Novel mRNA adjuvant ImmunER enhances prostate cancer tumor-associated antigen mRNA therapy via augmenting T cell activity.

Prostate cancer (PCa) is characterized as a "cold tumor" with limited immune responses, rendering the tumor resistant to immune checkpoint inhibitors (ICI). Therapeutic messenger RNA (mRNA) vaccines have emerged as a promising strategy to overcome this challenge by enhancing immune reactivity and significantly boosting anti-tumor efficacy. In our study, we synthesized Tetra, an mRNA vaccine mixed with multiple tumor-associated antigens, and ImmunER, an immune-enhancing adjuvant, aiming to induce potent anti-tumor immunity. ImmunER exhibited the capacity to promote dendritic cells (DCs) maturation, enhance DCs migration, and improve antigen presentation at both cellular and animal levels. Moreover, Tetra, in combination with ImmunER, induced a transformation of bone marrow-derived dendritic cells (BMDCs) to cDC1-CCL22 and up-regulated the JAK-STAT1 pathway, promoting the release of IL-12, TNF-α, and other cytokines. This cascade led to enhanced proliferation and activation of T cells, resulting in effective killing of tumor cells. In vivo experiments further revealed that Tetra + ImmunER increased CD8+T cell infiltration and activation in RM-1-PSMA tumor tissues. In summary, our findings underscore the promising potential of the integrated Tetra and ImmunER mRNA-LNP therapy for robust anti-tumor immunity in PCa.

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Optofluidic crystallithography for directed growth of single-crystalline halide perovskites.

Crystallization is a fundamental phenomenon which describes how the atomic building blocks such as atoms and molecules are arranged into ordered or quasi-ordered structure and form solid-state materials. While numerous studies have focused on the nucleation behavior, the precise and spatiotemporal control of growth kinetics, which dictates the defect density, the micromorphology, as well as the properties of the grown materials, remains elusive so far. Herein, we propose an optical strategy, termed optofluidic crystallithography (OCL), to solve this fundamental problem. Taking halide perovskites as an example, we use a laser beam to manipulate the molecular motion in the native precursor environment and create inhomogeneous spatial distribution of the molecular species. Harnessing the coordinated effect of laser-controlled local supersaturation and interfacial energy, we precisely steer the ionic reaction at the growth interface and directly print arbitrary single crystals of halide perovskites of high surface quality, crystallinity, and uniformity at a high printing speed of 102 µm s-1. The OCL technique can be potentially extended to the fabrication of single-crystal structures beyond halide perovskites, once crystallization can be triggered under the laser-directed local supersaturation.

Roles of IRF4 in various immune cells in systemic lupus erythematosus.

Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factors which mainly regulates the transcription of IFN. IRF4 is restrictively expressed in immune cells such as T and B cells, macrophages, as well as DC. It is essential for the development and function of these cells. Since these cells take part in the homeostasis of the immune system and dysfunction of them contributes to the initiation and progress of systemic lupus erythematosus (SLE), the roles of IRF4 in the SLE development becomes an important topic. Here we systemically discuss the biological characteristics of IRF4 in various immune cells and analyze the pathologic effects of IRF4 alteration in SLE and the potential targeting therapeutics of SLE.

Photosensitized 1,2-Difunctionalization of Alkenes to Access ß-Amino Sulfonamides.

A metal-free photosensitized 1,2-imino-sulfamoylation of olefins by employing a tailor-made sulfamoyl carbamate as the difunctionalization reagent has been established. This protocol exhibits versatility across a broad substrate scope, including aryl and aliphatic alkenes, leading to the synthesis of diverse ß-imino sulfonamides in moderate to good yields. This method is characterized by its metal-free reaction system, mild reaction conditions, excellent regioselectivity, and high atom economy, serving as a promising platform for the preparation of ß-amino sulfonamide-containing molecules, particularly in the context of drug discovery.

Super-Resolution Exciton Imaging of Nanobubbles in 2D Semiconductors with Near-Field Nanophotoluminescence Microscopy.

Two-dimensional (2D) semiconductors, such as transition metal dichalcogenides, have emerged as important candidate materials for next-generation chip-scale optoelectronic devices with the development of large-scale production techniques, such as chemical vapor deposition (CVD). However, 2D materials need to be transferred to other target substrates after growth, during which various micro- and nanoscale defects, such as nanobubbles, are inevitably generated. These nanodefects not only influence the uniformity of 2D semiconductors but also may significantly alter the local optoelectronic properties of the composed devices. Hence, super-resolution discrimination and characterization of nanodefects are highly demanded. Here, we report a near-field nanophotoluminescence (nano-PL) microscope that can quickly screen nanobubbles and investigate their impact on local excitonic properties of 2D semiconductors by directly visualize the PL emission distribution with a very high spatial resolution of ∼10 nm, far below the optical diffraction limit, and a high speed of 10 ms/point under ambient conditions. By using nano-PL microscopy to map the exciton and trion emission intensity distributions in transferred CVD-grown monolayer tungsten disulfide (1L-WS2) flakes, it is found that the PL intensity decreases by 13.4% as the height of the nanobubble increases by every nanometer, which is mainly caused by the suppression of trion emission due to the strong doping effect from the substrate. In addition to the nanobubbles, other types of nanodefects, such as cracks, stacks, and grain boundaries, can also be characterized. The nano-PL method is proven to be a powerful tool for the nondestructive quality inspection of nanodefects as well as the super-resolution exploration of local optoelectronic properties of 2D materials.

