DeepDynaForecast: Phylogenetic-informed graph deep learning for epidemic transmission dynamic prediction.

In the midst of an outbreak or sustained epidemic, reliable prediction of transmission risks and patterns of spread is critical to inform public health programs. Projections of transmission growth or decline among specific risk groups can aid in optimizing interventions, particularly when resources are limited. Phylogenetic trees have been widely used in the detection of transmission chains and high-risk populations. Moreover, tree topology and the incorporation of population parameters (phylodynamics) can be useful in reconstructing the evolutionary dynamics of an epidemic across space and time among individuals. We now demonstrate the utility of phylodynamic trees for transmission modeling and forecasting, developing a phylogeny-based deep learning system, referred to as DeepDynaForecast. Our approach leverages a primal-dual graph learning structure with shortcut multi-layer aggregation, which is suited for the early identification and prediction of transmission dynamics in emerging high-risk groups. We demonstrate the accuracy of DeepDynaForecast using simulated outbreak data and the utility of the learned model using empirical, large-scale data from the human immunodeficiency virus epidemic in Florida between 2012 and 2020. Our framework is available as open-source software (MIT license) at github.com/lab-smile/DeepDynaForcast.

miR-548ag promotes DPP4 expression in hepatocytes through activation of TLR(7/8)/NF-κB pathway.

OBJECTIVE: In our previous study, we identified a notable increase in miR-548ag content after obesity, which contributes to the progression of Type 2 diabetes Mellitus(T2DM) through the up-regulation of Dipeptidyl Peptidase-4(DPP4) expression within the liver. However, the precise molecular mechanisms underlying the upregulation of DPP4 by miR-548ag remain elusive. Mature miRNAs rich in GU sequences can activate the TLR(7/8)/NF-κB signalling pathway, which transcriptionally activates DPP4 expression. Notably, the proportion of GU sequences in hsa-miR-548ag was found to be 47.6%. The study proposes a hypothesis suggesting that miR-548ag could potentially increase DPP4 expression in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. METHODS: Male C57BL/6J mice were fed normal chow diet (NCD, n = 16) or high-fat diet (HFD, n = 16) for 12 weeks. For a duration of 6 weeks, NCD mice received intraperitoneal injections of a miR-548ag mimic, while HFD mice and db/db mice (n = 16) were administered intraperitoneal injections of a miR-548ag inhibitor. qRT-PCR and Western Blot were used to detect the expression level of miR-548ag, DPP4 and the activation of TLR(7/8)/NF-κB signalling pathway. HepG2 and L02 cells were transfected with miR-548ag mimic, miR-548ag inhibitor, TLR7/8 interfering fragment, and overexpression of miR-548ag while inhibiting TLR7/8, respectively. RESULTS: (1) We observed elevated levels of miR-548ag in the serum, adipose tissue, and liver of obese mice, accompanied by an upregulation of TLR7/8, pivotal protein in the NF-κB pathway, and DPP4 expression in the liver. (2) miR-548ag promotes DPP4 expression in hepatocytes via the TLR(7/8)/NF-κB signalling pathway, resulting in a reduction in the glucose consumption capacity of hepatocytes. (3) The administration of a miR-548ag inhibitor enhanced glucose tolerance and insulin sensitivity in db/db mice. CONCLUSIONS: MiR-548ag promotes the expression of DPP4 in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. MiR-548ag may be a potential target for the treatment of T2DM.

KLF7 promotes adipocyte inflammation and glucose metabolism disorder by activating the PKCζ/NF-κB pathway.

In the obesity context, inflammatory cytokines secreted by adipocytes lead to insulin resistance and are key to metabolic syndrome development. In our previous study, we found that the transcription factor KLF7 promoted the expression of p-p65 and IL-6 in adipocytes. However, the specific molecular mechanism remained unclear. In the present study, we found that the expression of KLF7, PKCζ, p-IκB, p-p65, and IL-6 in epididymal white adipose tissue (Epi WAT) in mice fed a high-fat diet (HFD) was significantly increased. In contrast, the expression of PKCζ, p-IκB, p-p65, and IL-6 was significantly decreased in Epi WAT of KLF7 fat conditional knockout mice. In 3T3-L1 adipocytes, KLF7 promoted the expression of IL-6 via the PKCζ/NF-κB pathway. In addition, we performed luciferase reporter and chromatin immunoprecipitation assays, which confirmed that KLF7 upregulated the expression of PKCζ transcripts in HEK-293T cells. Collectively, our results show that KLF7 promotes the expression of IL-6 by upregulating PKCζ expression and activating the NF-κB signaling pathway in adipocytes.

