Recombinant fibroblast growth factor 4 ameliorates axonal regeneration and functional recovery in acute spinal cord injury through altering microglia/macrophage phenotype.

Neuroinflammation is one of the extensive secondary injury processes that aggravate metabolic and cellular dysfunction and tissue loss following spinal cord injury (SCI). Thus, an anti-inflammatory strategy is crucial for modulating structural and functional restoration during the stage of acute and chronic SCI. Recombinant fibroblast growth factor 4 (rFGF4) has eliminated its mitogenic activity and demonstrated a metabolic regulator for alleviating hyperglycemia in type 2 diabetes and liver injury in non-alcoholic steatohepatitis. However, it remains to be explored whether or not rFGF4 has a neuroprotective effect for restoring neurological disorders, such as SCI. Here, we identified that rFGF4 could polarize microglia/macrophages into the restorative M2 subtype, thus exerting an anti-inflammatory effect to promote neurological functional recovery and nerve fiber regeneration after SCI. Importantly, these effects by rFGF4 were related to triggering PI3K/AKT/GSK3ß and attenuating TLR4/NF-κB signaling axes. Conversely, gene silencing of the PI3K/AKT/GSK3ß signaling or pharmacological reactivation of the TLR4/NF-κB axis aggravated inflammatory reaction. Thus, our findings highlight rFGF4 as a potentially therapeutic regulator for repairing SCI, and its outstanding effect is associated with regulating macrophage/microglial polarization.

Epidemic Features and Megagenomic Analysis of Childhood Mycoplasma Pneumoniae post COVID-19 Pandemic: A 6-year Study in Southern China.

With the atypical rise of Mycoplasma pneumoniae infection (MPI) in 2023, prompt studies are needed to determine the current epidemic features and risk factors with emerging trends of MPI to furnish a framework for subsequent investigations. This multicentre, retrospective study was designed to analyse the epidemic patterns of MPI before and after the COVID-19 pandemic, as well as genotypes and the macrolide resistance-associated mutations in MP sampled from pediatric patients in Southern China. Clinical data was collected from 133674 patients admitted into investigational hospitals from June 1, 2017, to November 30, 2023. Metagenomic next-generation sequencing (mNGS) data were retrieved based on MP sequence positive samples from 299 pediatric patients for macrolide resistance-associated mutations analysis. Pearson's chi-squared test was used to compare categorical variables between different time frames. The monthly average cases of pediatric common respiratory infection diseases were increased without enhanced public health measures after the pandemic, especially for influenza, respiratory syncytial virus infection, and MPI. The contribution of MPI to pneumoniae was similar to that in the outbreak in 2019. Compared mNGS data between 2019-2022 and 2023, the severity of MP did not grow stronger despite higher rates of macrolide-resistance hypervariable sites, including loci 2063 and 2064, were detected in childhood MP samples of 2023. Our findings indicated ongoing surveillance is necessary to understand the impact of post pandemic on MP transmission disruption on epidemic season and severity of clinical outcomes in different scenarios.

Exosomes from MicroRNA-125b-Modified Adipose-Derived Stem Cells Promote Wound Healing of Diabetic Foot Ulcers.

INTRODUCTION: Exosomes derived from Adipose-Derived Stem Cells (ADSCs-Exo) have been implicated in the enhancement of wound repair in Diabetic Foot Ulcers (DFU). OBJECTIVE: The current research was designed to explore the therapeutic potential and underlying mechanisms of ADSCs-Exo modified with microRNA-125b (miR-125b) in the context of DFU. METHODS: Rat models with DFU and human umbilical vein endothelial cells (HUVECs) subjected to high glucose (HG) conditions served as experimental systems and were administered miR-125b-engineered ADSCs-Exo. Then, the expressions of CD34, Ki-67, angiogenesis-related factors (VEGF and TGFß-1), angiogenesis inhibitor DLL-4, and inflammation-related proteins (TLR-4 and IL-6) were detected. RESULTS: MiR-125b was upregulated in ADSCs-Exo. MiR-125b-mimics transfection in ADSCs- Exo reduced inflammatory infiltration and promoted granulation formation and wound healing in wound tissues. MiR-125b-mimics-modified ADSCs-Exo injection increased the expression of CD34, Ki-67, VEGF, and TGFß-1, whereas decreased the expression of DLL-4, TLR-4, and IL-6 in wound tissues of DFU rats. In addition, miR-125b-mimics-ADSCs-Exo injection reversed the negative effects of HG on the proliferation, migration, and angiogenesis of HUVECs, as well as the positive effects of cell apoptosis. Moreover, miR-125b-inhibitor-ADSCs-Exo injection had the opposite effects to miR-125b-mimics-ADSCs-Exo. CONCLUSION: ADSCs-Exo promoted wound healing of DFU rats, especially when overexpressing miR-125b.

Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors.

Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.

Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China.

INTRODUCTION: Alport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem cells (MSCs) have recently emerged as a promising therapeutic strategy for chronic kidney disease. However, the safety and therapeutic potential of MSC transfusion for patients with AS are still need to be confirmed. Therefore, we have designed a clinical trial to evaluate the hypothesis that intravenous infusion of human umbilical cord-derived MSC (hUC-MSC) is safe, feasible, and well-tolerated in children with AS. METHODS AND ANALYSIS: We report the protocol of the first prospective, open-label, single-arm clinical trial to evaluate the safety and preliminary efficacy of hUC-MSC transfusion in children with early-stage AS. Paediatric patients diagnosed with AS who have persistent albuminuria will be candidates for screening. Twelve eligible patients are planned to recruit and will receive hUC-MSC infusions under close safety monitoring, and complete the efficacy assessments at scheduled follow-up visits. The primary endpoints include the occurrence of adverse events to assess safety and the albuminuria level for efficacy evaluation. Secondary endpoint assessments are based on haematuria and glomerular filtration measurements. Each patient's efficacy endpoints will be evaluated against their baseline levels. Additionally, the underlying mechanism of hUC-MSC therapy will be explored through transcriptomic and proteomic analysis of blood and urine samples. ETHICS AND DISSEMINATION: The protocol (V.1.0, date 17 January 2015) was approved by the institutional review board of the Affiliated Taihe Hospital of Hubei University of Medicine (ethical approval 03 March 2015). Written informed consent will be obtained from the patient and/or guardians before study specific process. In addition to publication in a peer-reviewed scientific journal, a lay summary of study will be available for participants and the public on the Chinese Organization for Rare Disorders website (http://www.cord.org.cn/). TRIAL REGISTRATION NUMBER: ISRCTN62094626.

Detecting and Grounding Multi-Modal Media Manipulation and Beyond.

Misinformation has become a pressing issue. Fake media, in both visual and textual forms, is widespread on the web. Whilevarious deepfake detection and text fake news detection methods have been proposed, they are only designed for single-modality forgery based on binary classification, let alone analyzing and reasoning subtle forgery traces across different modalities. In this paper, we highlight a new research problem for multi-modal fake media, namely Detecting and Grounding Multi-Modal Media Manipulation (DGM4). DGM4 aims to not only detect the authenticity of multi-modal media, but also ground the manipulated content, which requires deeper reasoning of multi-modal media manipulation. To support a large-scale investigation, we construct the first DGM4 dataset. Moreover, we propose a novel HierArchical Multi-modal Manipulation rEasoning tRansformer (HAMMER) to fully capture the fine-grained interaction between different modalities. HAMMER performs 1) manipulation-aware contrastive learning between two uni-modal encoders as shallow manipulation reasoning, and 2) modality-aware cross-attention by multi-modal aggregator as deep manipulation reasoning. Dedicated manipulation detection and grounding heads are integrated from shallow to deep levels based on the interacted multi-modal information. To exploit more fine-grained contrastive learning for cross-modal semantic alignment, we further integrate Manipulation-Aware Contrastive Loss with Local View and construct a more advanced model HAMMER++ Finally, we build an extensive benchmark and set up rigorous evaluation metrics for this new research problem. Comprehensive experiments demonstrate the superiority of HAMMER and HAMMER++; several valuable observations are also revealed to facilitate future research in multi-modal media manipulation..

Effects of public health interventions and zero COVID policy on paediatric diseases: A Southern China study.

Background: With the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in schools and communities, clinical evidence is needed to determine the impact of the pandemic and public health interventions under the zero coronavirus disease policy on the occurrence of common infectious diseases and non-infectious diseases among children. Methods: The current study was designed to analyse the occurrence of common infectious diseases before and after the pandemic outbreak in southern China. Data was obtained for 1 801 728 patients admitted into children's hospitals in Guangzhou between January 2017 and July 2022. Regression analysis was performed for data analysis. Results: The annual occurrence of common paediatric infectious diseases remarkably decreased after the pandemic compared to the baseline before the pandemic and the monthly occurrence. Cases per month of common paediatric infectious diseases were significantly lower in five periods during the local outbreak when enhanced public health measures were in place. Cases of acute non-infectious diseases such as bone fractures were not reduced. Non-pharmaceutical interventions decreased annual and monthly cases of paediatric respiratory and intestinal infections during the coronavirus disease 2019 (COVID-19) pandemic, especially when enhanced public health interventions were in place. Conclusions: Our findings provide clinical evidence that public health interventions under the dynamic zero COVID policy in the past three years had significant impacts on the occurrence of common respiratory and intestinal infectious diseases among children and adolescents but little impact on reducing non-infectious diseases such as leukaemia and bone fracture.

