alleles of Tmc6 or Tmc8. Either TMC6 or TMC8 deficiency induced a reduction in apparent molecular weight and/or amount of the other TMC molecule. Co-immunoprecipitation experiments indicated that TMC6 and TMC8 formed a protein complex in mouse and human T cells. MS and biochemical analysis demonstrated that TMC6 and TMC8 additionally interacted with the CIB1 protein to form TMC6-TMC8-CIB1 trimers. We demonstrated that TMC6 and TMC8 regulated CIB1 levels by protecting CIB1 from ubiquitination and proteasomal degradation. Reciprocally, CIB1 was needed for stabilizing TMC6 and TMC8 levels. These results suggest why inactivating mutations in any of the three human genes leads to similar clinical presentations. We also demonstrated that TMC6 and TMC8 levels are drastically lower and the proteins are less active in regulating CIB1 in keratinocytes than in T cells. Our study suggests that defects in lymphocytes may contribute to the etiology and pathogenesis of EV.

A copper catalyzed asymmetric tandem double Michael addition of diethylzinc to α,β-unsaturated ketones followed by trapping with nitroolefins has been developed using chiral P,N-ligands. The tandem products were obtained in good yields and excellent enantioselectivities with three contiguous stereocenters.

Background: The development of chemoresistance is one of the leading causes of chemotherapy failure in gastric cancer (GC). Emerging evidence highlights the multifunctional role of noncoding RNAs (ncRNAs) in GC chemoresistance. However, the comprehensive expression profile and competing endogenous RNAs (ceRNAs) regulatory network between ncRNAs and mRNAs in GC chemoresistance remain unanswered.Methods: GC cell line MGC-803 was employed to create cisplatin-resistant MGC-803/DDP cells by continuous exposure to increasing doses of cisplatin. The whole-transcriptome sequencing (RNA sequencing) was performed to comprehensively analyze the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in MGC-803/DDP and MGC-803 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions implicated with the DEncRNAs. Then, the cisplatin-resistant-related ceRNA network and potential regulatory axes were constructed by bioinformatic analysis.Results: We successfully generated cisplatin-resistant GC cell line MGC-803/DDP. Differential expression analysis showed that a total of 1,936 DElncRNAs, 2,194 DEmRNAs and 174 DEmiRNAs were identified. Functional enrichment analysis indicated that those DEncRNAs were mainly involved in neuroactive ligand-receptor interaction, drug metabolism, Hippo signaling pathway, cAMP pathway and P53 pathway. Subsequently, the cisplatin-resistant-related ceRNA network consisting of 71 DElncRNAs, 121 DEmRNAs and 8 DEmiRNAs was constructed with the widely accepted vital chemo-resistant-related genes and signaling pathways. In addition, two constructed regulatory axes (include FAM66C/miR-129-5p/7 mRNAs and SFTA1P/miR-206/FN1 or NRP1) were successfully validated by the Genomic Data Commons (GDC) GC data.Conclusion: Our study has shown that differentially expressed ncRNAs have complex and intricate interactions in the cisplatin resistance of GC. The novel ceRNA network and the potential regulatory axes may provide the most comprehensive view of GC chemoresistance to date. Our findings uncovered potential biomarkers for prognostic prediction and novel therapeutic targets for reversing cisplatin resistance in GC.

Background: Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients. Methods: We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria. Findings: Between July 8, 2018 and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At data cutoff (Feb 15, 2020), the median follow-up was 4.06 months (range: 0.30-16.7). For 84 patients in FAS, 33 achieved objective response (39.3%, 95% CI 28.80-50.55), of which 10 (11.9%) were complete response and 23 (27.4%) had partial response assessed by IRRC. The 6-month duration of response (DOR) rate was 61.8% (95% CI 41.4, 76.9). Patients with PD-L1 expression ≥50% derived more benefit from geptanolimab treatment compared to

The Ir-catalyzed asymmetric hydrogenation of simple aromatic ketones with chiral ferrocenyl P,N,N-ligands has been developed. Under the optimized conditions, a wide range of ketones were hydrogenated to afford the corresponding chiral alcohols in good to excellent enantioselectivities (up to 98% ee).

