The m6A writer KIAA1429 regulates photoaging progression via MFAP4-dependent collagen synthesis.

BACKGROUND: N6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown. OBJECTIVES: This study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging. METHODS: m6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay. RESULTS: m6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process. CONCLUSIONS: The increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging.

Individuals carrying the HLA-B*15 allele exhibit favorable responses to COVID-19 vaccines but are more susceptible to Omicron BA.5.2 and XBB.1.16 infection.

Background: Natural infection or vaccination have provided robust immune defense against SARS-CoV-2 invasion, nevertheless, Omicron variants still successfully cause breakthrough infection, and the underlying mechanisms are poorly understood. Methods: Sequential blood samples were continuously collected at different time points from 252 volunteers who were received the CanSino Ad5-nCoV (n= 183) vaccine or the Sinovac CoronaVac inactivated vaccine (n= 69). The anti-SARS-CoV-2 prototype and Omicron BA.5.2 as well as XBB.1.16 variant neutralizing antibodies (Nab) in sera were detected by ELISA. Sera were also used to measure pseudo and live virus neutralization assay. The associations between the anti-prototype Nab levels and different HLA-ABC alleles were analyzed using artificial intelligence (AI)-deep learning techniques. The frequency of B cells in PBMCs was investigated by flow cytometry assay (FACs). Results: Individuals carrying the HLA-B*15 allele manifested the highest concentrations of anti-SARS-CoV-2 prototype Nab after vax administration. Unfortunately, these volunteers are more susceptible to Omicron BA.5.2 breakthrough infection due to their sera have poorer anti-BA.5.2 Nab and lower levels of viral neutralization efficacy. FACs confirmed that a significant decrease in CD19+CD27+RBD+ memory B cells in these HLA-B*15 population compared to other cohorts. Importantly, generating lower concentrations of cross-reactive anti-XBB.1.16 Nab post-BA.5.2 infection caused HLA-B*15 individuals to be further infected by XBB.1.16 variant. Conclusions: Individuals carrying the HLA-B*15 allele respond better to COVID-19 vax including the CanSino Ad5-nCoV and the Sinovac CoronaVac inactivated vaccines, but are more susceptible to Omicron variant infection, thus, a novel vaccine against this population is necessary for COVID-19 pandemic control in the future.

Temporary Gasserian ganglion stimulation utilizing SNM electrode in subacute herpetic trigeminal neuralgia.

Objective: Gasserian ganglion stimulation (GGS) is a neuromodulation technique that has been extensively applied in treating postherpetic trigeminal neuralgia. However, permanent implantation of GGS was preferred in most treatment approaches. Few studies have investigated temporary GGS for the treatment of acute/subacute herpetic trigeminal neuralgia. Moreover, previous research has reported lead dislocation when utilizing traditional electrodes, which was associated with poor pain relief. In GGS research, preventing the accidental displacement of lead following implantation has consistently been a primary objective. Methods: We report a case of a 70-year-old woman with subacute herpetic trigeminal neuralgia who underwent temporary GGS for 14 days utilizing a sacral neuromodulation (SNM) quadripolar-tined lead. Computed tomography-guided percutaneous foramen ovale (FO) puncture and temporary SNM electrode implantation were performed during the surgery. A telephone interview was conducted to record a 12-month follow-up. Results: At admission, zoster-related trigeminal pain severity was assessed to be 9/10 on the visual analog scale (VAS). After a 14-day GGS treatment, the pain assessed on the VAS score reduced to 1/10 at discharge but increased to 4/10 at the 12-month follow-up after surgery. Additionally, the anxiety level improved from 58 points to 35 points on the Self-Rating Anxiety Scale (SAS), and the depression level improved from 62 points to 40 points on the Self-Rating Depression Scale (SDS). The Physical Component Summary score of the 12-item Short-Form Health Survey (SF-12) increased from 33.9 to 47.0, and the Mental Component Summary (MCS) score of the SF-12 increased from 27.4 to 41.9. Conclusion: Temporary GGS might be a potentially effective treatment for subacute herpetic trigeminal neuralgia, and an SNM electrode might be a good choice for reducing the risk of dislocation.