Delivery of mRNA Vaccine with 1, 2-Diesters-Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy.

Messenger RNA (mRNA) vaccine is explored as a promising strategy for cancer immunotherapy, but the side effects, especially the liver-related damage caused by LNP, raise concerns about its safety. In this study, a novel library of 248 ionizable lipids comprising 1,2-diesters is designed via a two-step process involving the epoxide ring-opening reaction with carboxyl group-containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2-diesters, the top-performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin-MC3-DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen-specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen-expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC-0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2-diester-derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens-expressing tumor models, which may be a safe and universal platform for mRNA vaccines.

Transesophageal echocardiography-guided percutaneous closure of the patent foramen ovale only uses the sheath.

Background: Percutaneous closure of the patent foramen ovale (PFO) is primarily guided by fluoroscopy in the catheter room, during which procedure both the guidewire and sheath need to pass through the PFO. We performed PFO closure using a transesophageal echocardiography (TEE)-guided approach and only the sheath was passed through the PFO during the procedure. This study aimed to evaluate the feasibility and safety of PFO closure using this technique. Methods: A retrospective observational study was performed. A total of 117 consecutive adult patients underwent percutaneous PFO closure without fluoroscopy, under the sole guidance of TEE in our hospital between December 2018 and December 2021. The data of each patient consisted of preoperative, operative, and postoperative variables collected. The primary outcome is that the occluder was successfully released. The secondary outcomes included perioperative and follow-up transthoracic echocardiography (TTE), Headache impact test-6 (HIT-6) score and clinical symptoms. Results: Transvenous PFO closure under TEE guidance was successful in all cases. The sample consisted of 93 females and 24 males with an average age of 42.3±7.8 years. There were 28 patients with preoperative cerebral infarction [Risk of Paradoxical Embolism (RoPE) score >6 points] and 89 patients with migraine. All patients underwent a preoperative TEE to confirm the presence of PFO, and contrast-enhanced transcranial Doppler (c-TCD) acoustic contrast suggested grades 3 to 4. The average time of surgery for patients (puncture to removal of the sheath) was 32 minutes. Three cases of vagus nerve reflex manifestations during surgery and two cases of transient ventricular arrhythmia all improved after symptomatic treatment. There were no instances of metal allergy, hemolysis, or other acute vascular procedural complications. For all 89 patients with migraine, significant relief or resolution was achieved during the first six-month follow-up (P<0.001). Conclusions: As a monotherapy, percutaneous closure of PFO guided by TEE where only the sheath passes through the PFO during the operation is an effective procedure with a high success rate and a low complication rate.

Integrated multifunctional nanoplatform for fluorescence detection and inactivation of Staphylococcus aureus.

Foodborne illness caused by Staphylococcus aureus (S. aureus) has posed a significant threat to human health. Herein, an integrated multifunctional nanoplatform was developed for fluorescence detection and inactivation of S. aureus based on cascade signal amplification coupled with single strand DNA-template copper nanoparticles (ssDNA-Cu NPs). Benefiting from reasonable design, one-step cascade signal amplification was achieved through strand displacement amplification combined with rolling circle amplification, followed by in-situ generation of copper nanoparticles. S. aureus detection could be performed through naked eye observation and microplate reader measurement of the red fluorescence signal. The multifunctional nanoplatform had satisfactory specificity and sensitivity, achieving 5.2 CFU mL-1 detection limit and successful detection of 7.3 CFU of S. aureus in spiked egg after < 5 h of enrichment. Moreover, ssDNA-Cu NPs could eliminate S. aureus to avoid secondary bacterial contamination without further treatment. Therefore, this multifunctional nanoplatform has potential application in food safety dtection.

Smart Biomimetic Nanozymes for Precise Molecular Imaging: Application and Challenges.