Mitogen-activated protein kinase (MAPK) cascades play an important role in extracellular signal transduction and are involved in the pathogenicity of fungal pathogens to host plants. In Curvularia lunata, the roles of two MAPK genes, Clk1 and Clm1, have already been studied. Clk1 is involved in conidia formation and pathogenicity, and Clm1 is closely related to pathogen cell wall formation and pathogenicity to maize leaves. In this study, a third C. lunata MAPK gene, Clh1, which is homologous to hog1, was successfully cloned. We found that a Clh1 deletion mutant had lower intracellular glycerol accumulation than the wild-type stain and was unable to grow normally under osmotic stress conditions. Furthermore, the deletion mutants of three C. lunata MAPK genes (Clk1, Clm1 and Clh1) had lower levels of acetyl-CoA, which is an important intermediate product in the synthesis of melanin and furan toxin, and down-regulated expression of pathogenicity-associated genes. Furthermore, pathogenicity and the ability to produce toxin were restored after adding acetyl-CoA to the culture medium, suggesting that acetyl-CoA is closely involved in the pathogen MAPK signaling pathway.

In the paper the whole heterojunction structure design process in LWIR type-II InAs/GaSb superlattices (T2SLs) detectors has been presented. The high quality T2SLs materials were grown and the high performance double heterojunction LWIR detectors have been fabricated. In the double heterojunction LWIR detectors a electrons barrier layer and a holes barrier layer were designed and introduced successively, based on the electrical properties measurement and compensation doping of the T2SLs intrinsic material. The processed double heterojunction structure photodiodes had a 100% cutoff wavelength of 12.5 μm at 80 K. The peak current responsivity was 2.5 A/W under zero applied bias, corresponding to a quantum efficiency of 30%. The R 0 A product at 80 K is 14.5 Ω cm 2 which leads to the peak detectivity D ∗ of 1.4 × 10 11 cm Hz 1/2 /W for the detector.

In this paper, the authors reported recent work on the growth and fabrication of InGaAs/GaAsSb type II superlattice detectors by solid source molecular beam epitaxy. Superlattice materials with different Beryllium (Be) doping concentration were grown and characterized by high resolution X-ray diffraction, Hall Effect technique, and photoluminescence. The results showed that doping concentration of the superlattice was sensitive to the Be temperature. A p-π-n InGaAs/GaAsSb T2SL photodiode was grown on an InP substrate. The full width at half maximum of the first order satellite peak from X-ray diffraction was 36 arcsec. The photodiode with 7 nm InGaAs and 5 nm GaAsSb in each period showed a 50% cutoff wavelength of 2.35 μm at 293 K. The dark current density at −50 mV bias was 0.54 mA/cm 2 and the resistance-area product at zero bias (R 0 A) was 46 Ω ⋅ cm 2 . The peak detectivity was 4.4 × 10 10 cm Hz 1/2 /W. The quantum efficiency at 2.1 μm was measured to be 48.2%.

Memory effect of time fractional Schrodinger equation plays a significant role in evolution of a single quantum state and quantum entanglement. We investigate the time fractional evolution of a single quantum state and entangled state respectively. Comparing to the results of standard Schrodinger equation, we find that the influence of memory action is unstable, which will change over time until the result is opposite to the initial effect. Our study might provide a new perspective on the role of time fractional Schrodinger equation.

High temperature around flowering and early grain filling greatly reduced maize yield. Hybrids responded differently to high temperature stress, but the underlying mechanisms are unclear, particularly from the perspective of growth season that is widely used to adapt different environments. For this, 162 maize inbred lines with different growing degree days (GDD) were planted at six different environments by adjusting sowing date over four years of 2015 – 2018, including two control treatments and four high temperature treatments during flowering and early grain filling. Yield was significantly positively correlated with GDD but negatively correlated with killing degree days (KDD) across six environments. Daily maximum temperature during flowering and early grain filling was a more important determinant of yield (R2 = 0.689) than solar radiation (R2 = 0.265) and precipitation (R2 = 0.288). Grain yield significantly reduced at high temperature mainly as a result of reduced kernel number per ear (KN/ear). KN/ear was reduced by 11 – 100% among inbred lines at heat stress, and the reductions followed the similar pattern for inbred lines that had different GDDs. Based on GDD, 162 inbred lines were divided into short – (SS) and long – season (LS) groups. Kernel number reductions (% / °C) in SS and LS groups were 14.4 and 12.0, respectively, with significant difference between groups. This revealed that long – season maize lines showed a higher heat tolerance than short – season lines in kernel number formation by maintaining a relatively stable anthesis – silking interval. SS maize was more tolerant to heat stress during early grain filling than LS maize in kernel weight development due to a shorter exposure to heat stress. It is feasible to select of or breed for heat tolerant maize in different regions where maize has different growth seasons. A proper sowing date, along with heat tolerant hybrids should be considered to offset the adverse effects of warming climate.