Additive-free oxychlorination of unsaturated C-C bonds with tert-butyl hypochlorite and water.

Herein we report an additive-free protocol for the facile synthesis of α,α-dichloroketones and α-chlorohydrins from various aryl terminal, diaryl internal, and aliphatic terminal alkynes and alkenes, respectively. The commercially available tert-butyl hypochlorite (tBuOCl) was employed as a suitable chlorinating reagent, being accompanied by the less harmful tBuOH as the by-product. In addition, the oxygen atoms in the products came from water rather than molecular oxygen, based on the 18O-labelling experiments. Meanwhile, the diastereoselectivity of the Z- and the corresponding E-alkenes has been compared and rationalized. Using a group of control experiments, the possible mechanisms have been proposed as the initial electrophilic chlorination of unsaturated C-C bonds in a Markovnikov-addition manner in general followed by a nucleophilic addition with water. This work simplified the oxychlorination method with a mild chlorine source and a green oxygen source under ambient conditions.

C-N cleavage of secondary amide to access primary amide by a Co(II)/Oxone oxidation system.

Cleavage of the C-N bond of a secondary amide could provide alternative access to primary amides; however, this strategy remains challenging due to oxidation resistance of the amide. Herein, we employed the cobalt(II)/Oxone catalytic system, one of the advanced oxidation processes (AOPs), to make it available to break the strong C-N bond of various secondary (sulfon)amides, especially those bearing electron-poor or ortho-substituted N-arenes, en route to desirable primary (sulfon)amides. Control experiments showed that it was probably not the generally-considered persulfate anion radical in the cobalt/peroxymonosulfate (Co/PMS) system but the proposed high-valent cobalt-oxo intermediate that should be the major active species for the initial N-H oxidation of N-aryl amides. In the case of N-alkylated secondary amides, the α-C-H bond, rather than the N-H bond, should be oxidized first by both the reactive radicals and high-valent cobalt-oxo species. This work not only establishes an efficient method for removing the N-substituents of secondary amides at low cost, with readily available and eco-friendly reagents, but also demonstrates further synthetic application and provides more insight into intermediates for metal-based AOPs in environmental remediation.

MRD-YOLO: A Multispectral Object Detection Algorithm for Complex Road Scenes.

Object detection is one of the core technologies for autonomous driving. Current road object detection mainly relies on visible light, which is prone to missed detections and false alarms in rainy, night-time, and foggy scenes. Multispectral object detection based on the fusion of RGB and infrared images can effectively address the challenges of complex and changing road scenes, improving the detection performance of current algorithms in complex scenarios. However, previous multispectral detection algorithms suffer from issues such as poor fusion of dual-mode information, poor detection performance for multi-scale objects, and inadequate utilization of semantic information. To address these challenges and enhance the detection performance in complex road scenes, this paper proposes a novel multispectral object detection algorithm called MRD-YOLO. In MRD-YOLO, we utilize interaction-based feature extraction to effectively fuse information and introduce the BIC-Fusion module with attention guidance to fuse different modal information. We also incorporate the SAConv module to improve the model's detection performance for multi-scale objects and utilize the AIFI structure to enhance the utilization of semantic information. Finally, we conduct experiments on two major public datasets, FLIR_Aligned and M3FD. The experimental results demonstrate that compared to other algorithms, the proposed algorithm achieves superior detection performance in complex road scenes.

Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.

BACKGROUND AND AIMS: Androgen receptor (AR) has been reported to play an important role in the development and progression of man's prostate cancer. Hepatocellular carcinoma (HCC) is also male-dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis. APPROACH AND RESULTS: In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high ARS96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease-free survival, which has been proven as an independent survival predictor for patients with HCC. CONCLUSIONS: AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man-biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.

YOLOv5s-DSD: An Improved Aerial Image Detection Algorithm Based on YOLOv5s.

