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Abstract Backgrounds The incidence of extramedullary diseases (EMDs) in patients diagnosed with acute myeloid leukemia (AML) is approximately 10–20%. These patients exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to patients without EMDs. CLL1 CAR-T therapy has been demonstrated satisfactory efficacy and safety in the treatment of refractory and relapsed AML patients. However, concerns have been raised regarding the potential impact of extramedullary niduses on the effectiveness of CLL1 CAR-T therapy. Methods A total of 47 patients were enrolled in this study, including 27 patients with isolated AML tumor bone marrow infiltration and 20 patients with both extramedullary and bone marrow infiltration of AML. CLL1 CAR-T cells were manufactured and subjected to rigorous quality control in the hematology laboratory of Tianjin First Central Hospital. The efficacy and adverse reactions were assessed following CAR-T cell infusion, while expansion of CAR-T cells, levels of cytokines releasing, and other indicators were closely monitored. Results Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission in bone marrow was achieved by 65.00% and 81.48% of patients, respectively. Meanwhile, among the patients with EMDs, 55.00% achieved complete remission while 10.00% achieved partial remission when assessing the efficacy of CLL1 CAR-T cells against extramedullary niduses. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications were comparable between both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell expansion and accompanying cytokines release between patients with and without EMDs. Conclusions Our study findings have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs, while also indicating manageable occurrence rates of complications within a tolerable range. The CLL1 CAR-T therapy, serving as an ideal strategy for AML patients irrespective of the presence of EMDs, effectively ameliorates the conditions of AML patients and provides them with an opportunity to undergo curative hematopoietic stem cell transplantation while significantly enhancing their prognosis.

The Yushuwan fault is located in the transition zone among the Yimeng uplift, Jinxi fold belt and Shanbei slope in the northeastern Ordos basin and marks the boundary between Palaeozoic and Mesozoic strata. According to the field geological survey and geophysical data, this study shows that the Yushuwan fault is a deep-cut northwest-southeast-oriented strike-slip basement fault. A total of 17 apatite and zircon fission track points show that the basin experienced several stages of uplift at 190 Ma, 150–170 Ma, 110–130 Ma, 60–80 Ma, and 20–40 Ma. The characteristics of the Yushuwan fault indicate that the northeastern part of the basin is not a simple slope but rather a step with a large drop. Therefore, in the area to the southwest of the Yushuwan fault, there should be high natural gas resource potential and good exploration prospects. The contour values of the magnetic anomaly on the southwestern side of the fault are high, and the contours are dense; in contrast, the contour values of the northwest magnetic anomaly are low, and the gradient is gentle. Therefore, the fault represents the eastern boundary of the Yimeng uplift, and restricts the eastward extent of the high magnetic anomaly zone in the Yimeng uplift area.

ABSTRACT Phosphatidylcholines (PCs) are a class of cell membrane phospholipids playing important roles in cellular integrity and signaling. In eukaryotes, PCs are biosynthesized via the Kennedy cytidine nucleotide and the Bremer-Greenberg pathways. The Aspergillus choC gene is predicted to encode a phospholipid methyltransferase, the key enzyme in the latter pathway. In this study, we have characterized choC in the opportunistic human pathogenic fungus Aspergillus fumigatus and show that ChoC plays a vital role in the endogenous biosynthesis of PC, which is necessary for proper vegetative growth, development, cell viability, and cell wall integrity of the fungus. Transcriptomic analyses have revealed that the deletion (Δ) of choC leads to the differential expression of diverse genes related to PC biosynthetic pathways, G protein signaling pathways, cell cycle, and autophagy. Importantly, the ΔchoC mutant averted cell death and regained cellular proliferation by regulating the expression of different PC synthesis genes after 4 days of incubation. Lipidomic analyses have demonstrated that ΔchoC directly leads to decreased PC synthesis, thereby affecting the length and unsaturation of PC fatty acid chains. In addition, ΔchoC leads to disturbed metabolism of other lipids, such as reduced phosphatidylethanolamine and neutral lipid triacylglycerol, but increased diacylglycerol amounts. Murine infection studies showed that invasive pathogenicity of the ΔchoC spores was significantly weakened coupled with a drastic reduction of their ability to colonize in kidneys. In summary, ChoC plays central roles in PC biosynthesis, lipid metabolism, cell membrane/wall integrity, endoplasmic reticulum function, and pathogenicity in A. fumigatus, implying that ChoC can be a novel target for antifungal therapy. IMPORTANCE This study explored the phospholipid metabolic pathway in A. fumigatus and its relationship with fungal growth, metabolism, and pathogenicity. ChoC, based on its critical roles in many aspects of the fungus and relatively conserved characteristics in filamentous fungi with low similarity with mammalian ones, can be a novel target of new antifungal drugs.

