Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.

3D spheroid culture synchronizes heterogeneous MSCs into an immunomodulatory phenotype with enhanced anti-inflammatory effects.

Mesenchymal stem cells (MSCs) are heterogeneous in morphology and transcriptome, resulting in varying therapeutic outcomes. In this study, we found that 3D spheroid culture of heterogeneous MSCs, which have undergone conventional 2D monolayer culture for 5-6 passages, synchronized the cells into a uniform cell population with dramatically reduced cell size, and considerably increased levels of immunosuppressive genes and growth factors. Single-cell RNA sequencing (scRNA-seq) analysis of the cells revealed that 3D MSCs consisted of 2 major cell subpopulations and both expressed high levels of immunosuppressive factors, compared to 6 subpopulations in 2D MSCs. In addition, 3D MSCs showed a greater suppressive effect on T cells. Moreover, intravenous infusion of a large dose of 3D MSCs prior to imiquimod (IMQ) treatment significantly improved psoriatic lesion. Thus, our results indicate that 3D spheroid culture reprograms heterogeneous MSCs into a uniform immunosuppressive phenotype and promises a novel therapeutic potential for inflammatory diseases.

Accelerating Relativistic Exact-Two-Component Density Functional Theory Calculations with Graphical Processing Units.

Numerical integration of the exchange-correlation potential is an inherently parallel problem that can be significantly accelerated by graphical processing units (GPUs). In this Letter, we present the first implementation of GPU-accelerated exchange-correlation potential in the GauXC library for relativistic, 2-component density functional theory. By benchmarking against copper, silver, and gold coinage metal clusters, we demonstrate the speed and efficiency of our implementation, achieving significant speedup compared to CPU-based calculations. One GPU card provides computational power equivalent to roughly 400 CPU cores in the context of this work. The speedup further increases for larger systems, highlighting the potential of our approach for future, more computationally demanding simulations. Our implementation supports arbitrary angular momentum basis functions, enabling the simulation of systems with heavy elements and providing substantial speedup to relativistic electronic structure calculations. This advancement paves the way for more efficient and extensive computational studies in the field of density functional theory.

Monosome Stalls the Translation Process Mediated by IGF2BP in Arcuate Nucleus for Puberty Onset Delay.

Puberty onset through hypothalamic-pituitary-gonad (HPG) axis as an important reproductive event in postnatal development is initiated from hypothalamic arcuate nucleus (ARC). The growing evidence indicates that translational control also plays an essential role in the final expression of gonadotropin genes. To investigate the role of protein translation and behavior of ribosomes in pubertal onset, the global profiles of transcriptome, single ribosome (monosome), polysome, and tandem mass tag proteome were comprehensively investigated in rat hypothalamic ARCs of different pubertal stages using RNA sequencing, polyribo sequencing, and mass spectrum. Transcriptome-wide enrichments of N6-methyladenosine and IGF2BP2 were investigated using meRIP and RIP sequencing. Monosome was robustly enriched on a large proportion of mRNA in early puberty rats (postnatal day (PND)-25) compared to late puberty (PND-35 and PND-45). Monosome-enriched mRNAs, including HPG axis-related genes, had a large number of upstream ORFs (uORF, < 100 nt) and displayed translational repression in early puberty. Furthermore, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) could particularly interact with and facilitate monosome to bind with mRNA in early puberty. Finally, ectopic over-expression of IGF2BP2 in hypothalamic ARC via lateral ventricle injection in vivo could recruit monosome to aggregate on mRNA and delay puberty onset. We uncovered a novel regulatory mechanism of IGF2BP2 and monosome for translational control in puberty onset, which shed light on the neuroendocrine regulatory network involved in HPG axis activation.

State Interaction for Relativistic Four-Component Methods: Choose the Right Zeroth-Order Hamiltonian for Late-Row Elements.