Due to the challenges of small detection targets, dense target distribution, and complex backgrounds in aerial images, existing object detection algorithms perform poorly in aerial image detection tasks. To address these issues, this paper proposes an improved algorithm called YOLOv5s-DSD based on YOLOv5s. Specifically, the SPDA-C3 structure is proposed and used to reduce information loss while focusing on useful features, effectively tackling the challenges of small detection targets and complex backgrounds. The novel decoupled head structure, Res-DHead, is introduced, along with an additional small object detection head, further improving the network's performance in detecting small objects. The original NMS is replaced by Soft-NMS-CIOU to address the issue of neighboring box suppression caused by dense object distribution. Finally, extensive ablation experiments and comparative tests are conducted on the VisDrone2019 dataset, and the results demonstrate that YOLOv5s-DSD outperforms current state-of-the-art object detection models in aerial image detection tasks. The proposed improved algorithm achieves a significant improvement compared with the original algorithm, with an increase of 17.4% in mAP@0.5 and 16.4% in mAP@0.5:0.95, validating the superiority of the proposed improvements.

Hepatic Glucose Metabolism Disorder Induced by Adipose Tissue-Derived miR-548ag via DPP4 Upregulation.

The present study aimed to explore the molecular mechanism underlying the regulation of glucose metabolism by miR-548ag. For the first time, we found that miR-548ag expression was elevated in the abdominal adipose tissue and serum of subjects with obesity and type 2 diabetes mellitus (T2DM). The conditional knockout of adipose tissue Dicer notably reduced the expression and content of miR-548ag in mouse adipose tissue, serum, and liver tissue. The combined use of RNAseq, an miRNA target gene prediction software, and the dual luciferase reporter assay confirmed that miR-548ag exerts a targeted regulatory effect on DNMT3B and DPP4. miR-548ag and DPP4 expression was increased in the adipose tissue, serum, and liver tissue of diet-induced obese mice, while DNMT3B expression was decreased. It was subsequently confirmed both in vitro and in vivo that adipose tissue-derived miR-548ag impaired glucose tolerance and insulin sensitivity by inhibiting DNMT3B and upregulating DPP4. Moreover, miR-548ag inhibitors significantly improved the adverse metabolic phenotype in both obese mice and db/db mice. These results revealed that the expression of the adipose tissue-derived miR-548ag increased in obese subjects, and that this could upregulate the expression of DPP4 by targeting DNMT3B, ultimately leading to glucose metabolism disorder. Therefore, miR-548ag could be utilized as a potential target in the treatment of T2DM.

Downregulated miR-187 contributes to the keratinocytes hyperproliferation in psoriasis.

Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. However, the pathogenesis of psoriasis is multifactorial and is not fully understood. MicroRNAs (miRNAs) represent a promising class of small, noncoding RNA molecules that have a large impact on cellular functions by regulating gene expression. Here we reported that microRNA-187 (miR-187), which is one of the most dynamic microRNAs identified in the deep screening miRNAs profile, is downregulated in inflammatory cytokines-stimulated keratinocytes and psoriatic skins. By luciferase activity assay and gain-of-function studies, we showed that miR-187 inhibits keratinocytes hyperproliferation by targeting CD276. Moreover, overexpression of miR-187 decreases acanthosis and reduces the disease severity in psoriasis mouse models. Taken together, the results of our study implies miR-187 as a critical factor in psoriasis pathogenesis, which could be a potent target for psoriasis treatment.

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice.

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-ß1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