Effects of perioperative hydrogen inhalation on brain edema and prognosis in patients with glioma: a single-center, randomized controlled study.

Introduction: Brain edema is a life-threatening complication that occurs after glioma surgery. There are no noninvasive and specific treatment methods for brain edema. Hydrogen is an anti-inflammatory and antioxidant gas that has demonstrated therapeutic and preventative effects on several diseases, particularly in the nervous system. This study aimed to determine the therapeutic effects of hydrogen administration on brain edema following glioma surgery and elucidate its mechanism. Methods: A single-center, randomized controlled clinical trial of hydrogen inhalation was conducted (China Clinical Trial Registry [ChiCTR-2300074362]). Participants in hydrogen (H) group that inhaled hydrogen experienced quicker alleviation of postoperative brain edema compared with participants in control (C) group that inhaled oxygen. Results: The volume of brain edema before discharge was significantly lower in the H group (p < 0.05). Additionally, the regression rate of brain edema was higher in the H group than in the C group, which was statistically significant (p < 0.05). Furthermore, 3 days after surgery, the H group had longer total sleep duration, improved sleep efficiency, shorter sleep latency, and lower numerical rating scale (NRS) scores (p < 0.05). Discussion: In conclusion, hydrogen/oxygen inhalation effectively reduced postoperative brain edema in glioma patients. Further research is necessary to understand the underlying mechanisms of hydrogen's therapeutic effects. Hydrogen is expected to become a new target for future adjuvant therapy for brain edema.

HiDiff: Hybrid Diffusion Framework for Medical Image Segmentation.

Medical image segmentation has been significantly advanced with the rapid development of deep learning (DL) techniques. Existing DL-based segmentation models are typically discriminative; i.e., they aim to learn a mapping from the input image to segmentation masks. However, these discriminative methods neglect the underlying data distribution and intrinsic class characteristics, suffering from unstable feature space. In this work, we propose to complement discriminative segmentation methods with the knowledge of underlying data distribution from generative models. To that end, we propose a novel hybrid diffusion framework for medical image segmentation, termed HiDiff, which can synergize the strengths of existing discriminative segmentation models and new generative diffusion models. HiDiff comprises two key components: discriminative segmentor and diffusion refiner. First, we utilize any conventional trained segmentation models as discriminative segmentor, which can provide a segmentation mask prior for diffusion refiner. Second, we propose a novel binary Bernoulli diffusion model (BBDM) as the diffusion refiner, which can effectively, efficiently, and interactively refine the segmentation mask by modeling the underlying data distribution. Third, we train the segmentor and BBDM in an alternate-collaborative manner to mutually boost each other. Extensive experimental results on abdomen organ, brain tumor, polyps, and retinal vessels segmentation datasets, covering four widely-used modalities, demonstrate the superior performance of HiDiff over existing medical segmentation algorithms, including the state-of-the-art transformer- and diffusion-based ones. In addition, HiDiff excels at segmenting small objects and generalizing to new datasets. Source codes are made available at https://github.com/takimailto/HiDiff.

Tumor microenvironment-responsive cell-penetrating peptides: Design principle and precision delivery.

Cell-penetrating peptides (CPPs) are promising vehicles for intracellular delivery of different cargoes. Although various CPPs are designed for targeted delivery of nanomedicines and anticancer drugs, their clinical approval is hampered by a lack of selectivity. In recent years, new approaches have been explored to address this drawback, and distinct strategies for tumor microenvironment (TME)-responsive activation have been developed. In this review, we first introduce the cellular uptake mechanisms of CPPs. We next extensively discuss the design principles and precision delivery of TME-responsive CPPs. Nine kinds of single stimulus-responsive CPPs, five kinds of multiple stimuli-responsive CPPs, three kinds of TME-responsive targeting CPPs, and two kinds of reversibly activatable CPPs (RACPPs) are systemically summarized. Then, TME-responsive CPPs for nanomedical applications are further discussed. Finally, we describe the translational applications of TME-responsive CPPs for anticancer drug delivery. These commentaries provide an insight into the design of next-generation activatable CPPs (ACPPs) for selective delivery of nanomedicines and anticancer drugs.

