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Abstract Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to

ObjectiveTo investigate the expression level of miR-4739 in gastric cancer (GC), analyze its diagnostic value in GC and the relationship with clinical pathological characteristics, and analyze its impact on the prognosis of patients.MethodsA total of 96 patients with GC who underwent radical gastrectomy in our hospital from March 2017 to June 2021 were selected. GC tissues from all patients were collected, and normal tissues adjacent to cancer were collected as controls. The expression level of miR-4739 in tissues was detected, the relationship between miR-4739 and different pathological features was analyzed, and the diagnostic value of miR-4739 in GC was analyzed. All patients were followed up after the operation, and the survival time of the patients was set as from the day of the first operation to 1 d when the patients died or the follow-up ended.ResultsThe relative expression level of miR-4739 in the GC tissue was (0.39 ± 0.06), lower than that in the paracancerous tissue (1.18 ± 0.19) (P

Researchers in many nations are focusing more on the growth and usage of the marine field, and it is apparent that study on the marine field will be the future development trend. The present study adopts the idea of polarization imaging based on liquid crystal phase retarder as a solution to the drawbacks of conventional industrial camera imaging clarity. Various optical thicknesses are employed to characterize the sea fog concentration; an outside optical imaging equipment is constructed for sea fog imaging research; and pictures comprising polarization characteristics may be determined through image processing. Using multi-band as factors, the benefit of polarization imaging in a sea fog environment is assessed objectively using contrast, information entropy, degree of polarization, and other evaluation indices. The results demonstrate that the quality of the polarization image is superior to that of the intensity image and that the outline of the target is more pronounced in the polarization image. Additionally, the polarization imaging effect is better in the 670 nm band, and the polarization contrast is increased by 1.9%. The contrast trend of the polarization picture is impacted by the time period, but it is roughly equivalent to that of the intensity image. This gives a solid platform for target surveys and civic operations under conditions of dense marine fog.

The Sr-containing magnesium alloys have unique characteristics and demonstrate potentials to broaden the application of magnesium alloys. The microstructures and room temperature tensile properties of the as-cast Mg-1Zn-1Ca-xSr (x = 0.1, 0.5, 1.5, 2.5 weight%) alloys were investigated in this study. The results indicated that the grains of the Sr-containing alloys were gradually refined and the quantity of second phases was obviously increased with increasing the Sr content. In addition, the phase constituents of the alloys were found to be α -Mg, Mg _2 Ca, Mg _6 Ca _2 Zn _3 and Mg _17 Sr _2 . The tensile results at room temperature showed that the tensile strength and elongation increased for low Sr-content alloys, but didn’t change or even decreased a little for high Sr-content alloys. The yield strength changed little with increasing Sr content. The alloy with 0.1% Sr exhibited the best comprehensive properties, with yield strength of 65.69 MPa, tensile strength of 118.23 MPa and elongation of 2.45%. Fracture analysis showed that the fracture mode of the alloys was mainly quasi-cleavage mechanism.

In this work, charge photogeneration and recombination processes of PM6:IDIC-4F and PM6:IDIC blend films were investigated by the steady-state and time-resolved spectroscopies, as well as the time-dependent density functional theory calculations. The peaks in absorption and photoluminescence (PL) spectra of IDIC and IDIC-4F solutions were assigned by combining the experiment and the simulation of UV–vis absorption and PL spectra. For neat acceptor films, the exciton diffusion length of neat IDIC and IDIC-4F films was estimated as ∼28.9 and ∼19.9 nm, respectively. For PM6-based blend films, we find that the fluorine substitution engineering on the IDIC acceptor material can increase the phase separate size of acceptor material in blend films, resulting in the reduction of dissociation efficiencies of acceptor excitons. In addition, we find that the charge recombination in PM6:IDIC-4F is dominated by bimolecular recombination, in comparison to geminate type carrier recombination in PM6:IDIC blend films. In addition, we find that thermal annealing treatment has a weak influence on carrier recombination but slightly reduces the exciton dissociation efficiency of acceptor in PM6:IDIC blend films, leading to a slightly reduced power conversion efficiency of PM6:IDIC solar cells. These results may shed light on the design of high-performance semiconductor molecules for application in solar cells. [ABSTRACT FROM AUTHOR]

Spurs have played an important role in the radiation of the genus Aquilegia, but little is known about how the spurless state arose in A. ecalcarata. Here we aim to characterize the genetic divergence within A. ecalcarata and gain insights into the origin of this species. A total of 19 populations from A. ecalcarata and 23 populations from three of its closest relatives (Aquilegia kansuensis, Aquilegia rockii and Aquilegia yabeana) were sampled in this study. We sequenced fifteen nuclear gene fragments across the genome and three chloroplast loci to conduct phylogenetic, PCoA and STRUCTURE analyses.Our analyses indicate that A. ecalcarata may not be monophyletic and can be divided into two distinct lineages (A. ecalcarata I and A. ecalcarata II). A. ecalcarata I is genetically close to A. kansuensis, whereas A. ecalcarata II is close to A. rockii. Isolation-with-migration analysis suggested that historical gene flow was low between A. ecalcarata I and A. rockii, as well as between A. ecalcarata II and A. kansuensis. The two distinct lineages of A. ecalcarata show significant divergence in 13 floral traits and also have distinct distributions. In addition, both A. ecalcarata I and II are adapted to a stony environment that differs from that of their closest relatives, indicating a habitat shift may have driven new adaptations. Our findings enrich the understanding of how floral evolution contributes to species diversification.

