Heterogeneity and interplay: the multifaceted role of cancer-associated fibroblasts in the tumor and therapeutic strategies.

The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.

Zinc-Iron Bimetallic Peroxides Modulate the Tumor Stromal Microenvironment and Enhance Cell Immunogenicity for Enhanced Breast Cancer Immunotherapy Therapy.

Immunotherapy has emerged as a potential approach for breast cancer treatment. However, the rigid stromal microenvironment and low immunogenicity of breast tumors strongly reduce sensitivity to immunotherapy. To sensitize patients to breast cancer immunotherapy, hyaluronic acid-modified zinc peroxide-iron nanocomposites (Fe-ZnO2@HA, abbreviated FZOH) were synthesized to remodel the stromal microenvironment and increase tumor immunogenicity. The constructed FZOH spontaneously generated highly oxidative hydroxyl radicals (·OH) that degrade hyaluronic acid (HA) in the tumor extracellular matrix (ECM), thereby reshaping the tumor stromal microenvironment and enhancing blood perfusion, drug penetration, and immune cell infiltration. Furthermore, FZOH not only triggers pyroptosis through the activation of the caspase-1/GSDMD-dependent pathway but also induces ferroptosis through various mechanisms, including increasing the levels of Fe2+ in the intracellular iron pool, downregulating the expression of FPN1 to inhibit iron efflux, and activating the p53 signaling pathway to cause the failure of the SLC7A11-GSH-GPX4 signaling axis. Upon treatment with FZOH, 4T1 cancer cells undergo both ferroptosis and pyroptosis, exhibiting a strong immunogenic response. The remodeling of the tumor stromal microenvironment and the immunogenic response of the cells induced by FZOH collectively compensate for the limitations of cancer immunotherapy and significantly enhance the antitumor immune response to the immune checkpoint inhibitor αPD-1. This study proposes a perspective for enhancing immune therapy for breast cancer.

Improved data quality and statistical power of trial-level event-related potentials with Bayesian random-shift Gaussian processes.

Studies of cognitive processes via electroencephalogram (EEG) recordings often analyze group-level event-related potentials (ERPs) averaged over multiple subjects and trials. This averaging procedure can obscure scientifically relevant variability across subjects and trials, but has been necessary due to the difficulties posed by inference of trial-level ERPs. We introduce the Bayesian Random Phase-Amplitude Gaussian Process (RPAGP) model, for inference of trial-level amplitude, latency, and ERP waveforms. We apply RPAGP to data from a study of ERP responses to emotionally arousing images. The model estimates of trial-specific signals are shown to greatly improve statistical power in detecting significant differences in experimental conditions compared to existing methods. Our results suggest that replacing the observed data with the de-noised RPAGP predictions can potentially improve the sensitivity and accuracy of many of the existing ERP analysis pipelines.

Landscape of global urban environmental resistome and its association with local socioeconomic and medical status.

Antimicrobial resistance (AMR) poses a critical threat to global health and development, with environmental factors-particularly in urban areas-contributing significantly to the spread of antibiotic resistance genes (ARGs). However, most research to date has been conducted at a local level, leaving significant gaps in our understanding of the global status of antibiotic resistance in urban environments. To address this issue, we thoroughly analyzed a total of 86,213 ARGs detected within 4,728 metagenome samples, which were collected by the MetaSUB International Consortium involving diverse urban environments in 60 cities of 27 countries, utilizing a deep-learning based methodology. Our findings demonstrated the strong geographical specificity of urban environmental resistome, and their correlation with various local socioeconomic and medical conditions. We also identified distinctive evolutionary patterns of ARG-related biosynthetic gene clusters (BGCs) across different countries, and discovered that the urban environment represents a rich source of novel antibiotics. Our study provides a comprehensive overview of the global urban environmental resistome, and fills a significant gap in our knowledge of large-scale urban antibiotic resistome analysis.

Oncolytic mineralized bacteria as potent locally administered immunotherapeutics.

Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics.

Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity.

Emerging and recurrent infectious diseases caused by human coronaviruses (HCoVs) continue to pose a significant threat to global public health security. In light of this ongoing threat, the development of a broad-spectrum drug to combat HCoVs is an urgently priority. Herein, we report a series of anti-pan-coronavirus ssDNA aptamers screened using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). These aptamers have nanomolar affinity with the nucleocapsid protein (NP) of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and also show excellent binding efficiency to the N proteins of both SARS, MERS, HCoV-OC43 and -NL63 with affinity KD values of 1.31 to 135.36 nM. Such aptamer-based therapeutics exhibited potent antiviral activity against both the authentic SARS-CoV-2 prototype strain and the Omicron variant (BA.5) with EC50 values at 2.00 nM and 41.08 nM, respectively. The protein docking analysis also evidenced that these aptamers exhibit strong affinities for N proteins of pan-coronavirus and other HCoVs (-229E and -HKU1). In conclusion, we have identified six aptamers with a high pan-coronavirus antiviral activity, which could potentially serve as an effective strategy for preventing infections by unknown coronaviruses and addressing the ongoing global health threat.

