Integrating Reinforcement Learning and Monte Carlo Tree Search for enhanced neoantigen vaccine design.

Recent advances in cancer immunotherapy have highlighted the potential of neoantigen-based vaccines. However, the design of such vaccines is hindered by the possibility of weak binding affinity between the peptides and the patient's specific human leukocyte antigen (HLA) alleles, which may not elicit a robust adaptive immune response. Triggering cross-immunity by utilizing peptide mutations that have enhanced binding affinity to target HLA molecules, while preserving their homology with the original one, can be a promising avenue for neoantigen vaccine design. In this study, we introduced UltraMutate, a novel algorithm that combines Reinforcement Learning and Monte Carlo Tree Search, which identifies peptide mutations that not only exhibit enhanced binding affinities to target HLA molecules but also retains a high degree of homology with the original neoantigen. UltraMutate outperformed existing state-of-the-art methods in identifying affinity-enhancing mutations in an independent test set consisting of 3660 peptide-HLA pairs. UltraMutate further showed its applicability in the design of peptide vaccines for Human Papillomavirus and Human Cytomegalovirus, demonstrating its potential as a promising tool in the advancement of personalized immunotherapy.

HLA-A+ tertiary lymphoid structures with reactivated tumor infiltrating lymphocytes are associated with a positive immunotherapy response in esophageal squamous cell carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.

Overcoming oxygen inhibition in UV photolithography for the fabrication of low-loss polymer waveguides.

Perfluorinated acrylate polymer materials exhibit low absorption loss at 1310 and 1550 nm, but molecular oxygen inhibits their photocuring. We propose a novel, to our knowledge, UV photolithography method incorporating a pre-exposure process for fabricating low-loss perfluorinated acrylate polymer waveguides. During the pre-exposure process, a partially cured thin layer forms on the core layer, effectively overcoming oxygen inhibition in subsequent lithography. Furthermore, the functional group contents of the polymerized materials were characterized by a Raman spectrometer to analyze the development reaction under the pre-exposure layer. Utilizing this improved method, we fabricated a straight waveguide with a length of 21 cm. The experiments showed that the propagation losses are 0.14 dB/cm at 1310 nm and 0.51 dB/cm at 1550 nm. The inter-channel cross talk for a core pitch of 250 µm was measured as low as -49 dB at 1310 nm. Error-free NRZ data transmission over this waveguide at 25 Gb/s was achieved, showcasing the potential in optical interconnect and communication applications.

ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.

Suppression of neuroinflammation using small molecule compounds targeting the key pathways in microglial inflammation has attracted great interest. Recently, increasing attention has been gained to the role of the second bromodomain (BD2) of the bromodomain and extra-terminal (BET) proteins, while its effect and molecular mechanism on microglial inflammation has not yet been explored. In this study, we evaluated the therapeutic effects of ABBV-744, a BD2 high selective BET inhibitor, on lipopolysaccharide (LPS)-induced microglial inflammation in vitro and in vivo, and explored the key pathways by which ABBV-744 regulated microglia-mediated neuroinflammation. We found that pretreatment of ABBV-744 concentration-dependently inhibited the expression of LPS-induced inflammatory mediators/enzymes including NO, TNF-α, IL-1ß, IL-6, iNOS, and COX-2 in BV-2 microglial cells. These effects were validated in LPS-treated primary microglial cells. Furthermore, we observed that administration of ABBV-744 significantly alleviated LPS-induced activation of microglia and transcriptional levels of pro-inflammatory factors TNF-α and IL-1ß in mouse hippocampus and cortex. RNA-Sequencing (RNA-seq) analysis revealed that ABBV-744 induced 508 differentially expressed genes (DEGs) in LPS-stimulated BV-2 cells, and gene enrichment and gene expression network analysis verified its regulation on activated microglial genes and inflammatory pathways. We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation.

High-bandwidth tilt-tip mirror with octagonal prism flexible mechanism.

The adaptive optical system requires a tilt-tip mirror (TTM) with high bandwidth to compensate for optical beam jitter caused by atmospheric turbulence in real time. This paper introduces a novel, to the best of our knowledge, design of a voice coil TTM using an octagonal flexible mechanism and optimizes its parameters through theoretical analysis and finite element simulations. The results show that its resonance frequency in the non-working direction is up to 1005.2 Hz, representing a 19.4% improvement in theoretical calculations and a 13.8% improvement in simulations compared to traditional cylindrical flexible mechanisms. Additionally, the non-working direction stiffness of the flexible support structure has been optimized, enhancing the third-order and higher resonance frequencies of the system to meet the high bandwidth requirements. A prototype of the TTM was developed based on this design, and its deflection angles and responses were measured in the laboratory, confirming the design's reliability. This low-cost, high-bandwidth TTM design facilitates miniaturization of adaptive optical systems, making it beneficial for applications in astronomical observations, laser communication, laser weapons, laser processing, and more.

