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Antarctic trace metal records provide important information for grasping the influence of human activities on the environment over the last centuries. The CA2016-75 ice core is located along the East Antarctic Zhongshan Station–Dome A, enhances the record of metals research in the East Antarctic region, and its high-resolution supplies data support for the study of high-frequency climatic drivers and the effect of human activities on the Antarctic environment. A thorough dataset on seven trace metals (Al, Fe, Mn, Cu, Zn, Ba and Pb) in a coastal ice core in eastern Antarctica during the previous 102 years (1915–2016) is presented in this study. Pb has the lowest concentration (9.51 ± 20.95 pg g−1), and Ba has the highest concentration (36.57 ± 51.35 ng g−1). Notable variations are observed between the pre-1968 AD and post-1968 AD phases for Mn, Zn and Ba. The abrupt, remarkable increase in the concentrations coincided with the change of metal smelting production in the southern hemisphere. In addition to this, it may also be related to local Antarctic scientific research activities. Al and Fe, the primary crustal elements, are essentially obtained from soil dust; Cu shows high crustal enrichment factors (EFc, >10), indicating that it is notably affected by anthropogenic activities. Moreover, the anthropogenic activities in the Southern Hemisphere have had an impact on lead deposition in Antarctica. This study not only enriches the trace metal historical record along the Zhongshan Station–Dome A but also provides a high-resolution ice core record, which is very crucial for the reconstruction of trace metal concentration changes in the last 100 years.

Summary: The serine/threonine phosphatase calcineurin is a component of the T cell receptor (TCR) signalosome, where it promotes T cell activation by dephosphorylating LckS59. Using small interfering RNA (siRNA)-mediated knockdown and CRISPR-Cas9-targeted genetic disruption of the calcineurin A chain α and β isoforms, we find that calcineurin also functions as an adaptor in TCR-signaled human T cells. Unlike inhibition of its phosphatase activity, in the absence of calcineurin A, TCR signaling results in attenuated actin rearrangement, markedly reduced TCR-Lck microcluster formation and recruitment of the adaptor RhoH, and diminished phosphorylation of critical targets downstream of Lck such as TCRζ and ZAP-70. Reconstitution of deficient T cells with either calcineurin Aα or Aβ restores TCR microcluster formation and signaling, as does reconstitution with a phosphatase-inactive Aα chain. These results assign a non-enzymatic adaptor function to calcineurin in the formation and stabilization of a functional TCR signaling complex.

Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Overlay accuracy, one of the three fundamental indicators of lithography, is directly influenced by alignment precision. During the alignment process based on the Moiré fringe method, a slight angular misalignment between the mask and wafer will cause the Moiré fringes to tilt, thereby affecting the alignment accuracy. This paper proposes a leveling strategy based on the DQN (Deep Q-Network) algorithm. This strategy involves using four consecutive frames of wafer tilt images as the input values for a convolutional neural network (CNN), which serves as the environment model. The environment model is divided into two groups: the horizontal plane tilt environment model and the vertical plane tilt environment model. After convolution through the CNN and training with the pooling operation, the Q-value consisting of n discrete actions is output. In the DQN algorithm, the main contributions of this paper lie in three points: the adaptive application of environmental model input, parameter optimization of the loss function, and the possibility of application in the actual environment to provide some ideas. The environment model input interface can be applied to different tilt models and more complex scenes. The optimization of the loss function can match the leveling of different tilt models. Considering the application of this strategy in actual scenarios, motion calibration and detection between the mask and the wafer provide some ideas. To verify the reliability of the algorithm, simulations were conducted to generate tilted Moiré fringes resulting from tilt angles of the wafer plate, and the phase of the tilted Moiré fringes was subsequently calculated. The angle of the wafer was automatically adjusted using the DQN algorithm, and then various angles were measured. Repeated measurements were also conducted at the same angle. The angle deviation accuracy of the horizontal plane tilt environment model reached 0.0011 degrees, and the accuracy of repeated measurements reached 0.00025 degrees. The angle deviation accuracy of the vertical plane tilt environment model reached 0.0043 degrees, and repeated measurements achieved a precision of 0.00027 degrees. Moreover, in practical applications, it also provides corresponding ideas to ensure the determination of the relative position between the mask and wafer and the detection of movement, offering the potential for its application in the industry.

In order to correct the integrated nonuniformity of a lithographic illumination field, a high-precision uniformity correction method for an advanced lithographic illumination system is proposed. The method adopts the opaque finger array structure and improves correction ability and accuracy by optimizing the arrangement and structure of the unit without changing the width of each unit. The correction accuracy is expressed as the percentage of the corrected integrated nonuniformity. Through theoretical analysis and simulation, it can be seen that the correction accuracy of a staggered finger array is better than 0.22%. When staggered and layered, the correction accuracy of a finger array is better than 0.14%, which is better than that of a non-layered finger array. When staggered, layered, and chamfered of each unit, the correction accuracy of the finger array structure is better than 0.12%.