New nanotechnologies for imaging molecules are widely being applied to visualize the expression of specific molecules (e.g., ions, biomarkers) for disease diagnosis. Among various nanoplatforms, nanozymes, which exhibit enzyme-like catalytic activities in vivo, have gained tremendously increasing attention in molecular imaging due to their unique properties such as diverse enzyme-mimicking activities, excellent biocompatibility, ease of surface tenability, and low cost. In addition, by integrating different nanoparticles with superparamagnetic, photoacoustic, fluorescence, and photothermal properties, the nanoenzymes are able to increase the imaging sensitivity and accuracy for better understanding the complexity and the biological process of disease. Moreover, these functions encourage the utilization of nanozymes as therapeutic agents to assist in treatment. In this review, we focus on the applications of nanozymes in molecular imaging and discuss the use of peroxidase (POD), oxidase (OXD), catalase (CAT), and superoxide dismutase (SOD) with different imaging modalities. Further, the applications of nanozymes for cancer treatment, bacterial infection, and inflammation image-guided therapy are discussed. Overall, this review aims to provide a complete reference for research in the interdisciplinary fields of nanotechnology and molecular imaging to promote the advancement and clinical translation of novel biomimetic nanozymes.

Catalytic Asymmetric Diels-Alder Reaction of 2'-Hydroxychalcone as a Dienophile with a VANOL-Borate Ester Complex.

Numerous flavonoid Diels-Alder-type natural products have been isolated and received great attention from the synthetic community. Herein, we reported a catalytic strategy for an asymmetric Diels-Alder reaction of 2'-hydroxychalcone with a range of diene substrates using a chiral ligand-boron Lewis acid complex. This method enables the convenient synthesis of a wide range of cyclohexene skeletons in excellent yields with moderate to good enantioselectivities, which is critical to prepare natural product congeners for further biological studies.

Quantum Emitters with Narrow Band and High Debye-Waller Factor in Aluminum Nitride Written by Femtosecond Laser.

Solid-state quantum emitters (QEs) are central components for photonic-based quantum information processing. Recently, bright QEs in III-nitride semiconductors, such as aluminum nitride (AlN), have attracted increasing interest because of the mature commercial application of the nitrides. However, the reported QEs in AlN suffer from broad phonon side bands (PSBs) and low Debye-Waller factors. Meanwhile, there is also a need for more reliable fabrication methods of AlN QEs for integrated quantum photonics. Here, we demonstrate that laser-induced QEs in AlN exhibit robust emission with a strong zero phonon line, narrow line width, and weak PSB. The creation yield of a single QE could be more than 50%. More importantly, they have a high Debye-Waller factor (>65%) at room temperature, which is the highest result among reported AlN QEs. Our results illustrate the potential of laser writing to create high-quality QEs for quantum technologies and provide further insight into laser writing defects in relevant materials.

A multicenter prospective study of next-generation sequencing-based newborn screening for monogenic genetic diseases in China.

BACKGROUND: Newborn screening (NBS) is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases. The development of next-generation sequencing (NGS) technology provides new opportunities to expand current newborn screening methodologies. METHODS: We designed a a newborn genetic screening (NBGS) panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS. With this panel, a large-scale, multicenter, prospective multidisease analysis was conducted on dried blood spot (DBS) profiles from 21,442 neonates nationwide. RESULTS: We presented the positive detection rate and carrier frequency of diseases and related variants in different regions; and 168 (0.78%) positive cases were detected. Glucose-6-Phosphate Dehydrogenase deficiency (G6PDD) and phenylketonuria (PKU) had higher prevalence rates, which were significantly different in different regions. The positive detection of G6PD variants was quite common in south China, whereas PAH variants were most commonly identified in north China. In addition, NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants, which were normal in conventional NBS, but were confirmed later as abnormal in repeated biochemical testing after recall. Eighty percent of high-frequency gene carriers and 60% of high-frequency variant carriers had obvious regional differences. On the premise that there was no significant difference in birth weight and gestational age, the biochemical indicators of SLC22A5 c.1400C > G and ACADSB c.1165A > G carriers were significantly different from those of non-carriers. CONCLUSIONS: We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods. Our data also showed that the prevalence of diseases has significant regional characteristics, which provides a theoretical basis for screening diseases in different regions.

All-Optical Reconfigurable Excitonic Charge States in Monolayer MoS2.

Excitons are quasi-particles composed of electron-hole pairs through Coulomb interaction. Due to the atomic-thin thickness, they are tightly bound in monolayer transition metal dichalcogenides (TMDs) and dominate their optical properties. The capability to manipulate the excitonic behavior can significantly influence the photon emission or carrier transport performance of TMD-based devices. However, on-demand and region-selective manipulation of the excitonic states in a reversible manner remains challenging so far. Herein, harnessing the coordinated effect of femtosecond-laser-driven atomic defect generation, interfacial electron transfer, and surface molecular desorption/adsorption, we develop an all-optical approach to manipulate the charge states of excitons in monolayer molybdenum disulfide (MoS2). Through steering the laser beam, we demonstrate reconfigurable optical encoding of the excitonic charge states (between neutral and negative states) on a single MoS2 flake. Our technique can be extended to other TMDs materials, which will guide the design of all-optical and reconfigurable TMD-based optoelectronic and nanophotonic devices.