Covalent PROTAC design method based on a sulfonyl pyridone probe.

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel-Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 µM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies.

Self-Training Boosted Multi-Factor Matching Network for Composed Image Retrieval.

The composed image retrieval (CIR) task aims to retrieve the desired target image for a given multimodal query, i.e., a reference image with its corresponding modification text. The key limitations encountered by existing efforts are two aspects: 1) ignoring the multiple query-target matching factors; 2) ignoring the potential unlabeled reference-target image pairs in existing benchmark datasets. To address these two limitations is non-trivial due to the following challenges: 1) how to effectively model the multiple matching factors in a latent way without direct supervision signals; 2) how to fully utilize the potential unlabeled reference-target image pairs to improve the generalization ability of the CIR model. To address these challenges, in this work, we first propose a CLIP-Transformer based muLtI-factor Matching Network (LIMN), which consists of three key modules: disentanglement-based latent factor tokens mining, dual aggregation-based matching token learning, and dual query-target matching modeling. Thereafter, we design an iterative dual self-training paradigm to further enhance the performance of LIMN by fully utilizing the potential unlabeled reference-target image pairs in a weakly-supervised manner. Specifically, we denote the iterative dual self-training paradigm enhanced LIMN as LIMN+. Extensive experiments on four datasets, including FashionIQ, Shoes, CIRR, and Fashion200 K, show that our proposed LIMN and LIMN+ significantly surpass the state-of-the-art baselines.

Covalent Peptide LSD1 Inhibitor Specifically Recognizes Cys360 in the Enzyme-Active Region.

Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target, especially in cancer treatment. Despite several LSD1 inhibitors being discovered for the cofactor pocket, none are FDA-approved. We aimed to develop stabilized peptides for irreversible LSD1 binding, focusing on unique cysteine residue Cys360 in LSD1 and SNAIL1. We created LSD1 C360-targeting peptides, like cyclic peptide S9-CMC1, using our Cysteine-Methionine cyclization strategy. S9-CMC1 effectively inhibited LSD1 at the protein level, as confirmed by MS analysis showing covalent bonding to Cys360. In cells, S9-CMC1 inhibited LSD1 activity, increasing H3K4me1 and H3K4me2 levels, leading to G1 cell cycle arrest and apoptosis and inhibiting cell proliferation. Remarkably, S9-CMC1 showed therapeutic potential in A549 xenograft animal models, regulating LSD1 activity and significantly inhibiting tumor growth with minimal organ damage. These findings suggest LSD1 C360 as a promising site for covalent LSD1 inhibitors' development.

Semantic-Aware Modular Capsule Routing for Visual Question Answering.

Visual Question Answering (VQA) is fundamentally compositional in nature, and many questions are simply answered by decomposing them into modular sub-problems. The recent proposed Neural Module Network (NMN) employ this strategy to question answering, whereas heavily rest with off-the-shelf layout parser or additional expert policy regarding the network architecture design instead of learning from the data. These strategies result in the unsatisfactory adaptability to the semantically-complicated variance of the inputs, thereby hindering the representational capacity and generalizability of the model. To tackle this problem, we propose a Semantic-aware modUlar caPsulE Routing framework, termed as SUPER, to better capture the instance-specific vision-semantic characteristics and refine the discriminative representations for prediction. Particularly, five powerful specialized modules as well as dynamic routers are tailored in each layer of the SUPER network, and the compact routing spaces are constructed such that a variety of customizable routes can be sufficiently exploited and the vision-semantic representations can be explicitly calibrated. We comparatively justify the effectiveness and generalization ability of our proposed SUPER scheme over five benchmark datasets, as well as the parametric-efficient advantage. It is worth emphasizing that this work is not to pursue the state-of-the-art results in VQA. Instead, we expect that our model is responsible to provide a novel perspective towards architecture learning and representation calibration for VQA.

Spleen tyrosine kinase (SYK) signals are implicated in cardio-cerebrovascular diseases.