Vapor condensation with daytime radiative cooling.

A radiative vapor condenser sheds heat in the form of infrared radiation and cools itself to below the ambient air temperature to produce liquid water from vapor. This effect has been known for centuries, and is exploited by some insects to survive in dry deserts. Humans have also been using radiative condensation for dew collection. However, all existing radiative vapor condensers must operate during the nighttime. Here, we develop daytime radiative condensers that continue to operate 24 h a day. These daytime radiative condensers can produce water from vapor under direct sunlight, without active consumption of energy. Combined with traditional passive cooling via convection and conduction, radiative cooling can substantially increase the performance of passive vapor condensation, which can be used for passive water extraction and purification technologies.

High-precision calculation and experiments on the thermal blooming of high-energy lasers.

Thermal blooming (TB) is one of the important factors affecting the quality of high-energy laser beams. Reasonable simulation of thermal blooming is important to the application of a high-energy laser. However, reported investigations on TB simulation are mainly based on one method, such as the perturbation method or the phase screen method, which often leads to obvious errors in some conditions. In the paper, the reasonable ranges of optical generalized distortion parameters for both methods are determined based on the reported experimental data, which solves the problem of accurate TB simulations for the first time. In addition, the dynamic effect of thermal blooming is also calculated. Finally, the formula method is presented to extract the phase of thermal blooming distortion. We then use LC-SLM (Liquid crystal spatial light modulator) to emulate thermal blooming effect in the lab. The experimental results are more consistent with the numerical simulation results than conventional phase extraction methods. Our work provides a quantitatively and programmable way to accurately simulate TB with LC-SLM in the lab.

Current Development and Future Application Prospects of Plants-Derived Polyphenol Bioactive Substance Curcumin as a Novel Feed Additive in Livestock and Poultry.

Curcumin (CUR) is a kind of natural orange-yellow phenolic compound mainly extracted from the stems and roots of turmeric plants and other species in the genus Curcuma, furthermore, it is also the most important active ingredient exerting pharmacological functions in turmeric. In recent years, CUR has been frequently reported and has attracted widespread attention from scholars all over the world due to its numerous biological functions and good application prospects, such as anti-inflammatory, anticancer, antioxidant and providing lipid-lowering effects, etc. In addition, adding a certain dose of CUR to livestock and poultry feed is important for animal growth and development, which plays a key role in animal metabolism, reproduction, immunity and clinical health care. This review aims to summarize, based on the published papers and our own observations, the physical and chemical properties and the biological functions of the plant-derived bioactive ingredient CUR, especially regarding the latest research progress in regulating intestinal health as well as its current development and future application prospects in livestock and poultry as a novel feed additive, so as to provide theoretical and practical references for the further study of the application of CUR as a novel feed additive and a potential new antibiotic substitute, thereby improving the research field of plant-derived bioactive ingredients and promoting the healthy development of livestock and poultry.

Pathogenicity evaluation and the genotype-phenotype analysis of OPA1 variants.

Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60-90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3' terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.

Investigation of daughter cell dissection coincidence of single budding yeast cells immobilized in microfluidic traps.

Microfluidic methodologies allow for automatic and high-throughput replicative lifespan (RLS) determination of single budding yeast cells. However, the resulted RLS is highly impacted by the robustness of experimental conditions, especially the microfluidic yeast-trapping structures, which are designed for cell retention, growth, budding, and daughter cell dissection. In this work, four microfluidic yeast-trapping structures, which were commonly used to immobilize mother cells and remove daughter cells for entire lifespan of budding yeast, were systematically investigated by means of finite element modeling (FEM). The results from this analysis led us to propose an optimized design, the yeast rotation (YRot) trap, which is a "leaky bowl"-shaped structure composed of two mirrored microcolumns facing each other. The YRot trap enables stable retention of mother cells in its "bowl" and hydrodynamic rotation of buds into its "leaky orifice" such that matured progenies can be dissected in a coincident direction. We validated the functions of the YRot trap in terms of cell rotation and daughter dissection by both FEM simulations and experiments. With the integration of denser YRot traps in microchannels, the microfluidic platform with stable single-yeast immobilization, long-term cell culturing, and coincident daughter dissection could potentially improve the robustness of experimental conditions for precise RLS determination in yeast aging studies.