Peucedanum praeruptorum Dunn leaf aqueous extract protects against alcoholic gastric injury by inhibiting inflammation and oxidative stress in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Peucedanum praeruptorum Dunn (PPD) was used to treat gastrointestinal disease in China before the Tang Dynasty, and it was considered a "Top-grade" herb in Shennong Bencaojing, known for its ability to relieve the stomach Qi and indigestion. AIM OF THE STUDY: Alcohol consumption can induce severe gastric mucosal injury that lacks effective and safe interventions. We aimed to investigate the gastroprotective effects of Peucedanum praeruptorum Dunn leaf (PPL) after bolting in alcohol-induced gastric damage in mice. MATERIALS AND METHODS: Mice were orally administered PPL aqueous extract at doses of 2.5, 5, and 10 g/kg for 5 consecutive days prior to the induction of gastric damage model with ethanol. Gastric tissue was stained by hematoxylin and eosin (H&E), and the levels of pro-inflammatory cytokines and oxidative stress indicators were determined using ELISA and RT-qPCR. RNA-seq was used to detect differentially expressed genes (DEGs) in the gastric tissue, while Western blotting was employed to measure the expressions of IL-17, TNF-a, and AKT pathways. RESULTS: Treatment with PPL alleviated alcohol-induced gastric damage in mice, whereas dried root (PPD) and stem (PPS) of Peucedanum praeruptorum Dunn had no gastroprotective function. The content of peucedanocoumarin I was higher in the dried PPL compared to PPD and PPS, with an increase in peucedanocoumarin I content in PPL after boiling. Additionally, PPL administration (5, 10 g/kg) decreased pro-inflammatory factors, such as interleukin-6 (IL-6), IL-8, IL-4, IL-1ß, IL-18, and tumor necrosis factor (TNF-a) in alcohol-induced gastric injury mice (p < 0.05), and improved oxidative stress markers, including superoxide dismutase enzymes (SOD), catalase (CAT), and malondialdehyde (MDA) (p < 0.05). RNA-seq data revealed that PPL treatment inhibited alcohol-induced inflammation-related signals, including IL-17 and TNF pathways, and restored alcohol-inhibited gastric digestive and metabolic functions, such as xenobiotics metabolism of cytochrome P450, and protein digestion and absorption pathways. Notably, treatment with PPL downregulated the expressions of IL-17 A, TNF-a, monocyte chemoattractant protein-1 (MCP-1), and AKT-phosphorylation induced by ethanol exposure (p < 0.05). Thus, the aqueous extract of PPL provided protection against alcohol-induced gastric injury by mitigating inflammation and oxidative stress in mice, suggesting a potential novel therapeutic approach for alcohol-induced gastric damage.

Analysis and Visualization of Single-Cell Sequencing Data with Scanpy and MetaCell: A Tutorial.

The emergence and development of single-cell RNA sequencing (scRNA-seq) techniques enable researchers to perform large-scale analysis of the transcriptomic profiling at cell-specific resolution. Unsupervised clustering of scRNA-seq data is central for most studies, which is essential to identify novel cell types and their gene expression logics. Although an increasing number of algorithms and tools are available for scRNA-seq analysis, a practical guide for users to navigate the landscape remains underrepresented. This chapter presents an overview of the scRNA-seq data analysis pipeline, quality control, batch effect correction, data standardization, cell clustering and visualization, cluster correlation analysis, and marker gene identification. Taking the two broadly used analysis packages, i.e., Scanpy and MetaCell, as examples, we provide a hands-on guideline and comparison regarding the best practices for the above essential analysis steps and data visualization. Additionally, we compare both packages and algorithms using a scRNA-seq dataset of the ctenophore Mnemiopsis leidyi, which is representative of one of the earliest animal lineages, critical to understanding the origin and evolution of animal novelties. This pipeline can also be helpful for analyses of other taxa, especially prebilaterian animals, where these tools are under development (e.g., placozoan and Porifera).

Fraxini cortex: Progresses in phytochemistry, pharmacology and ethnomedicinal uses.