We present several schemes based on the spin-separation of the Dirac-Coulomb-Breit Hamiltonian for the perturbative treatment of relativistic four-component Hamiltonians within the state interaction framework. While state interaction approaches traditionally use zeroth-order scalar-relativistic states, we develop augmented zeroth-order Hamiltonians with increasing accuracy and investigate convergence to the variational limit as a function of the choice of zeroth-order Hamiltonian. The state interaction schemes developed in this work are benchmarked using ground-state fine-structure splitting of late-row atoms and diatomic hyrides. Although the scalar-relativistic zeroth-order Hamiltonian exhibits significant errors in ground-state fine-structure splitting, the predictive accuracy can be improved by augmenting the zeroth-order Hamiltonian with one- and two-electron vector-relativistic operators (e.g., spin-orbit, spin-spin, orbit-orbit). This work lays the theoretical foundation for the development of low-scaling, high-accuracy perturbative relativistic methods suitable for late-row elements.

Real-time capture of nuclear motions influencing photoinduced electron transfer.

Although vibronic coupling phenomena have been recognized in the excite state dynamics of transition metal complexes, its impact on photoinduced electron transfer (PET) remains largely unexplored. This study investigates coherent wavepacket (CWP) dynamics during PET processes in a covalently linked electron donor-acceptor complex featuring a cyclometalated Pt(ii) dimer as the donor and naphthalene diimide (NDI) as the acceptors. Upon photoexciting the Pt(ii) dimer electron donor, ultrafast broadband transient absorption spectroscopy revealed direct modulation of NDI radical anion formation through certain CWP motions and correlated temporal evolutions of the amplitudes for these CWPs with the NDI radical anion formation. These results provide clear evidence that the CWP motions are the vibronic coherences coupled to the PET reaction coordinates. Normal mode analysis identified that the CWP motions originate from vibrational modes associated with the dihedral angles and bond lengths between the planes of the cyclometalating ligand and the NDI, the key modes altering their π-interaction, consequently influencing PET dynamics. The findings highlight the pivotal role of vibrations in shaping the favorable trajectories for the efficient PET processes.

Enhanced delivery of CRISPR/Cas9 system based on biomimetic nanoparticles for hepatitis B virus therapy.

The persistent presence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei poses a significant obstacle to achieving a comprehensive cure for hepatitis B virus (HBV). Current applications of CRISPR/Cas9 for targeting and eliminating cccDNA have been confined to in vitro studies due to challenges in stable cccDNA expression in animal models and the limited non-immunogenicity of delivery systems. This study addresses these limitations by introducing a novel non-viral gene delivery system utilizing Gemini Surfactant (GS). The developed system creates stable and targeted CRISPR/Cas9 nanodrugs with a negatively charged surface through modification with red blood cell membranes (RBCM) or hepatocyte membranes (HCM), resulting in GS-pDNA@Cas9-CMs complexes. These GS-pDNA complexes demonstrated complete formation at a 4:1 w/w ratio. The in vitro transfection efficiency of GS-pDNA-HCM reached 54.61%, showing homotypic targeting and excellent safety. Additionally, the study identified the most effective single-guide RNA (sgRNA) from six sequences delivered by GS-pDNA@Cas9-HCM. Using GS-pDNA@Cas9-HCM, a significant reduction of 96.47% in in vitro HBV cccDNA and a 52.34% reduction in in vivo HBV cccDNA were observed, along with a notable decrease in other HBV-related markers. The investigation of GS complex uptake by AML-12 cells under varied time and temperature conditions revealed clathrin-mediated endocytosis (CME) for GS-pDNA and caveolin-mediated endocytosis (CVME) for GS-pDNA-HCM and GS-pDNA-RBCM. In summary, this research presents biomimetic gene-editing nanovectors based on GS (GS-pDNA@Cas9-CMs) and explores their precise and targeted clearance of cccDNA using CRISPR/Cas9, demonstrating good biocompatibility both in vitro and in vivo. This innovative approach provides a promising therapeutic strategy for advancing the cure of HBV.

Generative Adversarial Network for Trimodal Medical Image Fusion using Primitive Relationship Reasoning.