Knockdown of microRNA390 Enhances Maize Brace Root Growth.

Brace root architecture is a critical determinant of maize's stalk anchorage and nutrition uptake, influencing root lodging resistance, stress tolerance, and plant growth. To identify the key microRNAs (miRNAs) in control of maize brace root growth, we performed small RNA sequencing using brace root samples at emergence and growth stages. We focused on the genetic modulation of brace root development in maize through manipulation of miR390 and its downstream regulated auxin response factors (ARFs). In the present study, miR167, miR166, miR172, and miR390 were identified to be involved in maize brace root growth in inbred line B73. Utilizing short tandem target mimic (STTM) technology, we further developed maize lines with reduced miR390 expression and analyzed their root architecture compared to wild-type controls. Our findings show that STTM390 maize lines exhibit enhanced brace root length and increased whorl numbers. Gene expression analyses revealed that the suppression of miR390 leads to upregulation of its downstream regulated ARF genes, specifically ZmARF11 and ZmARF26, which may significantly alter root architecture. Additionally, loss-of-function mutants for ZmARF11 and ZmARF26 were characterized to further confirm the role of these genes in brace root growth. These results demonstrate that miR390, ZmARF11, and ZmARF26 play crucial roles in regulating maize brace root growth; the involved complicated molecular mechanisms need to be further explored. This study provides a genetic basis for breeding maize varieties with improved lodging resistance and adaptability to diverse agricultural environments.

Revealing the vertical structure of in-situ fabricated perovskite nanocrystals films toward efficient pure red light-emitting diodes.

The development of efficient perovskite light-emitting diodes (PeLEDs) relies strongly on the fabrication of perovskite films with rationally designed structures (grain size, composition, surface, etc.). Therefore, an understanding of structure-performance relationships is of vital importance for developing high-performance perovskite devices, particularly for devices with in-situ fabricated perovskite nanocrystal films. In this study, we reveal the vertical structure of an in-situ fabricated quasi-two-dimensional perovskite film. By combining time-of-flight secondary ion mass spectrometry, energy dispersive spectroscopy, grazing incidence wide-angle X-ray scattering (GIWAXS), and low-temperature photoluminescence spectra, we illustrate that the resulting in-situ fabricated DPPA2Csn-1Pbn(Br0.3I0.7)3n+1 (DPPA+: 3,3-diphenylpropylammonium) film has a gradient structure with a very thin layer of ligands on the surface, predominantly small-n domains at the top, and predominantly large-n domains at the bottom owing to the solubility difference of the precursors. In addition, GIWAXS measurements show that the domain of n = 2 on the top layer has an ordered in-plane alignment. Based on the understanding of the film structure, we developed an in-situ fabrication process with ligand exchange to achieve efficient pure red PeLEDs at 638 nm with an average external quantum efficiency (EQE) of 7.4%. The optimized device had a maximum luminance of 623 cd/m2 with a peak EQE of 9.7%.

Distribution and Main Controlling Factors of Gas and Water in Tight Sandstone Gas Fields: A Case Study of Sudong 41-33 Block in Sulige Gas Field, Ordos Basin, China.