In response to the modeling difficulties and low search efficiency of traditional weapon-target assignment algorithms, this paper proposes a deep reinforcement learning-based intelligent weapon-target assignment method. A weapon-target intelligent assignment model with strong decision-making capabilities (RL4WTA) is obtained by training. Firstly, a multi-constraint weapon-target assignment optimization model is established to discretize the dynamic weapon-target assignment problem into a static weapon-target assignment problem. Furthermore, a planning and solving environment for the weapon-target assignment (WTA) problem is designed, and a Markov Decision Process (MDP) for WTA tasks is constructed based on the planning and solving model. This provides a foundation for solving the WTA problem using reinforcement learning algorithms. Additionally, a reinforcement learning-based WTA-solving model is proposed in this paper. By utilizing a multi-head Q-value network, the complex joint decision space is decoupled, thereby improving the efficiency of the WTA model. The use of a masking mechanism allows for inferring valid actions that satisfy the constraint conditions under the current situation, reducing uncertainty during the reinforcement learning training process. Experimental results show that the proposed model, RL4WTA, can generate satisfactory solutions adaptively in both small-scale and large-scale scenarios. Compared with traditional optimization algorithms, the model is superior in adaptability and computational efficiency, meeting the requirements of making optimal decisions for weapon-target assignment problems.

Abstract Concrete cracking caused by corrosion of reinforcement could significantly shorten the durability of reinforced concrete structure. It remains critical to investigate the process and mechanism of the corrosion occurring to concrete reinforcement and establish the theoretical prediction model of concrete expansion force for the whole process of corrosion cracking of reinforcement. Under the premise of uniform corrosion of reinforcing steel bars, the elastic mechanics analysis method is adopted to analyze the entire process starting from the corrosion of steel bars to the cracking of concrete due to corrosion. A relationship model between the expansion force of corrosion of steel bars and the surface strain of concrete is established. On the cuboid reinforced concrete specimens with square cross-sections, accelerated corrosion tests are carried out to calibrate and verify the established model. The model can be able to estimate the real-time expansion force of reinforced concrete at any time of the whole process from the initiation of steel corrosion to the end of concrete cracking by measuring the surface strain of concrete. It could be useful for quantitative real-time monitoring of steel corrosion in concrete structures.

A dual-wideband dual-polarized antenna using metasurface for the fifth generation (5G) millimeter wave (mm-wave) communications is proposed. It is designed and analyzed based on characteristic mode theory (CMT). The proposed metasurface is mainly composed of a 3×3 square-patch, in which its four corner patches are further sub-divided into a 4×4 sub-patch array, while the size of the other four edge patches is reduced and the center patch is etched with a pair of orthogonal slots. By doing so, the side lobe level can be effectively reduced and the main beam radiation can be enhanced. The metasurface is excited by a pair of orthogonally arranged substrate-integrated-waveguide (SIW) to grounded-coplanar-waveguide (GCPW) dual-polarized feeding networks that help to reduce the insertion loss and expand the frequency bandwidth of the feeding ports. In order to yield higher gain, four proposed metasurfaces are fed by a pair of 1-to-8-way power divider feeding networks including a pair of low-transmission-loss E-plane phase shifter. Measured results show desirable impedance bandwidths of 13.85% (24.2-27.8 GHz) and 14.81% (36.9-42.8 GHz) in the lower and upper frequency bands, respectively, and their corresponding average gains are 13.96 and 15.46 dBi.