Medical image fusion has become a hot biomedical image processing technology in recent years. The technology coalesces useful information from different modal medical images onto an informative single fused image to provide reasonable and effective medical assistance. Currently, research has mainly focused on dual-modal medical image fusion, and little attention has been paid on trimodal medical image fusion, which has greater application requirements and clinical significance. For this, the study proposes an end-to-end generative adversarial network for trimodal medical image fusion. Utilizing a multi-scale squeeze and excitation reasoning attention network, the proposed method generates an energy map for each source image, facilitating efficient trimodal medical image fusion under the guidance of an energy ratio fusion strategy. To obtain the global semantic information, we introduced squeeze and excitation reasoning attention blocks and enhanced the global feature by primitive relationship reasoning. Through extensive fusion experiments, we demonstrate that our method yields superior visual results and objective evaluation metric scores compared to state-of-the-art fusion methods. Furthermore, the proposed method also obtained the best accuracy in the glioma segmentation experiment. The code is publicly available at https://github.com/JasonWong30/PRRGAN.

SLC7A11 protects luminal A breast cancer cells against ferroptosis induced by CDK4/6 inhibitors.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

Stitching method for panoramic nail fold images based on capillary contour enhancement.

Nail fold capillaroscopy is an important means of monitoring human health. Panoramic nail fold images improve the efficiency and accuracy of examinations. However, the acquisition of panoramic nail fold images is seldom studied and the problem manifests of few matching feature points when image stitching is used for such images. Therefore, this paper presents a method for panoramic nail fold image stitching based on vascular contour enhancement, which first solves the problem of few matching feature points by pre-processing the image with contrast-constrained adaptive histogram equalization (CLAHE), bilateral filtering (BF), and sharpening algorithms. The panoramic images of the nail fold blood vessels are then successfully stitched using the fast robust feature (SURF), fast library of approximate nearest neighbors (FLANN) and random sample agreement (RANSAC) algorithms. The experimental results show that the panoramic image stitched by this paper's algorithm has a field of view width of 7.43 mm, which improves the efficiency and accuracy of diagnosis.

Derived from fangchinoline, LYY-35 exhibits an inhibiting effect on human NSCLC cancer A549 cells.

Although fangchinoline has been widely used as an adjunct therapy for a variety of inflammatory and cancerous diseases, its mechanism of action on tumor cells remains unclear. Fangchinoline derivative LYY-35 reduced the number of A549 cells, deformed cell morphology and increased cell debris. Cell viability was significantly reduced, while the same concentration of LYY-35 had little effect on BEAS-2B viability of normal lung epithelial cells. In addition, LYY-35 can also reduce the migration, proliferation and invasion ability of A549 cells. Levels of ß-catenin, ZO-1 and ZEB-1 proteins, biomarkers of cell adhesion and epithelial mesenchymal transformation, were significantly reduced. The levels of superoxide dismutase and lactate dehydrogenase decreased gradually, while the levels of glutathione, malondialdehyde and intracellular and extracellular ROS increased significantly. At the same time, LYY-35 induced increased apoptosis, increased expression of Bax, cleaved caspase3, cleaved PARP1, and decreased expression of Bcl-xl, which blocked the cell cycle to G0/G1 phase. The expressions of cell cycle checkpoint proteins Cyclin B1, Cyclin E1, CDK6, PCNA and PICH were significantly decreased. With the increase of LYY-35 concentration, the trailing phenomenon was more obvious in single cell gel electrophoresis. DNA damage repair proteins: BLM, BRCA-1 and PARP-1 expression decreased gradually.LYY-35 can inhibit the proliferation of non-small cell lung cancer A549 cells, block cell cycle, promote apoptosis, increase ROS production, cause DNA damage and interfere with DNA replication. LYY-35 is promising for the treatment of non-small cell lung cancer in the future.

Relativistic Coupled Cluster with Completely Renormalized and Perturbative Triples Corrections.

We have implemented noniterative triples corrections to the energy from coupled-cluster with single and double excitations (CCSD) within the 1-electron exact two-component (1eX2C) relativistic framework. The effectiveness of both the CCSD(T) and the completely renormalized (CR) CC(2,3) approaches are demonstrated by performing all-electron computations of the potential energy curves and spectroscopic constants of copper, silver, and gold dimers in their ground electronic states. Spin-orbit coupling effects captured via the 1eX2C framework are shown to be crucial for recovering the correct shape of the potential energy curves, and the correlation effects due to triples in these systems change the dissociation energies by about 0.1-0.2 eV or about 4-7%. We also demonstrate that relativistic effects and basis set size and contraction scheme are significantly more important in Au2 than in Ag2 or Cu2.