Adaptive characteristics of plants, such as those associated with photosynthesis and resource use efficiency, are usually affected by synthesis costs and resource availability. The impact of extreme climate events such as long-term drought on plant physiological functions needs to be examined, particularly as it concerns the internal management of water and nitrogen (N) resources. In this study, we evaluated the resource management strategies for water and N by xerophytic shrubs, Artemisia ordosica and Salix psammophila, under extreme summer drought. This was carried out by comparing the plants’ physiological status during periods of wet and dry summer conditions in 2019 and 2021. Compared with the wet period, A. ordosica and S. psammophila both decreased their light-saturated net carbon (C) assimilation rate (Asat), stomatal conductance (gs), transpiration rate (E), leaf N content per leaf area (Narea), and photosynthetic N use efficiency (PNUE) during the summer drought. Whether in wet or dry summers, the gas-exchange parameters and PNUE of A. ordosica were generally greater than those associated with S. psammophila. The instantaneous water use efficiency (IWUE) response to drought varied with species. As a drought-tolerant species, the A. ordosica shrubs increased their IWUE during drought, whereas the S. psammophila shrubs (less drought-tolerant) decreased theirs. The divergent responses to drought by the two species were largely related to differences in the sensitivity of gs, and as a result, E. Compared with A. ordosica, S. psammophila’s inferior plasticity regarding gs response affected its ability to conserve water during drought. Our research illustrates the need for assessing plasticity in gs when addressing plant adaptation to long-term drought. A high dry-season IWUE in xerophytic shrubs can benefit the plants by augmenting their C gain.

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

The six-degree-of-freedom (6-DOF) micromotion mechanism is a key component in extreme ultraviolet (EUV) projection lithography objectives to compensate for wavefront aberration and ensure performance stability. It is required to have high precision and high reliability. A 6-DOF mirror micromotion mechanism of an EUV lithography objective lens with Stewart configuration is proposed, and based on the RPY (Roll-Pitch-Yaw) angular rotation method and the second-type Lagrange method, the kinematic and dynamic models of the mechanism are constructed to realize the decoupling of the mechanism’s kinematics and the solution of the driving force. Comparative verification with finite element transient analysis shows that the response value of the dynamic model and the finite element method (FEM) differs by 4.8% in a specific posture. A hybrid optimization method, combining genetic algorithms and particle-swarm optimization (GA-PSO), was proposed to optimize the structural parameters of the initial design of the motion outriggers in a micromotion mechanism. The results demonstrate a 15.1% reduction in maximum driving force, significantly enhancing outrigger driving smoothness.

As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ+ CD8+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ tumor-specific CD8+ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

Inverse lithography technologies (ILTs) are critical for improving the imaging performance of lithography in advanced technology nodes. Pixel-based source optimization (SO), as an efficient part of ILTs, can be implemented via heuristic approaches to achieve high-performance lithographic imaging. In this paper, a SO approach based on a combination of the particle-swarm optimization and genetic algorithms (PSO–GA) is proposed to determine the optimal intensity distribution of the source via iterations. The pixelated source can be decoded into the optimized variables of the merit functions in the SO model. The proposed PSO–GA algorithm, as a high-efficiency hybrid algorithm, can transform the discrete SO problem into the optimal search solution for the merit function, thereby inversely enhancing the lithographic-imaging performance. In the forward-imaging model in the lithography, the extraction of the mask's effective diffraction spectrum is implemented to calculate the layout of resist patterns. The simulation results highlight the superior performance of the proposed approach in achieving pixelated SO over the traditional GA and PSO algorithm in terms of convergence capacity.

Alignment precision is a crucial factor that directly impacts overlay accuracy, which is one of three fundamental indicators of lithography. The alignment method based on the Moiré fringe has the advantages of a simple measurement optical path and high measurement accuracy. However, it requires strict control of the distance between the mask and wafer to ensure imaging quality. This limitation restricts its application scenarios. A depth–DOF (depth of focus) Moiré fringe alignment by broad–spectrum modulation is presented to enhance the range of the alignment signals. This method establishes a broad–spectrum Moiré fringe model based on the Talbot effect principle, and it effectively covers the width of dark field (WDF) between different wavelength imaging ranges, thereby extending the DOF range of the alignment process, and employs a hybrid of genetic algorithms and the particle-swarm optimization (GA–PSO) algorithm to combine various spectral components in a white spectrum. By calculating the optimal ratio of each wavelength and using white light incoherent illumination in combination with this ratio, it achieves the optimal DOF range of a broad–spectrum Moiré fringe imaging model. The simulation results demonstrate that the available DOF range of the alignment system has been expanded from 400 μm to 800 μm. Additionally, the alignment precision of the system was analyzed, under the same conditions, and the accuracy analysis of the noise resistance, translation amount, and tilt amount was conducted for the Moiré fringe and broad–spectrum Moiré fringe. Compared to a single wavelength, the alignment precision of the broad–spectrum Moiré fringe decreased by an average of 0.0495 nm, equivalent to a 1.5% reduction in the original alignment precision, when using a 4 μm mask and a 4.4 μm wafer. However, the alignment precision can still reach 3.795 nm, effectively enhancing the available depth of focus range and reducing the loss of alignment precision.