Curvularia leaf spot, caused mainly by Curvularia lunata, is a widespread plant disease in China. In the recent years, directional host selection by the pathogen, which likely results in the virulence differentiation in pathogens, is widely reported. Among the hallmarks potentially associated to pathogen variation in virulence, superoxide dismutase gene Sod has been found to be closely related to the enhancement of virulence. In the present study, the full-length of Sod was obtained via Blastn alignment against GenBank and the whole genome of C. lunata. In order to understand the role of Sod in the virulence variation in C. lunata, targeted gene disruption was performed to construct Sod mutants. The cell wall degrading enzyme (CWDE) activities and toxin production of ΔSod were not distinctly different from wild-type strain CX-3 and its complon. However, at an early stage of infection, ΔSod virulence appeared to be lower than CX-3 and the complon, while at a later stage, its virulence gradually returned to the level of CX-3 and the complon. Furthermore, the melanin production of ΔSod was significantly reduced compared to CX-3 and the complon, suggesting that Sod gene influences the virulence by regulating melanin production at an early stage of infection but is not essential for pathogenicity. However, the disruption of Sod did not significantly affect the transcriptional expression of the melanin biosynthesis-associated genes, brn1 and scd. Therefore, we infer that Sod in C. lunata are involved, to some extent, with the virulence in maize leaf, but still needs further studies to have a clear understanding of its mechanism.

Engineering characteristics of calcareous soils are more peculiar due to the grain geometries, hardness and intraparticle voids. In the fringing reef in Sanya, calcareous soils were mixed with some terrestrial deposits, such as quartz sand and clay. In this paper, a series of laboratory and in-situ tests are conducted on calcareous soils to investigate the engineering characteristics and the effect of water saturation: laboratory large-scale direct shear tests, large-scale oedometer tests, X-Ray diffraction experiments, in-situ Plate Load Tests (PLTs) and Dynamic Cone Penetration Tests (DCPTs). The results showed that: (i) apparent cohesion of calcareous soils is quite higher than that of quartz sand but decreases significantly due to the softening effect of water; (ii) the bearing capacity decreases by 43% and deformation modulus decreases by 31% at the presence of 20% clay minerals; (iii) deformation modulus reduces 80% in saturated condition compared to dry condition; (iv) the relationship between N63.5 and bearing capacity of calcareous soils was established; therefore, engineers can decrease the amount of PLTs and increase DCPTs in the site exploration of fringing coral reef according to the testing results.

The curd is a specialized organ and the most important product organ of cauliflower (Brassica oleracea L. var. botrytis). However, the mechanism underlying the regulation of curd formation and development remains largely unknown. In the present study, a novel homologous gene containing the Organ Size Related (OSR) domain, namely, CDAG1 (Curd Development Associated Gene 1) was identified in cauliflower. Quantitative analysis indicated that CDAG1 showed significantly higher transcript levels in young tissues. Functional analysis demonstrated that the ectopic overexpression of CDAG1 in Arabidopsis and cauliflower could significantly promote organ growth and result in larger organ size and increased biomass. Organ enlargement was predominantly due to increased cell number. In addition, 228 genes involved in the CDAG1-mediated regulatory network were discovered by transcriptome analysis. Among these genes, CDAG1 was confirmed to inhibit the transcriptional expression of the endogenous OSR genes, ARGOS and ARL, while a series of ethylene-responsive transcription factors (ERFs) were found to increased expression in 35S:CDAG1 transgenic Arabidopsis plants. This implies that CDAG1 may function in the ethylene-mediated signal pathway. These findings provide new insight into the function of OSR genes, and suggest potential applications of CDAG1 in breeding high-yielding crops.

A copper-catalyzed asymmetric etherification of propargylic acetates with oximes as O-nucleophiles has been developed. The employment of a chiral tridentate P,N,N-ligand proved to be crucial for the success of the reaction. The reaction features a broad scope on either reaction partners and led to a variety of etherification products in good yields and enantioselectivities.