Mimic defense is an active defense theory, which aims to fundamentally change the “easy to attack and difficult to defend” situation of network security. In this paper, we propose an evaluation method based on the probability of being attack successfully, and improve the evaluation scheme of historical confidence. We combine the two evaluation schemes with the TOPSIS (technique for order performance by similarity to ideal solution) algorithm, and finally form a complete heterogeneous variant dynamic scheduling model. Different from traditional multi-mode voting algorithms, the effect of the heterogeneous degree in voting is considered, and we use Bayesian estimation to obtain the optimal result in the probabilistic sense. Finally, simulation results show that the proposed algorithm can effectively enhance the dynamic and security of the mimic defense model, and give full play to the characteristics of mimic defense.

This study analyzes the function of different muscles during arm wrestling and proposes a method to analyze the optimal forearm angle for professional arm wrestlers. We built a professional arm-wrestling platform to measure the shape and deformation of the skin at the biceps brachii of a volunteer in vivo during arm wrestling. We observed the banding phenomenon of arm skin strain during muscle contraction and developed a model to evaluate the moment provided by the biceps brachii. According to this model, the strain field of the area of interest on the skin was measured, and the forearm angles most favorable and unfavorable to the work of the biceps brachii were analyzed. This study demonstrates the considerable potential of applying DIC and its extension method to the in vivo measurement of human skin and facilitates the use of the in vivo measurement of skin deformation in various sports in the future.

Chimeric antigen receptor (CAR)-T cell therapy has become an important method for the treatment of hematological tumors. Lentiviruses are commonly used gene transfer vectors for preparing CAR-T cells, and the conditions for preparing CAR-T cells vary greatly. This study reported for the first time the influence of differences in infection temperature on the phenotype and function of produced CAR-T cells. Our results show that infection at 4 degrees produces the highest CAR-positive rate of T cells, infection at 37 degrees produces the fastest proliferation in CAR-T cells, and infection at 32 degrees produces CAR-T cells with the greatest proportion of naive cells and the lowest expression of immune checkpoints. Therefore, infection at 32 degrees is recommended to prepare CAR-T cells. CAR-T cells derived from infection at 32 degrees seem to have a balance between function and phenotype. Importantly, they have increased oncolytic ability. This research will help optimize the generation of CAR-T cells and improve the quality of CAR-T cell products.

A novel Microcystis bloom caused by Microcystis densa has occurred in a typical subtropical reservoir every spring and summer since 2012, and it has caused several ecological and economic losses. To determine the environmental factors that influence the growth and physiological characteristics of M. densa, we investigated the variations in physicochemical factors and M. densa cell density from 2007 to 2017. The results showed that the urea-N concentration increased significantly (from 0.02 ± 0.00–0.20 ± 0.01 mg N l−1), whereas other factors did not vary significantly. NO3−-N and urea-N concentrations were higher than the NH4+-N concentration during the M. densa bloom. The nitrogen composition changed, and urea-N and NO3−-N became a major nitrogen sources in the reservoir. Water temperature and increased urea-N concentrations were the primary factors that influenced variations in M. densa cell density (45.5%, p

In fringe projection profilometry, high-order harmonics information of distorted fringe will lead to errors in the phase estimation. In order to solve this problem, a point-wise phase estimation method based on a neural network (PWPE-NN) is proposed in this paper. The complex nonlinear mapping relationship between the gray values and the phase under non-sinusoidal distortion is constructed by using the simple neural network model. It establishes a novel implicit expression for phase solution without complicated measurement operations. Compared with the previous method of combining local image information, it can accurately calculate each phase value by point. The comparison results show that the traditional method is with periodic phase errors, while the proposed method can effectively eliminate phase errors caused by non-sinusoidal phase shifting.