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Background: Focal segmental glomerulosclerosis (FSGS) is a kidney disease that is commonly associated with proteinuria and the progressive loss of renal function, which is characterized by podocyte injury and the depletion and collapse of glomerular capillary segments. The pathogenesis of FSGS has not been completely elucidated; however, recent advances in molecular genetics have provided increasing evidence that podocyte structural and functional disruption is central to FSGS pathogenesis. Here, we identified a patient with FSGS and aimed to characterize the pathogenic gene and verify its mechanism. Methods: Using next-generation sequencing and Sanger sequencing, we screened the causative gene that was linked to FSGS in this study. The patient's total blood RNA was extracted to validate the messenger RNA (mRNA) expression of coenzyme Q10 monooxygenase 6 (COQ6) and validated it by immunohistochemistry. COQ6 knockdown in podocytes was performed in vitro with small interfering RNA, and then, F-actin was determined using immunofluorescence staining. Cell apoptosis was evaluated by flow cytometry, the expression of active caspase-3 was determined by Western blot, and mitochondrial function was detected by MitoSOX. Results: Using whole-exome sequencing and Sanger sequencing, we screened a new causative gene, COQ6, NM_182480: exon1: c.G41A: p.W14X. The mRNA expression of COQ6 in the proband showed decreased. Moreover, the expression of COQ6, which was validated by immunohistochemistry, also had the same change in the proband. Finally, we focused on the COQ6 gene to clarify the mechanism of podocyte injury. Flow cytometry showed significantly increased in apoptotic podocytes, and Western blotting showed increases in active caspase-3 in si-COQ6 podocytes. Meanwhile, reactive oxygen species (ROS) levels were increased and F-actin immunofluorescence was irregularly distributed in the si-COQ6 group. Conclusions: This study reported a possible mechanism for FSGS and suggested that a new mutation in COQ6, which could cause respiratory chain defect, increase the generation of ROS, destroy the podocyte cytoskeleton, and induce apoptosis. It provides basic theoretical basis for the screening of FSGS in the future.

Deep neural network-based programs can be applied to protein structure modeling by inputting amino acid sequences. Here, we aimed to evaluate the AlphaFold2-modeled myocilin wild-type and variant protein structures and compare to the experimentally determined protein structures. Molecular dynamic and ligand binding properties of the experimentally determined and AlphaFold2-modeled protein structures were also analyzed. AlphaFold2-modeled myocilin variant protein structures showed high similarities in overall structure to the experimentally determined mutant protein structures, but the orientations and geometries of amino acid side chains were slightly different. The olfactomedin-like domain of the modeled missense variant protein structures showed fewer folding changes than the nonsense variant when compared to the predicted wild-type protein structure. Differences were also observed in molecular dynamics and ligand binding sites between the AlphaFold2-modeled and experimentally determined structures as well as between the wild-type and variant structures. In summary, the folding of the AlphaFold2-modeled MYOC variant protein structures could be similar to that determined by the experiments but with differences in amino acid side chain orientations and geometries. Careful comparisons with experimentally determined structures are needed before the applications of the in silico modeled variant protein structures. [ABSTRACT FROM AUTHOR]

Fascin is a major actin‐binding protein (ABP) in filopodia and is highly expressed in metastatic tumors. To inhibit its function, a potent inhibitor called NP‐G2‐044 is currently in phase II clinical trials. However, the binding mode of this inhibitor remains unclear. In this study, the binding mode of NP‐G2‐044 in fascin and predicted drug resistance mutations is investigated. The rough binding position and pose can be deduce based on information from its derivant NP‐G2‐029, whose crystal structure with fascin has been solved. Molecular docking, free energy perturbation (FEP) simulation and metadynamics simulation are performed to confirm the binding pose. Based on the molecular docking results, two binding modes of NP‐G2‐044, pose A and B, are obtained, with pose A being more favorable. For pose A, the planar indazole moiety has the same orientation as NP‐G2‐029 in the complex with fascin, while for pose B, it rotates ≈90°. FEP and metadynamics simulations indicate that both binding poses are possible. Relative binding free energies for mutation effects calculated by FEP predict E215A and R217A are drug resistance mutations. These findings are important for further drug development targeting fascin. [ABSTRACT FROM AUTHOR]

It is possible that neonates with pneumonia also have unrecognized sepsis. Identifying sepsis in neonates with pneumonia may cause some trouble for clinicians. This study aimed to evaluate the clinical value of the procalcitonin-to-albumin ratio (PAR) in identifying sepsis in neonates with pneumonia. We retrospectively included 912 neonates with pneumonia from January 2016 to July 2021. Clinical and laboratory data were collected from electronic medical records. Among neonates with pneumonia, 561 neonates were diagnosed with sepsis, according to the International Pediatric Sepsis Consensus. Neonates were divided into a sepsis group and a pneumonia group. A multivariate logistic regression analysis was used to evaluate whether PAR was a potential independent indicator for identifying sepsis in neonates with pneumonia. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of PAR in sepsis. Neonates with sepsis have a higher PAR (p < 0.001). Correlation analysis showed that PAR was positively correlated with the level of C-reactive protein (r = 0.446, p < 0.001). Multiple logistic regression analysis showed that PAR was an independent predictor of the presence of sepsis in neonates with pneumonia. ROC curve analysis revealed that PAR had good power in identifying sepsis in neonates with pneumonia (area under curve (AUC) = 0.72, 95% confidence interval (CI), 0.68-0.75, p < 0.001). PAR can be used as a new biomarker to identify sepsis in neonates with pneumonia. Compared with neonates with pneumonia, neonates with both pneumonia and sepsis had a higher PAR. PAR was a useful biomarker in distinguishing septic neonates from neonates with pneumonia. [ABSTRACT FROM AUTHOR]