Flexible Scaffold Modulation of Spatial Structure and Function of Hierarchically Porous Nanoparticle@ZIF-8 Composites to Enhance Field Deployable Disease Diagnostics.

Catalytic nanoparticle@metal-organic framework (MOF) composites have attracted significant interest in point-of-care testing (POCT) owing to their prominent catalytic activity. However, the trade-off between high loading efficiency and high catalytic activity remains challenging because high concentrations of nanoparticles tend to cause the misjoining and collapse of the MOFs. Herein, a facile strategy is reported to encapsulate high concentrations of platinum (Pt) nanoparticles into zeolitic imidazolate framework-8 (ZIF-8) using polydopamine (PDA) as a support for Pt@ZIF-8 and as a flexible scaffold for further immobilization of Pt nanoparticles. The resulting composite (Pt@ZIF-8@PDA@Pt) exhibits ultrahigh Pt nanoparticle loading efficiency, exceptional catalytic activity, stability, and a bright colorimetric signal. Following integration with lateral flow immunoassay (LFIA), the detection limits for pre- and post-catalysis detection of B-type natriuretic peptide (NT-proBNP) are 0.18 and 0.015 ng mL-1, respectively, representing a 6-fold and 70-fold improvement compared to gold nanoparticle-based LFIA. Moreover, Pt@ZIF-8@PDA@Pt-based LFIA achieves 100% diagnostic sensitivity for NT-proBNP in a cohort of 184 clinical samples.

Direct Probe of Conical Intersection Photochemistry by Time-Resolved X-ray Magnetic Circular Dichroism.

The direct probing of photochemical dynamics by detecting the electronic coherence generated during passage through conical intersections is an intriguing challenge. The weak coherence signal and the difficulty in preparing purely excited wave packets that exclude coherence from other sources make it experimentally challenging. We propose to use time-resolved X-ray magnetic circular dichroism to probe the wave packet dynamics around the conical intersection. The magnetic field amplifies the relative strength of the electronic coherence signal compared to populations through the magnetic field response anisotropy. More importantly, since the excited state relaxation through conical intersections involves a change of parity, the magnetic coupling matches the symmetry of the response function with the electronic coherence, making the coherence signal only sensitive to the conical intersection induced coherence and excludes the pump pulse induced coherence between the ground state and excited state. In this theoretical study, we apply this technique to the photodissociation dynamics of a pyrrole molecule and demonstrate its capability of probing electronic coherence at a conical intersection as well as population transfer. We demonstrate that a magnetic field can be effectively used to extract novel information about electron and nuclear molecular dynamics.

Leveraging pharmacokinetic parameters as covariate in Bayesian logistic regression model to optimize dose selection in early phase oncology trial.

Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.

Generation of B7-H3 isoform regulated by ANXA2/NSUN2/YBX1 axis in human glioma.

In recent years, in the development of emerging immunotherapy, B7-H3 is also termed as CD276 and has become a novel chimeric antigen receptor (CAR)-T target against glioma and other tumours, and aroused extensive attention. However, B7-H3 has three isoforms (2, 3 and 4Ig) with the controversial expression and elusive function in tumour especially glioma. The current study mainly focuses on the regulatory factors and related mechanisms of generation of different B7-H3 isoforms. First, we have determined that 2Ig is dominant in glioma with high malignancy, and 4Ig is widely expressed, whereas 3Ig shows negative expression in all glioma. Next, we have further found that RNA binding protein annexin A2 (ANXA2) is essential for B7-H3 isoform maintenance, but fail to determine the choice of 4Ig or 2Ig. RNA methyltransferase NOP2/Sun RNA methyltransferase 2 (NSUN2) and 5-methylcytosine reader Y-box binding protein 1 (YBX1) facilitate the production of 2Ig. Our findings have uncovered a series of factors (ANXA2/NSUN2/YBX1) that can determine the alternative generation of different isoforms of B7-H3 in glioma. Our result aims to help peers gain a clearer understanding of the expression and regulatory mechanisms of B7H3 in tumour patients, and to provide better strategies for designing B7H3 as a target in immunotherapy.