B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.

Background: Chromosomal abnormalities play an important role in the diagnosis and prognosis of patients with myelodysplastic syndromes (MDSs). The single-nucleotide polymorphism array (SNP-A) technique has gained popularity due to its improved resolution compared to that of metaphase cytogenetic (MC) analysis.Methods: A total of 376 individuals were recruited from two medical centers in China, including 350 patients and 26 healthy individuals. Among these patients, 200 were diagnosed with de novo MDS, 25 with myeloproliferative neoplasm (MPN), 63 with primary acute myeloid leukemia (AML), and 62 with idiopathic cytopenia of undetermined significance (ICUS). We evaluated the significance of abnormal chromosomes detected by SNP-A in the diagnosis and prognosis of MDS-related disorders.Results: (1) When certain chromosomal abnormalities could not be detected by conventional MC methods, these abnormalities could be detected more efficiently by the SNP-A method. With SNP-A, the detection rates of submicroscopic or cryptic aberrations in the MDS, MPN, and AML patients with normal MC findings were 32.8, 30.8, and 30%, respectively. (2) The chromosomal abnormalities detected by SNP-A had a very important value for the prognosis of patients with MDSs, especially in the low-risk group. The survival of patients with abnormal chromosomes detected by SNP-A was significantly lower than that of patients with no detected chromosomal abnormalities; this difference was observed in overall survival (OS) (P = 0.001) and progression-free survival (PFS) [24 months vs. not reach (NR); P = 0.008]. The patients with multiple chromosomal abnormalities detected by SNP-A had an inferior prognosis, and SNP-A abnormalities (≥3 per patient) were found to be an independent predictor of poor prognosis in patients with MDSs [hazard ratio (HR) = 2.40, P = 0.002]. (3) Patients with ICUS may progress to myeloid malignancies, but most patients often maintain a stable ICUS status for many years without progression. An ICUS patient found to have an MDS-related karyotype would be rediagnosed with MDS. SNP-A can efficiently detect chromosomal abnormalities, which would be important for assessing the evolution of ICUS. In our study, 17 ICUS patients with SNP-A-detected abnormalities developed typical MDSs.Conclusions: SNP-A can help evaluate the prognosis of patients with MDSs and better assess the risk of disease progression for patients with ICUS.

Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment for patients with refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), and combination with PD1 inhibitors may further improve the efficacy of anti-CD19 CAR (CD19 CAR)-T cells in the treatment of lymphomas. In a single-center study, we evaluated the safety and efficacy of a combination therapy with CD19 CAR-T cells and an anti-PD-1 antibody (nivolumab) in patients with relapsed/refractory B-NHL. A total of 11 patients with refractory/relapsed B-NHL were recruited and subsequently received CD19 CAR-T cells and nivolumab. The primary end points were safety and feasibility. The infusions were safe, and no dose-limiting toxicities occurred. Grade 1 or 2 cytokine release syndrome (CRS) was observed in 25% (3/11) and 50% (6/11) of the patients, respectively, and only one patient (1/11) experienced neurotoxicity. The objective response rate (ORR) and complete response (CR) rate were 81.81% (9/11) and 45.45% (5/11), respectively. The median follow-up time was 6 (1~15) months. The median progression-free survival (PFS) time was 6 months (1~14 months), and 3 patients continued to have a response at the time of this writing. Our study demonstrated that the combination of CD19 CAR-T cells and nivolumab was feasible and safe and mediated potent anti-lymphoma activity, which should be examined further in prospective clinical trials in refractory/relapsed B-NHL.

There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the RUNX1S291fs-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.