ETHNOPHARMACOLOGICAL RELEVANCE: Fraxini cortex, which has been widely used as a traditional Chinese medicine for 2000 years, is made from the dried bark of four plant species: Fraxinus chinensis subsp. rhynchophylla (Hance) A.E.Murray, Fraxinus chinensis Roxb., Fraxinus chinensis subsp. chinensis and Fraxinus stylosa Lingelsh.. In Chinese traditional medicine, it possesses the properties of heat-clearing and dampness-drying, asthma relief and cough suppression, as well as vision improvement. It is utilized for treating bacterial disorders, enteritis, leukorrhea, chronic bronitis, painful red eyes with swelling, lacrimation due to windward exposure, psoriasis, and other diseases or related symptoms. AIM OF THE STUDY: Fraxini cortex is abundant in chemical constituents and has garnered significant attention from plant chemists, particularly regarding coumarins, as evidenced by the recently identified three coumarin compounds. Considering the current dearth of systematic reporting on studies pertaining to Fraxini cortex, herein we provide a comprehensive summary of the advancements in phytochemistry, pharmacology, detection methods, and ethnomedicinal applications of Fraxini cortex. MATERIALS AND METHODS: We conducted a comprehensive search across online data sources (Web of Science, Public Medicine (PubMed), China National Knowledge Infrastructure (CNKI), as well as Chinese dissertations) and traditional Chinese medicine classics to gather the necessary literature resources for this review. RESULTS: Briefly, The Fraxini cortex yielded a total of 132 phytochemicals, including coumarins, lignans, secoiridoids, phenylethanol glycosides, flavonoids, triterpenoids, and other compounds. Among them, the main active ingredients are coumarins which possess a diverse range of pharmacological activities such as anti-inflammatory effects, anti-tumor properties, prevention of tissue fibrosis and oxidation damage as well as cardioprotective effects. CONCLUSIONS: All types of research conducted on Fraxini cortex, particularly in the field of ethnopharmacology, phytochemistry, and pharmacology, have been thoroughly reviewed. However, certain traditional applications and pharmacological activities of Fraxini cortex lack scientific evaluation or convincing evidence due to incomplete methodologies and ambiguous results, as well as a lack of clinical data. To validate its pharmacological activity, clinical efficacy, and safety profile, a systematic and comprehensive research evaluation is imperative. As an important traditional Chinese medicine, Fraxini cortex should be further explored to facilitate the development of novel drugs and therapeutics for various diseases. Greater attention should be given to how it can be better utilized.

Genome-wide screening of meta-QTL and candidate genes controlling yield and yield-related traits in barley (Hordeum vulgare L.).

Increasing yield is an important goal of barley breeding. In this study, 54 papers published from 2001-2022 on QTL mapping for yield and yield-related traits in barley were collected, which contained 1080 QTLs mapped to the barley high-density consensus map for QTL meta-analysis. These initial QTLs were integrated into 85 meta-QTLs (MQTL) with a mean confidence interval (CI) of 2.76 cM, which was 7.86-fold narrower than the CI of the initial QTL. Among these 85 MQTLs, 68 MQTLs were validated in GWAS studies, and 25 breeder's MQTLs were screened from them. Seventeen barley orthologs of yield-related genes in rice and maize were identified within the hcMQTL region based on comparative genomics strategy and were presumed to be reliable candidates for controlling yield-related traits. The results of this study provide useful information for molecular marker-assisted breeding and candidate gene mining of yield-related traits in barley.

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis.

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

Palmitic acid promotes miRNA release from adipocyte exosomes by activating NF-κB/ER stress.

OBJECTIVE: The release of adipose tissue-derived miRNAs is increased under conditions of obesity, but the exact molecular mechanisms involved have not been elucidated. This study investigated whether obesity-induced increases in palmitic acid (PA) content could activate the NF-κB/endoplasmic reticulum stress (ER stress) pathway and promote the expression and release of exosomal miRNAs in adipocytes. METHODS: Abdominal adipose tissue and serum samples were collected from normal weight individuals and people with obesity to clarify the correlation of serum PA content with NF-κB/ER stress and the release of exosomal miRNAs. NF-κB and ER stress were blocked in obese mice and in vitro cultured adipocytes to demonstrate the molecular mechanisms by which PA promotes the release of exosomal miRNAs.The morphology, particle size and distribution of the exosomes were observed via transmission electron microscopy and NTA. RESULTS: Accompanied by increased serum PA levels, the NF-κB/ER stress pathway was activated in the adipose tissue of people with obesity and in high-fat diet (HFD)-induced obese mice; moreover, the levels of miRNAs in both adipose tissue and serum were increased. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reduced the levels of miRNAs in abdominal adipose tissue and serum, decreased blood glucose levels, and improved glucose tolerance and insulin sensitivity in obese mice. In 3T3-L1 adipocytes, high concentrations of PA activated the NF-κB/ER stress pathway and increased the expression and release of miRNAs in exosomes. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reversed the increased release exosomal miRNAs cause by PA. CONCLUSIONS: Obesity-induced increases in PA content increase the expression and release of miRNAs in adipocyte exosomes by activating the NF-κB/ER stress pathway.