Studying the gas-water distribution characteristics is essential in guiding the efficient development of gas fields. The relationship between gas and water in the Sudong 41-33 Block is complicated and has not been adequately researched. In recent years, gas wells have suffered from increased water/gas ratios and significant liquid loadings, which greatly affect the development of the block. A comprehensive analysis of formation water, log interpretation, and production data was conducted to determine the gas-water distribution characteristics and main controlling factors in the Sudong 41-33 Block. The findings indicate the following. (1) The formation water in the study area consists mainly of CaCl2 brine with high total dissolved solids (TDS) (with an average value of 36.06 g/L). The hydrochemical characteristics indicate that the formation water is typical sedimentary buried water under well-sealing conditions, which is markedly different from shallow river water and seawater. (2) The formation water can be categorized into three types: edge-bottom water under the gas layer (Type I), stagnant water in tight sandstone (Type II), and isolated lenticular water (Type III). The water layer distribution in the plane is mainly concentrated in the northwest region, whereas it is dispersed in other regions. On the vertical, the water layer mainly appears in P2x8-1, P2x8-2, and P1s2 Members. (3) The physical properties of the reservoir, hydrocarbon generation intensity (HGI), source rock-reservoir relationship, and mini-structure are the main factors affecting the gas-water distribution in the study area. Based on the clarification of the characteristics of gas and water distribution and its main controlling factors, it is of great importance to accurately identify the water layer, avoid the direct development of the water layer, adopt the proper production pressure differential, and carry out drainage gas production measures in time to ensure the effective development of the gas field.

Human Umbilical Cord Mesenchymal Stromal Cell-Derived Extracellular Vesicles Induce Fetal Wound Healing Features Revealed by Single-Cell RNA Sequencing.

The potential of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) in wound healing is promising, yet a comprehensive understanding of how fibroblasts and keratinocytes respond to this treatment remains limited. This study utilizes single-cell RNA sequencing (scRNA-seq) to investigate the impact of hucMSC-EVs on the cutaneous wound microenvironment in mice. Through rigorous single-cell analyses, we unveil the emergence of hucMSC-EV-induced hematopoietic fibroblasts and MMP13+ fibroblasts. Notably, MMP13+ fibroblasts exhibit fetal-like expressions of MMP13, MMP9, and HAS1, accompanied by heightened migrasome activity. Activation of MMP13+ fibroblasts is orchestrated by a distinctive PIEZO1-calcium-HIF1α-VEGF-MMP13 pathway, validated through murine models and dermal fibroblast assays. Organotypic culture assays further affirm that these activated fibroblasts induce keratinocyte migration via MMP13-LRP1 interactions. This study significantly contributes to our understanding of fibroblast heterogeneities as well as intercellular interactions in wound healing and identifies hucMSC-EV-induced hematopoietic fibroblasts as potential targets for reprogramming. The therapeutic targets presented by these fibroblasts offer exciting prospects for advancing wound healing strategies.

Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth Through Stabilizing BRD2.

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase, mediated by Zinc finger E-box binding homeobox 1. PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine (cCr) leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment. Significance: Glioblastoma (GBM) exhibits an adaptable metabolism crucial for survival and therapy resistance. We demonstrate that GBM stem cells modify their epigenetics by producing phosphocreatine (PCr), which prevents bromodomain containing protein 2 (BRD2) degradation and promotes accurate chromosome segregation. Disrupting PCr biosynthesis impedes tumor growth and improves the efficacy of BRD2 inhibitors in mouse GBM models.

Formation of cation bridges and its promoting mechanism for sorption of sulfamethoxazole by montmorillonite.

The coexistence of metal cations is often accompanied by organic pollution and could affect the environmental fate of organics by mediating the formation of cation bridges. However, the environmental fate and risk of organics in cation co-existing environments are poorly understood due to the lack of accurate identification of cation bridge formation and stability. In this study, the sorption of sulfamethoxazole (SMX) on montmorillonite (MT) with the coexistence of three different valence metal cations (Na+, Ca2+, and Cr3+) was investigated. Ca2+ and Cr3+ can significantly promote the sorption of SMX on MT for about 5∼10 times promotion, respectively, while Na+ bridges displayed little effect on the sorption of SMX. The sorption binding energy of SMX with MT-Ca (-44.01 kcal/mol) and MT-Cr (-64.57 kcal/mol) bridges was significantly lower than that with MT-Na (-38.45 kcal/mol) and MT (-39.39 kcal/mol), indicating that the sorption affinity of SMX on Cr and Ca bridges was much stronger. The higher valence of the cations also resulted in a more stable adsorbed SMX with less desorption fluctuation. In addition, the relatively higher initial concentration of SMX and the valence of cations increased the bonding density of the cation bridges, thus promoting the apparent sorption of SMX on MT to a certain extent. This work reveals the formation and function of cation bridges in the sorption of SMX on MT. It lays a theoretical foundation for further understanding the environmental fate and risk of organics.