Post-translational modifications regulate numerous biochemical reactions and functions through covalent attachment to proteins. Phosphorylation, acetylation and ubiquitination account for over 90% of all reported post-translational modifications. As one of the tyrosine protein kinases, spleen tyrosine kinase (SYK) plays crucial roles in many pathophysiological processes and affects the pathogenesis and progression of various diseases. SYK is expressed in tissues outside the hematopoietic system, especially the heart, and is involved in the progression of various cardio-cerebrovascular diseases, such as atherosclerosis, heart failure, diabetic cardiomyopathy, stroke and others. Knowledge on the role of SYK in the progress of cardio-cerebrovascular diseases is accumulating, and many related mechanisms have been discovered and validated. This review summarizes the role of SYK in the progression of various cardio-cerebrovascular diseases, and aims to provide a theoretical basis for future experimental and clinical research targeting SYK as a therapeutic option for these diseases.

Neighbor-Guided Consistent and Contrastive Learning for Semi-Supervised Action Recognition.

Semi-supervised learning has been well established in the area of image classification but remains to be explored in video-based action recognition. FixMatch is a state-of-the-art semi-supervised method for image classification, but it does not work well when transferred directly to the video domain since it only utilizes the single RGB modality, which contains insufficient motion information. Moreover, it only leverages highly-confident pseudo-labels to explore consistency between strongly-augmented and weakly-augmented samples, resulting in limited supervised signals, long training time, and insufficient feature discriminability. To address the above issues, we propose neighbor-guided consistent and contrastive learning (NCCL), which takes both RGB and temporal gradient (TG) as input and is based on the teacher-student framework. Due to the limitation of labelled samples, we first incorporate neighbors information as a self-supervised signal to explore the consistent property, which compensates for the lack of supervised signals and the shortcoming of long training time of FixMatch. To learn more discriminative feature representations, we further propose a novel neighbor-guided category-level contrastive learning term to minimize the intra-class distance and enlarge the inter-class distance. We conduct extensive experiments on four datasets to validate the effectiveness. Compared with the state-of-the-art methods, our proposed NCCL achieves superior performance with much lower computational cost.

Mitochondrion: A bridge linking aging and degenerative diseases.

Aging is a natural process, characterized by progressive loss of physiological integrity, impaired function, and increased vulnerability to death. For centuries, people have been trying hard to understand the process of aging and find effective ways to delay it. However, limited breakthroughs have been made in anti-aging area. Since the hallmarks of aging were summarized in 2013, increasing studies focus on the role of mitochondrial dysfunction in aging and aging-related degenerative diseases, such as neurodegenerative diseases, osteoarthritis, metabolic diseases, and cardiovascular diseases. Accumulating evidence indicates that restoring mitochondrial function and biogenesis exerts beneficial effects in extending lifespan and promoting healthy aging. In this paper, we provide an overview of mitochondrial changes during aging and summarize the advanced studies in mitochondrial therapies for the treatment of degenerative diseases. Current challenges and future perspectives are proposed to provide novel and promising directions for future research.

A Blumgart Anastomosis-Based Half-Invagination Pancreaticoenterostomy with Better Applicability to Laparoscopy and Lower Incidence of Pancreatic Leakage.

Background: The Blumgart anastomosis (BA) is one of the safest anastomoses for pancreatic stump reconstruction. The incidence of postoperative pancreatic fistula (POPF) and postoperative complications is low. However, how to make laparoscopic pancreaticoenterostomy easier and safer is still a topic to be discussed. Methods: The data of patients who underwent laparoscopic pancreaticoduodenectomy (PD) from April 2014 to December 2019 were analyzed retrospectively. Results: Half-invagination anastomosis was performed in 20 cases (HI group), and the Cattell-Warren anastomosis was carried out in 26 cases (CW group). The amount of intraoperative bleeding, operation time, and postoperative catheterization time in the HI group was significantly less than those in the CW group. Besides, the number of patients at the Clavien-Dindo grade III and above in the HI group was significantly less than that in the control group. Moreover, the incidence of POPF in the HI group was significantly lower than that in the CW group. Furthermore, fistula risk score (FRS) analysis showed that there was no high-risk group, and the highest risk in the medium-risk group was pancreatic leakage. In addition, the incidence of pancreatic leakage in the HI group and CW group was 7.7% and 46.67%, respectively, while the incidence of pancreatic leakage in the HI group was significantly lower than that in the CW group. Conclusions: The half-invagination pancreaticoenterostomy based on the Blumgart anastomosis should have good applicability under laparoscopy and could effectively reduce the incidence of postoperative pancreatic leakage.

Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach.