A steel-fiber-reinforced polymer (FRP) composite bar (SFCB) is a kind of rebar with inner steel bar wrapped by FRP, which can achieve a better anticorrosion performance than that of ordinary steel bar. The high ultimate strength of FRP can also provide a significant increase in load bearing capacity. Based on the adequate simulation of the load-displacement behaviors of concrete beams reinforced by SFCBs, a parametric analysis of the moment-curvature behaviors of concrete beams that are singly reinforced by SFCB was conducted. The critical reinforcement ratio for differentiating the beam’s failure mode was presented, and the concept of the maximum possible peak curvature (MPPC) was proposed. After the ultimate curvature reached MPPC, it decreased with an increase in the postyield stiffness ratio (rsf), and the theoretical calculation method about the curvatures before and after the MPPC was derived. The influence of the reinforcement ratio, effective depth, and FRP ultimate strain on the ultimate point was studied by the dimensionless moment and curvature. By calculating the envelope area under the moment-curvature curve, the energy ductility index can obtain a balance between the bearing capacity and the deformation ability. This paper can provide a reference for the design of concrete beams that are reinforced by SFCB or hybrid steel bar/FRP bar.

The factory-produced steel-fiber reinforced polymer composite bar (SFCB) is a new kind of reinforcement for concrete structures. The manufacturing technology of SFCB is presented based on a large number of handmade specimens. The calculated stress-strain curves of ordinary steel bar and SFCB under repeated tensile loading agree well with the corresponding experimental results. The energy-dissipation capacity and residual strain of both steel bar and SFCB were analyzed. Based on the good simulation results of ordinary steel bar and FRP bar under compressive loading, the compressive behavior of SFCB under monotonic loading was studied using the principle of equivalent flexural rigidity. There are three failure modes of SFCB under compressive loading: elastic buckling, postyield buckling, and no buckling (ultimate compressive strength is reached). The increase in the postyield stiffness of SFCB rsf can delay the postyield buckling of SFCB with a large length-to-diameter ratio, and an empirical equation for the relationship between the postbuckling stress and rsf is suggested, which can be used for the design of concrete structures reinforced by SFCB to consider the effect of reinforcement buckling.

Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 mutation. We find that many mutant STAG2 proteins retain their ability to interact with cohesin; however, the presence of mutant STAG2 resulted in a reduction in the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Using AAV-mediated gene targeting, we then introduced nine tumor-derived mutations into the endogenous allele of STAG2 in cultured human cells. While all nonsense mutations led to defects in sister chromatid cohesion and a subset induced anaphase defects, missense mutations behaved like wild-type in these assays. Furthermore, only one of nine tumor-derived mutations tested induced overt alterations in chromosome counts. These data indicate that not all tumor-derived STAG2 mutations confer defects in cohesion, chromosome segregation, and ploidy, suggesting that there are likely to be other functional effects of STAG2 inactivation in human cancer cells that are relevant to cancer pathogenesis.

To study the main molecular mechanisms responsible for itraconazole resistance in clinical isolates of Candida krusei.The 14α-demethylases encoded by ERG11 gene in the 16 C.krusei clinical isolates were amplified by polymerase chain reaction (PCR), and their nucleotide sequences were determined to detect point mutations. Meanwhile, ERG11 and efflux transporters (ABC1 and ABC2) genes were determined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) for their expression in itraconazole-resistant (R), itraconazole-susceptible dose dependent (SDD) and itraconazole-susceptible (S) C.krusei at the mRNA level.We found 7-point mutations in ERG11 gene of all the C.krusei clinical isolates, including 6 synonymous mutations and 1 missense mutation (C44T). However, the missense mutation was found in the three groups. The mRNA levels of ERG11 gene in itraconazole-resistant isolates showed higher expression compared with itraconazole-susceptible dose dependent and itraconazole-susceptible ones (P = 0.015 and P = 0.002 respectively). ABC2 gene mRNA levels in itraconazole-resistant group was significantly higher than the other two groups, and the levels of their expression in the isolates appeared to increase with the decrease of susceptibility to itraconazole (P = 0.007 in SDD compared with S, P = 0.016 in SDD with R, and P

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