Vacuum Evaporation Plating Enabling ≤ 10 µm Ultrathin Lithium Foils for Lithium Metal Batteries.

Lithium (Li) metal is widely recognized as a viable candidate for anode material in future battery technologies due to its exceptional energy density. Nevertheless, the commercial Li foils in common use are too thick (≈100 µm), resulting in a waste of Li resources. Herein, by applying the vacuum evaporation plating technology, the ultra-thin Li foils (VELi) with high purity, strong adhesion, and thickness of less than 10 µm are successfully prepared. The manipulation of evaporation temperature allows for convenient regulation of the thickness of the fabricated Li film. This physical thinning method allows for fast, continuous, and highly accurate mass production. With a current density of 0.5 mA cm-2 for a plating amount of 0.5 mAh cm-2, VELi||VELi cells can stably cycle for 200 h. The maximum utilization of Li is already more than 25%. Furthermore, LiFePO4||VELi full cells present excellent cycling performance at 1 C (1 C = 155 mAh g-1) with a capacity retention rate of 90.56% after 240 cycles. VELi increases the utilization of active Li and significantly reduces the cost of Li usage while ensuring anode cycling and multiplication performance. Vacuum evaporation plating technology provides a feasible strategy for the practical application of ultra-thin Li anodes.

MS4A6D Promotes carrageenan-induced footpad swelling in mice through enhancing macrophages-derived inflammation.

Our previous work has demonstrated that the tetraspan MS4A6D interacts with MHC-II to be a complex that promotes macrophage activation (Mol Immunol. 2023; 160: 121-132), however, the exact role of MS4A6D in controlling macrophage-derived inflammation is still poorly understood. Here, we showed that Ms4a6d-deficient (Ms4a6d-/-) mice manifested a lower level of footpad swelling induced by subcutaneous injection of 100 µL of 1% Carrageenan (CGN, w/v) plus CaCl2 (50 mM), a phenomenon that is similar to Nlrp3-/-, Casp-1-/-, and Ilr1-/- mice. Mechanistically, F4/80+ macrophages infiltrated in the footpad tissues of the Ms4A6d-/- mice was significantly lower than that of the WT littermates, leading to dramatically lower levels of proIL-1ß in vivo. Moreover, macrophages from Ms4a6d-/- mice also showed a dramatical reduction of Il-1ß secretion following NLRP3 inflammsome activation in vitro. Interestingly, both Ms4a6dC237G mutant (Interruption of MS4A6D homodimerization) and Ms4a6dY241G mutant (deletion of heITAM motif) mice also significantly inhibited CGN-induced footpad swelling due to lower levels of Il-1ß secretion in vivo. Collectively, MS4A6D aggravates CGN-induced footpad swelling in mice by enhancing NLRP3 inflammasome in macrophages and inducing the release of IL-1ß, indicating that MS4A6D promotes the progression of acute inflammation.

Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor.

The manipulation of cell identity by reprograming holds immense potential in regenerative medicine, but is often limited by the inefficient acquisition of fully functional cells. This problem can potentially be resolved by better understanding the reprogramming process using in vivo genetic models, which are currently scarce. Here we report that both enterocytes (ECs) and enteroendocrine cells (EEs) in adult Drosophila midgut show a surprising degree of cell plasticity. Depleting the transcription factor Tramtrack in the differentiated ECs can initiate Prospero-mediated cell transdifferentiation, leading to EE-like cells. On the other hand, depletion of Prospero in the differentiated EEs can lead to the loss of EE-specific transcription programs and the gain of intestinal progenitor cell identity, allowing cell cycle re-entry or differentiation into ECs. We find that intestinal progenitor cells, ECs, and EEs have a similar chromatin accessibility profile, supporting the concept that cell plasticity is enabled by pre-existing chromatin accessibility with switchable transcription programs. Further genetic analysis with this system reveals that the NuRD chromatin remodeling complex, cell lineage confliction, and age act as barriers to EC-to-EE transdifferentiation. The establishment of this genetically tractable in vivo model should facilitate mechanistic investigation of cell plasticity at the molecular and genetic level.