Background: Classical Hodgkin's lymphoma (cHL) is a life-threatening malignancy, typified by frequent genetic alterations at the 9p24.1 locus leading to overexpression of programmed death 1 (PD-1) ligands. Sintilimab, a highly selective, fully humanized monoclonal antibody, blocks the interaction between PD-1 and its ligands. We have assessed the efficacy and safety profile of single agent sintilimab as a treatment for relapsed/refractory (r/r) cHL in Chinese patients. Methods: ORIENT-1 (ClinicalTrials.gov, identifier: NCT03114683) is a single-arm phase II study of sintilimab in Chinese patients with r/r cHL. Patients received sintilimab 200 mg once every 3 weeks until progression, death, unacceptable toxicity or withdrawal of consent. The primary outcome was objective response rate (ORR) as assessed by an independent radiological review committee (IRRC) in full analysis set (FAS). Safety was assessed in all treated patients. Findings: A total of 96 patients were enrolled and treated. Median duration of follow-up was 10 months (range, 4 to 12). The ORR assessed by IRRC in FAS (n=92) was 80.4% (95%CI, 70.9%, 88.0%). The most common treatment related AE was pyrexia (40.6%). The majority of treatment related AEs were grade 1-2. Most common treatment related AE ≥ grade 3 was pyrexia (3.1%). Serious AE of any cause were reported in 14 (14.6%) patients. No patient died in the study. Interpretation: Sintilimab therapy was associated with high response rates and an acceptable safety profile in Chinese patients with r/r cHL. Therefore, sintilimab could be a new treatment option for this patient population with high unmet medical needs. Trial Registration Number: ClinicalTrials.gov, identifier: NCT03114683 Funding: The study was sponsored by Innovent Biologics, and co-funded by Innovent Biologics & Eli Lilly and Company. The study was also supported by the National New Drug Innovation Program (2014ZX09201041-001 and 2017ZX0930415) and the National Key Scientific Program Precision Medicine Research Fund (2017YFC0909801) of China. Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The study was done in accordance with the Declaration of Helsinki. The protocol, amendments, and patient informed consent received appropriate approval by the Independent Ethics Committee at each participating site before study initiation. Written informed consent form was obtained from all patients before trial enrolment.

Rh-catalyzed asymmetric hydrogenation of challenging α-keto phosphonates has been developed. With a new chiral phosphine–phosphoramidite ligand, a wide range of α-keto phosphonates were hydrogenated to afford the corresponding ( R )-α-hydroxy phosphonates with moderate to good enantioselectivities (up to 87% ee).

To investigate thermomechanical contacts between an elastic–plastic sphere and a rigid flat, simulations with slip rates ranging from 0.1 m/s to 10 m/s were performed. As interfaces with strong interfacial bonding but weak substrate were specifically targeted, slip initiation was treated as shear failure of the softer material in numerical simulations. The simulations show that both sliding friction coefficient and friction stress are significantly dependent on slip rate while the maximum static friction coefficient is independent of that. Moreover, the energy release during the transition from full stick to full slip is comparable to the shear fracture energy of the material.

In this paper we report on the growth of mid-wavelength infrared superlattice materials by molecular beam epitaxy. We focused on the effects of process parameters, such as arsenic beam equivalent pressure and shutter sequences, on the key material properties, such as the lattice mismatch and the surface morphology. Though a smaller As beam equivalent pressure helps to reduce the lattice mismatch between the superlattice and the GaSb substrate, the As beam equivalent pressure itself has a lower limit below which the material’s surface morphology will degrade. To achieve fully lattice-matched superlattice materials, a novel shutter sequence in the growth process was designed. With well-designed interface structures, a high quality P-I-N superlattice mid-infrared detector structure was realized. At 77 K the dark current density at −50 mV bias was 2.4 × 10−8 A/cm2 and the resistance-area product (RA) at maximum (−50 mV bias) was 2.4 × 106 Ω cm2, and the peak detectivity was then calculated to be 9.0 × 1012 cm Hz1/2/W. The background limited infrared photodetector (BLIP) level can be achieved at a temperature of 113 K.