Low-temperature CO preferential oxidation in H2-rich stream over Indium modified Pd-Cu/Al2O3 catalyst.

The impact of Indium (In) doping upon the catalytic performance of Pd-Cu/Al2O3 for carbon monoxide preferential oxidation (CO-PROX) in hydrogen (H2) rich atmosphere at low temperature has been studied. A series of catalysts with extremely low palladium (Pd) loading (0.06 wt%) are synthesized by the facile co-impregnation method. When the In/copper (Cu) atomic ratio equals 0.25, Pd-Cu-In0.25/Al2O3 can keep 40% CO conversion and 100% carbon dioxide (CO2) selectivity at least 120 min at 30 °C, which is significantly superior to the catalytic performance of Pd-Cu/Al2O3. The elaborate characterization findings reveal that the added In species to Pd-Cu/Al2O3 causes Indium oxide (In2O3) to generate, which produces the interaction of In2O3 with Pd-Cu/Al2O3, further promoting the dispersion of copper chloride hydroxide (Cu2Cl(OH)3). Moreover, the modification of In facilitates the re-oxidation of Pd0 to Pd+ through reducing the formation of palladium hydride (PdHx) during the CO-PROX reaction. Meanwhile, the addition of In leads to the decrease of Cu+ electron cloud density, making it easier to be oxidized to Cu2+. Collectively, the easy re-oxidation of Pd0 and Cu+ is favorable to fulfill the Wacker cycle between Pd and Cu species, thus improving the catalytic performance for CO-PROX.

PEDV-spike-protein-expressing mRNA vaccine protects piglets against PEDV challenge.

Porcine epidemic diarrhea virus (PEDV), a swine enteropathogenic coronavirus, causes severe diarrhea in neonatal piglets, which is associated with a high mortality rate. Thus, developing effective and safe vaccines remains a top priority for controlling PEDV infection. Here, we designed two lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) vaccines encoding either the full-length PEDV spike (S) protein or a multiepitope chimeric spike (Sm) protein. We found that the S mRNA-LNP vaccine was superior to the Sm mRNA-LNP vaccine at inducing antibody and cellular immune responses in mice. Evaluation of the immunogenicity and efficacy of the S mRNA vaccine in piglets confirmed that it induced robust PEDV-specific humoral and cellular immune responses in vivo. Importantly, the S mRNA-LNP vaccine not only protected actively immunized piglets against PEDV but also equipped neonatal piglets with effective passive anti-PEDV immunity in the form of colostrum-derived antibodies after the immunization of sows. Our findings suggest that the PEDV-S mRNA-LNP vaccine is a promising candidate for combating PEDV infection.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) continues to harm the global swine industry. It is important to develop a highly effective vaccine to control PEDV infection. Here, we report a PEDV spike (S) mRNA vaccine that primes a potent antibody response and antigen-specific T-cell responses in immunized piglets. Active and passive immunization can protect piglets against PED following the virus challenge. This study highlights the efficiency of the PEDV-S mRNA vaccine and represents a viable approach for developing an efficient PEDV vaccine.

Dependence of copper(I) stability on long-range electromagnetic effects of Au under reducing atmospheres: the size effect of Au cores.

It has been widely recognized that adjusting the size of Au particles has emerged as a significant approach in catalyst design, catalyst screening, and comprehension of reaction mechanisms. However, the essential factors of Au nanoparticles used only as an additive to enhance the activity of traditional multicomponent thermocatalysts have not been fully revealed. In this study, a series of Au@Cu2O core-shell nanocatalysts were synthesized through a controllable method, featuring core sizes ranging from 11 to 33 nm and an average shell thickness of approximately 55 nm. It was revealed that the size effect of Au cores plays a very vital role in the stability of the active Cu+ species under reducing atmospheres (H2, acetylene and formaldehyde) as well as the catalytic performance of the catalysts in the ethynylation of formaldehyde. The experimental findings revealed that Au@Cu2O core-shell catalysts with Au core sizes ranging from 11 to 16 nm exhibited a higher abundance of electron-deficient Cu+ species in the shell, which is attributed to the strong long-range electromagnetic effects of the Au core in the absence of photoexcitation or an applied electric field. Additionally, the active Cu+ species demonstrated remarkable stability under reducing atmospheres. Although the stability of Cu+ decreased slightly when the Au core size exceeded 16 nm, the Cu+ content remained above 80%. Notably, the Au@Cu2O catalysts with Au core sizes ranging from 11 to 16 nm exhibited excellent catalytic activity in the ethynylation of formaldehyde.