The development of bifunction al molecules, which can enable targeted RNA degradation, targeted protein acetylation, or targeted protein degradation, remains a time-consuming process that requires tedious optimization. We propose a split-and-mix nanoplatform that serves as a self-adjustable platform capable of facile screening, programmable ligand ratios, self-optimized biomolecule spatial recognition, and multifunctional applications. Herein, we demonstrate the potential of our proposed nanoplatform by showcasing proteolysis-targeting chimeras (PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight the scope of our platform through the targeted disruption of intracellular therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4, BCR-ABL, etc. These studies confirm the effectiveness and universality of the SM-PROTAC platform for proximity-induced applications. This platform is programmable, with significant potential applications to biomolecule regulation, including the fields of epigenetics, gene editing, and biomolecule modification regulation.

Pharmacokinetics and bioequivalence studies of fluvoxamine maleate tablets in healthy Chinese subjects.

Fluvoxamine is a selective serotonin reuptake inhibitor commonly used for various types of depression. The purpose of this study was to evaluate the pharmacokinetics and bioequivalence of fluvoxamine maleate tablets orally on an empty stomach and after a meal in healthy adult Chinese subjects and to preliminarily evaluate their safety. A single-center, randomized, open-label, two-drug, two-period, crossover, single-dose trial protocol was designed. Sixty healthy Chinese participants were enrolled and randomly classified into fasting (n = 30) and fed groups (n = 30). Each week, subjects took fluvoxamine maleate tablets 50 mg orally once as a test preparation or as a reference preparation on an empty stomach/after meals. To evaluate the bioequivalence of test and reference tables, the concentration of fluvoxamine maleate in the plasma of the subjects at different time points after administration was detected by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters including the maximum plasma drug concentration (Cmax ), the time to reach maximum concentration (Tmax ), the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0-t ) and the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) were calculated. Our data revealed that the 90% confidence intervals of the geometric mean ratio of the test or reference drugs for the Cmax , AUC0-t and AUC0-∞ fell within the acceptance range for bioequivalence (92.30-102.77%). The absorption, measured by AUC, did not show a significant difference between the two groups. There were no suspected serious adverse reactions or serious adverse events over the entire trial. Our results demonstrated that the test and reference tablets were bioequivalent under fasting and fed conditions.

Tissue-engineered bones with adipose-derived stem cells - composite polymer for repair of bone defects.

Background: Development of alternative bone tissue graft materials based on tissue engineering technology has gradually become a research focus. Engineered bone composed of biodegradable, biosafe and bioactive materials is attractive, but also challenging. Materials & methods: An adipose-derived stem cell/poly(L-glutamic acid)/chitosan composite scaffold was further developed for construction of biodegradable and bone-promoting tissue-engineered bone. A series of composite scaffold materials with different physical properties such as structure, pore size, porosity and pore diameter was developed. Results: The composite scaffold showed good biodegradability and water absorption, and exhibited an excellent ability to promote bone differentiation. Conclusion: This type of biodegradable scaffold is expected to be applied to the field of bone repair or bone tissue engineering.

In recent years, the application of bone graft materials in bone defect repair has become a research hotspot. Engineered bone composed of biodegradable, biosafe and bioactive materials is attractive but also challenging. A composite scaffold composed of adipose-derived stem cells and two polymers was developed for construction of biodegradable and bone-promoting tissue-engineered bone. A series of composite scaffold materials with different physical properties was prepared and studied. The composite scaffold showed good biodegradability and water absorption, and exhibited excellent ability to promote bone differentiation ­ that is, bone defect repair function. This kind of biodegradable scaffold is expected to be applied to the field of bone repair or bone tissue engineering.

TryonCM2: Try-on-Enhanced Fashion Compatibility Modeling Framework.

Recently, fashion compatibility modeling, which can score the matching degree of several complementary fashion items, has gained increasing research attention. Previous studies have primarily learned the features of fashion items and utilize their interaction as the fashion compatibility. However, the try-on looking of an outfit help us to learn the fashion compatibility in a combined manner, where items are spatially distributed and partially covered by other items. Inspired by this, we design a try-on-enhanced fashion compatibility modeling framework, named TryonCM2, which incorporates the try-on appearance with the item interaction to enhance the fashion compatibility modeling. Specifically, we treat each outfit as a sequence of items and adopt the bidirectional long short-term memory (LSTM) network to capture the latent interaction of fashion items. Meanwhile, we synthesize a try-on template image to depict the try-on appearance of an outfit. And then, we regard the outfit as a sequence of multiple image stripes, i.e., local content, of the try-on template, and adopt the bidirectional LSTM network to capture the contextual structure in the try-on appearance. Ultimately, we combine the fashion compatibility lying in the item interaction and try-on appearance as the final compatibility of the outfit. Both the objective and subjective experiments on the existing FOTOS dataset demonstrate the superiority of our framework over the state-of-the-art methods.