Epithelial cell adhesion molecule (EpCAM) (CD326) is a surface glycoprotein expressed by invasive carcinomas and some epithelia. Herein, we report that EpCAM regulates the composition and function of tight junctions (TJ). EpCAM accumulated on the lateral interfaces of human colon carcinoma and normal intestinal epithelial cells but did not co-localize with TJ. Knockdown of EpCAM in T84 and Caco-2 cells using shRNAs led to changes in morphology and adhesiveness. TJ formed readily after EpCAM knockdown; the acquisition of trans-epithelial electroresistance was enhanced, and TJ showed increased resistance to disruption by calcium chelation. Preparative immunoprecipitation demonstrated that EpCAM bound tightly to claudin-7. Co-immunoprecipitation documented associations of EpCAM with claudin-7 and claudin-1 but not claudin-2 or claudin-4. Claudin-1 associated with claudin-7 in co-transfection experiments, and claudin-7 was required for association of claudin-1 with EpCAM. EpCAM knockdown resulted in decreases in claudin-7 and claudin-1 proteins that were reversed with lysosome inhibitors. Immunofluorescence microscopy revealed that claudin-7 and claudin-1 continually trafficked into lysosomes. Although EpCAM knockdown decreased claudin-1 and claudin-7 protein levels overall, accumulations of claudin-1 and claudin-7 in TJ increased. Physical interactions between EpCAM and claudins were required for claudin stabilization. These findings suggest that EpCAM modulates adhesion and TJ function by regulating intracellular localization and degradation of selected claudins.

A new distributed activation energy model is presented using the logistic distribution to mathematically represent the pyrolysis kinetics of complex solid fuels. A numerical parametric study of the logistic distributed activation energy model is conducted to evaluate the influences of the model parameters on the numerical results of the model. The parameters studied include the heating rate, reaction order, frequency factor, mean of the logistic activation energy distribution, standard deviation of the logistic activation energy distribution. The parametric study addresses the dependence on the forms of the calculated α-T and dα/dT-T curves (α: reaction conversion, T: temperature). The study results would be very helpful to the application of the logistic distributed activation energy model, which is the main subject of the next part of this series.

Unsymmetrical hybrid chiral ferrocenyl phosphine-phosphoramidite ligands have been applied for the first time in the Cu-catalyzed asymmetric 1,4-reduction of beta-aryl substituted alpha,beta-unsaturated esters. The results show that the ligand bearing (S(c))-central, (R(p))-planar, and (R(a))-axial chiralities gave the best performance. The present catalytic system proved to be highly substrate-dependent, catalyzing the conjugate reduction of alpha,beta-unsaturated esters in moderate to excellent enantioselectivities. (C) 2011 Elsevier Ltd. All rights reserved.

A new high linearity 32-channel X-ray readout integrated circuit (ROIC) is proposed in this paper. This ROIC has integrated analog circuit and digital circuit on the wafer. The analog circuit picked up the weak current signal from the detector, which includes low power charge sensitive amplifier (CSA), sample and hold circuit, and output buffer. The digital circuit generate control signal which the analog circuit needs. All 32 channels share one common current output buffer to drive a load resistor. With maximum 500pF detector parasitic capacitor ( C d ) , the linearity is about 99.93%. This 32-channel X-ray ROIC is also features with selectable gains, LVDS protocol compatible, selectable integration modes, selectable read out directions. 32-channel ROIC has been designed and a single-channel test chip is being fabricated with 0.5 μm 2P3M process.

Racemic 12-hydroxyl-1,15-pentadecanlactam 2 was resolved using glucose as a chiral auxiliary for the first time. Both the ( R )- and ( S )-isomers were obtained in high enantiomeric excesses (>99% by HPLC). The absolute configuration of (+)- 2b and (−)- 2a was determined by Horeau’s method and a modified Mosher’s method.

NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase (IKK) that activates NF-kappaB, is essential for NF-kappaB activation. NEMO was recently found to contain a region that preferentially binds Lys (K)63-linked but not K48-linked polyubiquitin (polyUb) chains, and the ability of NEMO to bind to K63-linked polyUb RIP (receptor-interacting protein) is necessary for efficient tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. Optineurin is a homolog of NEMO, and mutations in the optineurin gene are found in a subset of patients with glaucoma, a neurodegenerative disease involving the loss of retinal ganglion cells. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKKalpha and IKKbeta, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-kappaB activation. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNFalpha receptor 1 (TNFR1). Here we show that optineurin has a K63-linked polyUb-binding region similar to that of NEMO, and like NEMO, it bound K63- but not K48-linked polyUb. Optineurin competitively antagonized NEMO's binding to polyUb RIP, and its overexpression inhibited TNFalpha-induced NF-kappaB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFalpha-induced NF-kappaB activity. These results reveal a physiologic role for optineurin in dampening TNFalpha signaling, and this role might provide an explanation for its association with glaucoma.