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma.

Background: Hypoxia induces hepatocellular carcinoma (HCC) malignancies; yet it also offers treatment opportunities, exemplified by developing hypoxia-activated prodrugs (HAPs). Although HAP TH-302 combined with therapeutic antibody (Ab) has synergistic effects, the clinical benefits are limited by the on-target off-tumor toxicity of Ab. Here, we sought to develop a hypoxia-activated anti-M2 splice isoform of pyruvate kinase (PKM2) Ab combined with TH-302 for potentiated targeting therapy. Methods: Codon-optimized and hypoxia-activation strategies were used to develop H103 Ab-azo-PEG5k (HAP103) Ab. Hypoxia-activated HAP103 Ab was characterized, and hypoxia-dependent antitumor and immune activities were evaluated. Selective imaging and targeting therapy with HAP103 Ab were assessed in HCC-xenografted mouse models. Targeting selectivity, systemic toxicity, and synergistic therapeutic efficacy of HAP103 Ab with TH-302 were evaluated. Results: Human full-length H103 Ab was produced in a large-scale bioreactor. Azobenzene (azo)-linked PEG5k conjugation endowed HAP103 Ab with hypoxia-activated targeting features. Conditional HAP103 Ab effectively inhibited HCC cell growth, enhanced apoptosis, and induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) functions. Analysis of HCC-xenografted mouse models showed that HAP103 Ab selectively targeted hypoxic HCC tissues and induced potent tumor-inhibitory activity either alone or in combination with TH-302. Besides the synergistic effects, HAP103 Ab had negligible side effects when compared to parent H103 Ab. Conclusion: The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.

Hypoxia-activated ADCC-enhanced humanized anti-CD147 antibody for liver cancer imaging and targeted therapy with improved selectivity.

Therapeutic antibodies (Abs) improve the clinical outcome of cancer patients. However, on-target off-tumor toxicity limits Ab-based therapeutics. Cluster of differentiation 147 (CD147) is a tumor-associated membrane antigen overexpressed in cancer cells. Ab-based drugs targeting CD147 have achieved inadequate clinical benefits for liver cancer due to side effects. Here, by using glycoengineering and hypoxia-activation strategies, we developed a conditional Ab-dependent cellular cytotoxicity (ADCC)-enhanced humanized anti-CD147 Ab, HcHAb18-azo-PEG5000 (HAP18). Afucosylated ADCC-enhanced HcHAb18 Ab was produced by a fed-batch cell culture system. Azobenzene (Azo)-linked PEG5000 conjugation endowed HAP18 Ab with features of hypoxia-responsive delivery and selective targeting. HAP18 Ab potently inhibits the migration, invasion, and matrix metalloproteinase secretion, triggers the cytotoxicity and apoptosis of cancer cells, and induces ADCC, complement-dependent cytotoxicity, and Ab-dependent cellular phagocytosis under hypoxia. In xenograft mouse models, HAP18 Ab selectively targets hypoxic liver cancer tissues but not normal organs or tissues, and has potent tumor-inhibiting effects. HAP18 Ab caused negligible side effects and exhibited superior pharmacokinetics compared to those of parent HcHAb18 Ab. The hypoxia-activated ADCC-enhanced humanized HAP18 Ab safely confers therapeutic efficacy against liver cancer with improved selectivity. This study highlights that hypoxia activation is a promising strategy for improving the tumor targeting potential of anti-CD147 Ab drugs.