Membrane Protein Structures in Native Cellular Membranes Revealed by Solid-State NMR Spectroscopy.

The structural characterization of membrane proteins within the cellular membrane environment is critical for understanding the molecular mechanism in their native functional context. However, conducting residue site-specific structural analysis of membrane proteins in native membranes by solid-state NMR faces challenges due to poor spectral sensitivity and serious interference from background protein signals. In this study, we present a new protocol that combines various strategies for cellular membrane sample preparations, enabling us to reveal the secondary structure of the mechanosensitive channel of large conductance from Methanosarcina acetivorans (MaMscL) in Escherichia coli inner membranes. Our findings demonstrate the feasibility of achieving complete resonance assignments and the potential for determining the 3D structures of membrane proteins within cellular membranes. We find that the use of the BL21(DE3) strain in this protocol is crucial for effectively suppressing background protein labeling without compromising the sensitivity of the target protein. Furthermore, our data reveal that the structures of different proteins exhibit varying degrees of sensitivity to the membrane environment. These results underscore the significance of studying membrane proteins within their native cellular membranes when performing structural characterizations. Overall, this study opens up a new avenue for achieving the atomic-resolution structural characterization of membrane proteins within their native cellular membranes, providing valuable insights into the nativeness of membrane proteins.

Solid-state NMR structure determination of a membrane protein in E. coli cellular inner membrane.

Structure determination of membrane proteins in native cellular membranes is critical to precisely reveal their structures in physiological conditions. However, it remains challenging for solid-state nuclear magnetic resonance (ssNMR) due to the low sensitivity and high complexity of ssNMR spectra of cellular membranes. Here, we present the structure determination of aquaporin Z (AqpZ) by ssNMR in Escherichia coli inner membranes. To enhance the signal sensitivity of AqpZ, we optimized protein overexpression and removed outer membrane components. To suppress the interference of background proteins, we used a "dual-media" expression approach and antibiotic treatment. Using 1017 distance restraints obtained from two-dimensional 13C-13C spectra based on the complete chemical shift assignments, the 1.7-Å ssNMR structure of AqpZ is determined in E. coli inner membranes. This cellular ssNMR structure determination paves the way for analyzing the atomic structural details for membrane proteins in native cellular membranes.

Investigation of Ni-Cu-acid multifunctional synergism in NiCu-phyllosilicate catalysts toward the 1,4-butynediol hydrogenation to 1,4-butanediol.

We studied the Ni-Cu-acid multifunctional synergism in NiCu-phyllosilicate catalysts toward 1,4-butynediol hydrogenation to 1,4-butanediol by varying the reduction temperature, which can activate different bimetal and support interactions. Compared with a monometallic Ni phyllosilicate (phy), which only showed one type of metal species when reduced at ∼750 °C, there are three types of metal species for the bimetallic Ni-Cu-phyllosilicate derived catalysts, namely Cuphy, differentiated Ni, and Niphy. Thorough structure-activity/selectivity correlation investigations showed that, although the Ni9Cu1-P catalyst matrix can produce tiny amounts of differentiated Ni0 species under the induction of reduced Cu0 at R250 condition, it could not form Ni-Cu bimetallic interactions for the collaborative hydrogenation of 1,4-butynediol, and the product stays in the semi hydrogenated state. When the reduction temperature is raised to 500 °C, stable Ni-Cu alloy active sites exist, accompanied by the strong metal support interaction and metal acid effect derived from the intimate contact between the extracted metal sites and the surviving functional phyllosilicate support; these functionalities yield a supreme hydrogenation performance of the R500 sample with a 1,4-butanediol yield larger than 91.2%.

Application of CRISPR-Cas system in the diagnosis and therapy of ESKAPE infections.

Antimicrobial-resistant ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens represent a global threat to human health. ESKAPE pathogens are the most common opportunistic pathogens in nosocomial infections, and a considerable number of their clinical isolates are not susceptible to conventional antimicrobial therapy. Therefore, innovative therapeutic strategies that can effectively deal with ESKAPE pathogens will bring huge social and economic benefits and ease the suffering of tens of thousands of patients. Among these strategies, CRISPR (clustered regularly interspaced short palindromic repeats) system has received extra attention due to its high specificity. Regrettably, there is currently no direct CRISPR-system-based anti-infective treatment. This paper reviews the applications of CRISPR-Cas system in the study of ESKAPE pathogens, aiming to provide directions for the research of ideal new drugs and provide a reference for solving a series of problems caused by multidrug-resistant bacteria (MDR) in the post-antibiotic era. However, most research is still far from clinical application.