Synthesis of Mesoionic N-Heterocyclic Olefins and Catalytic Application for Hydroboration Reactions.

Mesoionic N-heterocyclic olefins have been developed, which feature high ylidic character. These compounds have been used as efficient catalysts for hydroboration of imines, nitriles, and N-heteroarenes.

Halogen-bonding-induced diverse aggregation of 4,5-diiodo-1,2,3-triazolium salts with different anions.

The synthesis of 4,5-diiodo-1,3-dimesityl-1,2,3-triazolium salts with different anions have been developed. These triazolium salts show diverse aggregation via halogen bonding between C-I bonds and anions. Triazolium with halide anions exists as a tetramer with saddle conformation. Triazolium tetrafluoroborate exists as a trimer with Chinese lantern shape conformation. Triazolium trifluoroacetate and acetate exist as dimers, respectively, while the former shows boat conformation and the latter forms rectangle conformation. Triazolium salts form a linear polymer with polyiodide.

Molecular Network-Based Drug Prediction in Thyroid Cancer.

As a common malignant tumor disease, thyroid cancer lacks effective preventive and therapeutic drugs. Thus, it is crucial to provide an effective drug selection method for thyroid cancer patients. The connectivity map (CMAP) project provides an experimental validated strategy to repurpose and optimize cancer drugs, the rationale behind which is to select drugs to reverse the gene expression variations induced by cancer. However, it has a few limitations. Firstly, CMAP was performed on cell lines, which are usually different from human tissues. Secondly, only gene expression information was considered, while the information about gene regulations and modules/pathways was more or less ignored. In this study, we first measured comprehensively the perturbations of thyroid cancer on a patient including variations at gene expression level, gene co-expression level and gene module level. After that, we provided a drug selection pipeline to reverse the perturbations based on drug signatures derived from tissue studies. We applied the analyses pipeline to the cancer genome atlas (TCGA) thyroid cancer data consisting of 56 normal and 500 cancer samples. As a result, we obtained 812 up-regulated and 213 down-regulated genes, whose functions are significantly enriched in extracellular matrix and receptor localization to synapses. In addition, a total of 33,778 significant differentiated co-expressed gene pairs were found, which form a larger module associated with impaired immune function and low immunity. Finally, we predicted drugs and gene perturbations that could reverse the gene expression and co-expression changes incurred by the development of thyroid cancer through the Fisher's exact test. Top predicted drugs included validated drugs like baclofen, nevirapine, glucocorticoid, formaldehyde and so on. Combining our analyses with literature mining, we inferred that the regulation of thyroid hormone secretion might be closely related to the inhibition of the proliferation of thyroid cancer cells.

A Hybrid Deep Learning Model for Predicting Protein Hydroxylation Sites.

Protein hydroxylation is one type of post-translational modifications (PTMs) playing critical roles in human diseases. It is known that protein sequence contains many uncharacterized residues of proline and lysine. The question that needs to be answered is: which residue can be hydroxylated, and which one cannot. The answer will not only help understand the mechanism of hydroxylation but can also benefit the development of new drugs. In this paper, we proposed a novel approach for predicting hydroxylation using a hybrid deep learning model integrating the convolutional neural network (CNN) and long short-term memory network (LSTM). We employed a pseudo amino acid composition (PseAAC) method to construct valid benchmark datasets based on a sliding window strategy and used the position-specific scoring matrix (PSSM) to represent samples as inputs to the deep learning model. In addition, we compared our method with popular predictors including CNN, iHyd-PseAAC, and iHyd-PseCp. The results for 5-fold cross-validations all demonstrated that our method significantly outperforms the other methods in prediction accuracy.

Improved magnetic and magnetoelectric properties in BaFe12O19 nanostructures.