Because of their ability to induce lymphocyte apoptosis, glucocorticoids (GC) are widely used to treat hematological malignancies such as lymphomas and multiple myeloma. Their effectiveness is often limited, however, due to the development of glucocorticoid resistance by a variety of molecular mechanisms. Here we performed an unbiased genome-wide CRISPR screen with the human T-cell leukemia cell line Jurkat to find previously unidentified genes required for GC-induced apoptosis. One such gene was KMT2D (also known as MLL2 or MLL4), which encodes a histone lysine methyltransferase whose mutations are associated with a variety of cancers, blood malignancies in particular, and are considered markers of poor prognosis. Knockout of KMT2D by CRISPR/Cas9 gene editing in Jurkat and several multiple myeloma cell lines downregulated GR protein expression. Surprisingly, this was not due to a reduction in GR transcripts, but rather to a decrease in the protein’s half-life, primarily due to proteasomal degradation. Reconstitution of KMT2D expression restored GR levels. In contrast to the known ability of KMT2D to control gene transcription through covalent histone methylation, KMT2D-mediated upregulation of GR levels did not require its methyltransferase activity. Co-immunoprecipitation and proximity ligation assays found constitutive binding of KMT2D to the GR, which was enhanced in the presence of GC. These observations reveal KMT2D to be essential for the stabilization of cellular GR levels, and suggest a possible mechanism by which KMT2D mutations may lead to GC resistance in some malignancies. [ABSTRACT FROM AUTHOR]

The efficient pyrolysis and conversion of organic matter in organic-rich shale, as well as the effective recovery of pyrolysis shale oil and gas, play a vital role in alleviating energy pressure. The state of carbon dioxide (CO2) in the pyrolysis environment of shale reservoirs is the supercritical state. Its unique supercritical fluid properties not only effectively heat organic matter, displace pyrolysis products and change shale pore structure, but also achieve carbon storage to a certain extent. Shale samples were made into powder and three sizes of cores, and nitrogen (N2) and supercritical carbon dioxide (ScCO2) pyrolysis experiments were performed at different final pyrolysis temperatures. The properties and mineral characteristics of the pyrolysis products were studied based on gas chromatography analysis, Xray diffraction tests, and mass spectrometry analysis. Besides, the pore structure characteristics at different regions of cores before and after pyrolysis were analyzed using N2 adsorption tests to clarify the impact of fracturing degree on the pyrolysis effect. The results indicate that the optimal pyrolysis temperature of Longkou shale is about 430 °C. Compared with N2, the oil yield of ScCO2 pyrolysis is higher. The pyrolysis oil obtained by ScCO2 extraction has more intermediate fractions and higher relative molecular weight. The ScCO2 can effectively improve the pore diameter of shale and its effect is better than that of N2. The micropores are produced in shale after pyrolysis, and the macropores only are generated in ScCO2 pyrolysis environments with temperatures greater than 430 °C. The pore structure has different development characteristics at different pyrolysis temperatures, which are mainly affected by the pressure holding of volatile matter and products blocking. Compared to the surface of the core, the pore development effect inside the core is better. With the decrease in core size, the pore diameter, specific surface area, and pore volume of cores all increase after pyrolysis. [ABSTRACT FROM AUTHOR]

Source mask optimization (SMO), a primary resolution enhancement technology, is one of the most pivotal technologies for enhancing lithography imaging quality. Due to the high computation complexity of SMO, patterns should be selected by a selection algorithm before optimization. However, the limitations of existing selection methods are twofold: they are computationally intensive and they produce biased selection results. The representative method having the former limitation is the diffraction signature method. And IBM’s method utilizing the rigid transfer function tends to cause biased selection results. To address this problem, this study proposes a novel pattern cluster and selection algorithm architecture based on a convolutional neural network (CNN). The proposed method provides a paradigm for solving the critical pattern selection problem by CNN to transfer patterns from the source image domain to unified embeddings in a K-dimensional feature space, exhibiting higher efficiency and maintaining high accuracy.

The projection objective lens holds a pivotal role in lithography, directly influencing imaging system quality and, consequently, the lithography machine’s feature dimensions. Optical inspection methods for this lens require advancements in calibrating systematic error and enhancing alignment precision of auxiliary devices, given their impact on calibration accuracy. In the random averaging method, random ball can give rise to additional wavefront aberrations due to misalignment and numerical aperture mismatch. To mitigate these aberrations and enhance the accuracy of systematic error calibration, this paper introduces a random ball residual compensation (RBRC) model. Additionally, when combined with the random averaging technique, it elevates the calibration accuracy of the measured lens’s wavefront aberrations. The experimental results underscore the method’s effectiveness, accurately determining optical component eccentricities and numerical aperture errors. After eliminating these errors, more accurate values of lens wavefront aberrations are achieved. This research significantly contributes to enhancing error calibration of lithography objective lens systems.