Novel porphyrin derivative containing cations as new photodynamic antimicrobial agent with high efficiency.

Bacterial infections from chronic wounds affect about 175 million people each year and are a significant clinical problem. Through the integration of photodynamic therapy (PDT) and chemotherapy, a new photosensitizer consisting of ammonium salt N,N-bis-(2-hydroxyethyl)-N-(6-(4-(10,15,20-trimesitylporphyrin-5-yl) phenoxy) hexane)-N-methanaminium bromide, TMP(+) was successfully synthesized with a total reaction yield of 10%. The novel photosensitizer consists of two parts, a porphyrin photosensitizer part and a quaternary ammonium salt part, to achieve the synergistic effect of photodynamic and chemical antibacterial activity. With the increase of TMP(+) concentration, the diameter of the PCT fiber membranes (POL/COL/TMP(+); POL, polycaprolactone; COL, collagen) gradually increased, which was caused by the charge of the quaternary ammonium salt. At the same time, the antibacterial properties were gradually improved. We finally selected the PCT 0.5% group for the antibacterial experiment, with excellent performance in fiber uniformity, hydrophobicity and biosafety. The antibacterial experiment showed that the modified porphyrin TMP(+) had a better antibacterial effect than others. In vivo chronic wound healing experiments proved that the antibacterial and anti-inflammatory effect of the PCTL group was the best, further confirmed by H&E histological analysis, immunofluorescence and immunohistochemistry mechanism experiments. This research lays the foundation for the manufacture of novel molecules that combine chemical and photodynamic strategies.

Combining photodynamic therapy and cascade chemotherapy for enhanced tumor cytotoxicity: the role of CTT2P@B nanoparticles.

The mitochondria act as the main producers of reactive oxygen species (ROS) within cells. Elevated levels of ROS can activate the mitochondrial apoptotic pathway, leading to cell apoptosis. In this study, we devised a molecular prodrug named CTT2P, demonstrating notable efficacy in facilitating mitochondrial apoptosis. To develop nanomedicine, we enveloped CTT2P within bovine serum albumin (BSA), resulting in the formulation known as CTT2P@B. The molecular prodrug CTT2P is achieved by covalently conjugating mitochondrial targeting triphenylphosphine (PPh3), photosensitizer TPPOH2, ROS-sensitive thioketal (TK), and chemotherapeutic drug camptothecin (CPT). The prodrug, which is chemically bonded, prevents the escape of drugs while they circulate throughout the body, guaranteeing the coordinated dispersion of both medications inside the organism. Additionally, the concurrent integration of targeted photodynamic therapy and cascade chemotherapy synergistically enhances the therapeutic efficacy of pharmaceutical agents. Experimental results indicated that the covalently attached prodrug significantly mitigated CPT cytotoxicity under dark conditions. In contrast, TPPOH2, CTT2, CTT2P, and CTT2P@B nanoparticles exhibited increasing tumor cell-killing effects and suppressed tumor growth when exposed to light at 660 nm with an intensity of 280 mW cm-2. Consequently, this laser-triggered, mitochondria-targeted, combined photodynamic therapy and chemotherapy nano drug delivery system, adept at efficiently promoting mitochondrial apoptosis, presents a promising and innovative approach to cancer treatment.

T helper 17 (Th17) cell responses to the gut microbiota in human diseases.

The gut microbiota colonizing the gastrointestinal tract, is an indispensable "invisible organ" that affects multiple aspects of human health. The gut microbial community has been assumed to be an important stimulus to the immune homeostasis and development, and increasing data support the role of the gut microbiota-immunity axis in autoimmune diseases. Host's immune system requires recognition tools to communicate with the gut microbial evolutionary partners. Among these microbial perceptions, T cells enable the widest spectrum of gut microbial recognition resolution. Specific gut microbiota direct the induction and differentiation of Th17 cells in intestine. However, the detailed links between the gut microbiota and Th17 cells have not been well established. In this review, we describe the generation and characterization of Th17 cells. Notably, we discuss the induction and differentiation of Th17 cells by the gut microbiota and their metabolites, as well as recent advances in our understanding of interactions between Th17 cells and the gut microbiota in human diseases. In addition, we provide the emerging evidences in support of interventions targeting the gut microbes/Th17 cells in human diseases.