Exacerbation of Pre-Existing Chronic Pain in Older Adults After SARS-CoV-2 Infection: A Single-Center, Cross-Sectional, Observational Study.

Purpose: To identify the prevalence of exacerbation of pre-existing chronic pain after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and investigate the impact of exacerbated previous chronic pain on quality of life, sleep quality, anxiety and depression levels and risk factors associated with exacerbated chronic pain among elderly coronavirus disease of 2019 (COVID-19) survivors. Patients and Methods: In this cross-sectional study, elderly COVID-19 survivors with chronic pain residing in Continuing Care Retirement Community (CCRC) were recruited from April 2023 to June 2023. Eligible individuals were divided into exacerbation and non-exacerbation groups based on the patient-reported worsening symptoms of previous chronic pain after SARS-CoV-2 infection. Baseline information, COVID-19 symptoms, laboratory parameters, characteristics of exacerbated chronic pain, quality of life, anxiety and depression levels were systematically collected. Results: Ninety-five (95/441, 21.5%) older adults suffered from exacerbated chronic pain with a median numerical rating scale (NRS) score of 6 (4-7) on a median duration of 4.9 (4.3-5.6) months after SARS-CoV-2 infection. More participants were not vaccinated against COVID-19 (46.5%, 40/86 vs 26.1%, 86/330, P < 0.001) in exacerbation group. Exacerbation group exhibited poor quality of life (EQ5D index: 0.734 [0.536-0.862] vs 0.837 [0.716-0.942], P < 0.001), more severe anxiety (GAD-7: 2 [0-5] vs 0 [0-3], P < 0.001) and depression (PHQ-9: 4 [2-7] vs 2.5 [0-5], P < 0.001) than non-exacerbation group. Risk factors significantly associated with exacerbation of pre-existing chronic pain were neuropathic pain (aOR 4.81, 95% CI 1.73-13.32, P = 0.003), lymphocyte count (aOR 0.31, 95% CI 0.12-0.78, P = 0.013) and D-dimer levels (aOR 6.46, 95% CI 1.92-21.74, P = 0.003). Conclusion: Our study observed a prevalence of 21.5% exacerbation of pre-existing chronic pain after SARS-CoV-2 infection, with a consequence of poor quality of life, more severe anxiety and depression. Previous chronic neuropathic pain, lower lymphocyte count and higher D-dimer levels were risk factors associated with the development of exacerbated previous chronic pain.

Rombocin, a Short Stable Natural Nisin Variant, Displays Selective Antimicrobial Activity against Listeria monocytogenes and Employs a Dual Mode of Action to Kill Target Bacterial Strains.

Nisin, with its unique mode of action and potent antimicrobial activity, serves as a remarkable inspiration for the design of novel antibiotics. However, peptides possess inherent weaknesses, particularly their susceptibility to proteolytic degradation, such as by trypsin, which limits their broader applications. This led us to speculate that natural variants of nisin produced by underexplored bacterial species can potentially overcome these limitations. We carried out genome mining of two Romboutsia sedimentorum strains, RC001 and RC002, leading to the discovery of rombocin A, which is a 25 amino acid residue short nisin variant that is predicted to have only four macrocycles compared to the known 31-35 amino acids long nisin variants with five macrocycles. Using the nisin-controlled expression system, we heterologously expressed fully modified and functional rombocin A in Lactococcus lactis and demonstrated its selective antimicrobial activity against Listeria monocytogenes. Rombocin A uses a dual mode of action involving lipid II binding activity and dissipation of the membrane potential to kill target bacteria. Stability tests confirmed its high stability at different pH values, temperatures, and in particular, against enzymatic degradation. With its gene-encoded characteristic, rombocin A is amenable to bioengineering to generate novel derivatives. Further mutation studies led to the identification of rombocin K, a mutant with enhanced bioactivity against L. monocytogenes. Our findings suggest that rombocin A and its bioengineered variant, rombocin K, are promising candidates for development as food preservatives or antibiotics against L. monocytogenes.