The structural, magnetic and magnetoelectric properties were investigated for sol-gel prepared BaFe12O19 nanorods and plate-like nanoparticles. Based on comparative experiments with bulk ceramics, it is found that larger structural distortion is present in nanostructures, which could cause the enhancement of magnetocrystalline anisotropy and the off-center displacement of Fe3+ ions, and thus result in improved magnetic and magnetoelectric properties in BaFe12O19 plate-like nanoparticles. Meanwhile, the local (Fe2+-Fe3+) dipoles, which usually appear during a high temperature sintering process, can also contribute to the negative magnetoelectric effect of BaFe12O19 nanorods and a large room temperature magnetodielectric coefficient of about -13% is observed at 104 Hz and 9 kOe.

Induced core-shell structure and the electric properties of (K0.48Na0.52)0.95Li0.05Nb0.95Sb0.05O3 ceramics.

The relationship among dielectric anomaly, ferroelectric response, defects, and microstructures was established for (K0.48(1+x)Na0.52)0.95Li0.05Nb0.95Sb0.05O3 (x = 0.04, 0.00, -0.02, -0.04 and -0.08) ceramics. For x = -0.02 and -0.04, larger coercive fields and lower remnant polarizations were obtained; besides, an additional dielectric relaxation behavior was observed with the activation energy Ea being about 2.19 eV and 1.92 eV, respectively. Furthermore, the grain and grain boundary contributions to the capacitance were separated using impedance spectroscopy, which, combined with back-scattering characterization, firmly indicates the core-shell structure of K-deficient samples (x = -0.02 and -0.04). Unlike the cores, the shells possess a large amount of K+ vacancies (). This work paves a way for regulating the fine structure and more on the electrical properties of KNN-based materials.

Effect of Surface Charge on Surface-Initiated Atom Transfer Radical Polymerization from Cellulose Nanocrystals in Aqueous Media.

Cellulose nanocrystals (CNCs) with different charge densities were utilized to examine the role of electrostatic interactions on surface-initiated atom transfer radical polymerization (SI-ATRP) in aqueous media. To this end, growth of hydrophilic uncharged poly(N,N-dimethylacrylamide) (PDMAM) brushes was monitored by electrophoresis, (1)H NMR spectroscopy, and dynamic light scattering (DLS). Molecular weight and polydispersity of PDMAM brushes was determined by GPC analysis of hydrolytically cleaved polymers. Initiator and polymer brush grafting densities, and thus, initiator efficiencies were derived from elemental analysis. Higher initiator efficiency of polymer brush growth was observed for CNCs with higher anionic surface sulfate half-ester group density, but at the expense of high polydispersity caused by inefficient deactivation. PDMAM grafts with number-average molecular weights up to 530 kDa and polydispersity indices <1.5 were obtained under highly diluted monomer concentrations. The role of surface chemistry on the growth of neutral polymer brushes from CNCs in water is emphasized and a model of the interfacial region at the onset of polymerization is proposed. The results presented here could have implications for other substrates that present surface charges and for the assumption that the kinetics of Cu-mediated SI-CRP are analogous to those conducted in solution.

Synthesis and decreasing Aß content evaluation of arctigenin-4-yl carbamate derivatives.

A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing ß-amyloid (Aß) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aß content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aß content reduction at 20µM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aß content was better than arctigenin under the concentrations of 1, 10 and 20µM.

Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors.

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13 µM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 µM, respectively.

Hollow carbon fiber wrapped by regular rGO wave-like folds for efficient solar driven interfacial water steam generation.

Efficient seawater desalination is an effective way to solve the shortages of fresh water and energy but with limitations of the low fresh water production rate and high cost. Here, a hollow carbon fiber (HCF) wrapped by regular reduced graphene oxide (rGO) wave-like folds (rGO@HCF) is prepared on account of the differences in thermal shrinkage performance between graphene oxide (GO) and willow catkins fiber. Under one sun irradiation (1 kW m-2), the dry and wet surface temperature of the resulting evaporator reached up to 119.1 °C and 61.7 °C, respectively, and the water steam production rate reached 3.42 kg m-2 h-1. Also, for the outdoor experiment, the rGO@HCF exhibits good evaporator performance which reach up 27.8 kg m-2 day-1. Additionally, rGO@HCF also shows good seawater desalination performance and excellent durability for longtime work. DSC results indicate that the evaporation enthalpy of bulk water and adsorbed water decreased from 2503.92 to 1020.54 J g-1. The excellent evaporating performance is mainly attributed to the regular wave-like microstructure surface of the HCF, which can enhance the light absorption, reduced the vaporization enthalpy of the adsorption water. The findings not only introduce a novel approach for agricultural utilization, but also establish a crucial theoretical foundation for the design of regular wave-like microstructures.