Genetic signatures associated with the virulence of porcine epidemic diarrhea virus AH2012/12.

IMPORTANCE: Porcine epidemic diarrhea (PED) caused by PED virus (PEDV) remains a big threat to the swine industry worldwide. Vaccination with live attenuated vaccine is a promising method to prevent and control PED, because it can elicit a more protective immunity than the killed vaccine, subunit vaccine, and so on. In this study, we found two obvious deletions in the genome of a high passage of AH2012/12. We further confirmed the second deletion which contains seven amino acids at the carboxy-terminus of the S2 gene and the start codon of ORF3 can reduce its pathogenicity in vivo. Animal experiments indicated that the recombinant PEDV with deleted carboxy-terminus of S gene showed higher IgG, IgA, neutralization antibodies, and protection effects against virus challenge than the killed vaccine. These data reveal that the engineering of the carboxy-terminus of the S2 gene may be a promising method to develop live attenuated vaccine candidates of PEDV.

Stem Cells and Exosome Applications for Cutaneous Wound Healing: From Ground to Microgravity Environment.

The increasing number of astronauts entering microgravity environments for long-term space missions has resulted in serious health problems, including accidental injury and trauma. Skin, as the largest organ and outermost layer of the human body, has the ability to self-renew and withstand a variety of harmful biological and environmental influences. Recent spaceflight experiments and simulated studies have begun to concern the effects of microgravity on the growth of skin cells and the process of cutaneous wound healing. However, the mechanisms of the adverse effects of microgravity on skin cells and potential intervention measures are still limited. Stem cells and their exosomes provide unique opportunities for the cutaneous wound healing as they have been used to improve skin repair. This review discusses the effects of microgravity on wound healing, from cell morphological changes to molecular level alterations. Furthermore, the current research on wound healing treatment utilizing stem cells and their exosomes on the ground is summarized. Finally, this review proposes promising therapeutic strategies using stem cells or exosomes for wound healing in the microgravity environment. Graphical Abstract.

Correlation between the IgG/IgA Antibody Response against PEDV Structural Protein and Virus Neutralization.

Porcine epidemic diarrhea (PED) is a highly contagious intestinal infectious disease caused by porcine epidemic diarrhea virus (PEDV). Large-scale outbreaks of PEDV have caused huge economic losses to the pig industry since 2010. Neutralizing antibodies play a pivotal role in protecting piglets from enteric infections. However, there has been no systematic report on the correlations between neutralizing antibody titers (NTs) and absorbance values of IgG or IgA to all PEDV individual structural proteins in clinical serum, fecal, and colostrum samples. In this study, the spike protein S1 domain (S1), membrane protein (M), envelope protein (E), and nucleocapsid protein (N) of the variant PEDV strain AH2012/12 were expressed and purified by using the human embryonic kidney (HEK) 293F expression system. A total of 92 clinical serum samples, 46 fecal samples, and 33 colostrum samples were collected, and the correlations between IgG or IgA absorbance values and NTs were analyzed. R2 values revealed that anti-S1 IgA absorbance values show the highest agreement with NTs in all serum, fecal, and colostrum samples, followed by the N protein. The correlations between anti-E or M IgA and NTs were very low. However, in the colostrum samples, both IgG and IgA to S1 showed high correlations with NTs. In addition, compared with E and M, the highest correlations of IgA absorbance values were with N and S1 in serum and fecal samples. Overall, this study revealed the highest correlation between NTs and IgA to PEDV S1 protein. Therefore, the diagnostic method with anti-S1 IgA can be used as a powerful tool for assessing the immune status of pigs. IMPORTANCE The humoral immune response plays an important role in virus neutralization. Against PEDV, both IgG and the mucosal immune component IgA play roles in virus neutralization. However, which plays a more prominent role and whether there are differences in different tissue samples are not clearly reported. Additionally, the relationship between IgG and IgA against individual structural proteins and viral neutralization remains unclear. In this study, we systematically determined the relationship between IgG and IgA against all PEDV structural proteins and viral neutralization in different clinical samples and found the highest correlation between neutralization activity and IgA to PEDV S1 protein. Our data have important guiding implications in the evaluation of immune protection.