A new anthraquinone from mangrove endophytic fungus Aspergillus sp. 16-5C.

A new anthraquinone, asperquinone A (1), and four known anthraquinone derivatives 2-5 were isolated from the mangrove endophytic fungus Aspergillus sp. 16-5C. These structures were elucidated by spectroscopic analysis and the absolute configuration of 1 was unambiguously determined by ECD calculation. Compounds 1-5 showed no significant inhibitory effect against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB).

3D nanoprinting of semiconductor quantum dots by photoexcitation-induced chemical bonding.

Three-dimensional (3D) laser nanoprinting allows maskless manufacturing of diverse nanostructures with nanoscale resolution. However, 3D manufacturing of inorganic nanostructures typically requires nanomaterial-polymer composites and is limited by a photopolymerization mechanism, resulting in a reduction of material purity and degradation of intrinsic properties. We developed a polymerization-independent, laser direct writing technique called photoexcitation-induced chemical bonding. Without any additives, the holes excited inside semiconductor quantum dots are transferred to the nanocrystal surface and improve their chemical reactivity, leading to interparticle chemical bonding. As a proof of concept, we printed arbitrary 3D quantum dot architectures at a resolution beyond the diffraction limit. Our strategy will enable the manufacturing of free-form quantum dot optoelectronic devices such as light-emitting devices or photodetectors.

Optical Visualization of Photoexcitation Diffusion in All-Inorganic Perovskite at High Temperature.

All-inorganic halide perovskites are promising candidates for optoelectronic and photovoltaic devices because of their good thermal stability and remarkable optoelectronic properties. Among those properties, carrier transport properties are critical as they inherently dominate the device performance. The transport properties of perovskites have been widely studied at room and lower temperatures, but their high-temperature (i.e., tens of degrees above room temperature) characteristics are not fully understood. Here, the photoexcitation diffusion is optically visualized by transient photoluminescence microscopy (TPLM), through which the temperature-dependent transport characteristics from room temperature to 80 °C are studied in all-inorganic CsPbBr3 single-crystalline microplates. We reveal the decreasing trend of diffusion coefficient and the almost unchanged trend of diffusion length when heating the sample to high temperature. The phonon scattering in combination with the variation of effective mass is proposed for the explanation of the temperature-dependent diffusion behavior.

Case report: Radiotherapy plus pneumococcal conjugate vaccine stimulates abscopal immune response in a patient with ALK+ NSCLC.

Most patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) could benefit from the treatment with selected tyrosine kinase inhibitors (TKIs) for a period of time, but almost inevitably progress due to drug resistance. It was reported that these patients were generally unresponsive to immune-based therapies. Here, we reported that stereotactic body radiotherapy (SBRT) combined with pneumococcal conjugate vaccine (PCV) produced excellent therapeutic outcomes in a patient after multiple lines of TKI treatment. The patient's metastasis lesion experienced regression after SBRT for lumbar spine. Unexpectedly, the patient also experienced an abscopal complete pathological response (CPR) just after combination use of SBRT and PCV. Biopsy analysis indicated that the primary lung lesion was map-like necrotic and infiltrated by tumor-infiltrating lymphocytes (TILs), and multifocal granulomas and early tertiary lymphoid structures (TLS) were formed. Our case reported that radiotherapy plus PCV could specifically stimulate immune response and remodel the tumor immune microenvironment in TKI-resistant NSCLC, which may provide a new perspective for future immunotherapy in this challenging clinical situation.

Transcriptomic analysis reveals process of autolysis of Kluyveromyces marxianus in vacuum negative pressure and the higher temperature

Kluyveromyces marxianus is expected to be used in the production of yeast extracts due to its good fermentation ability and nutritional properties. Yeast autolysis is a key process to produce yeast extract and vacuum negative pressure stress can be used as an effective way to assist autolysis. However, the molecular mechanism of initiating Kluyveromyces marxianus autolysis induced by vacuum negative pressure and the higher temperature is still unclear. In this study, RNA-seq technology was performed mainly to analyze autolytic processes in Kluyveromyces marxianus strains. Considerable differentially expressed genes (DEGs) of downregulation were significantly enriched in 7 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to synthesis and transport of RNA and ribosome, which indicated that abnormal protein translations had already occurred in autolytic process. Interestingly, due to obvious change of related DEGs, endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated and cell wall integrity pathway was hindered. Under the continuous influence of the external stress environment, the long-term changes of the above pathways triggered a vicious circle of gradual damage to yeast cells, which is the main cause of yeast autolysis. These results may provide important clues for the in-depth interpretation of the yeast autolytic mechanism.(AU)