PRDX1 Interfering Peptide Disrupts Amino Acids 70-90 of PRDX1 to Inhibit the TLR4/NF-κB Signaling Pathway and Attenuate Neuroinflammation and Ischemic Brain Injury.

Ischemic stroke ranks among the leading causes of death and disability in humans and is accompanied by motor and cognitive impairment. However, the precise mechanisms underlying injury after stroke and effective treatment strategies require further investigation. Peroxiredoxin-1 (PRDX1) triggers an extensive inflammatory cascade that plays a pivotal role in the pathology of ischemic stroke, resulting in severe brain damage from activated microglia. In the present study, we used molecular dynamics simulation and nuclear magnetic resonance to detect the interaction between PRDX1 and a specific interfering peptide. We used behavioral, morphological, and molecular experimental methods to demonstrate the effect of PRDX1-peptide on cerebral ischemia-reperfusion (I/R) in mice and to investigate the related mechanism. We found that PRDX1-peptide bound specifically to PRDX1 and improved motor and cognitive functions in I/R mice. In addition, pretreatment with PRDX1-peptide reduced the infarct area and decreased the number of apoptotic cells in the penumbra. Furthermore, PRDX1-peptide inhibited microglial activation and downregulated proinflammatory cytokines including IL-1ß, IL-6, and TNF-α through inhibition of the TLR4/NF-κB signaling pathway, thereby attenuating ischemic brain injury. Our findings clarify the precise mechanism underlying PRDX1-induced inflammation after ischemic stroke and suggest that the PRDX1-peptide can significantly alleviate the postischemic inflammatory response by interfering with PRDX1 amino acids 70-90 and thereby inhibiting the TLR4/NF-κB signaling pathway. Our study provides a theoretical basis for a new therapeutic strategy to treat ischemic stroke.

Proteome-wide Mendelian randomization identifies potential therapeutic targets for nonalcoholic fatty liver diseases.

Nonalcoholic fatty liver disease (NAFLD) is the predominant cause of liver pathology. Current evidence highlights plasma proteins as potential therapeutic targets. However, their mechanistic roles in NAFLD remain unclear. This study investigated the involvement of specific plasma proteins and intermediate risk factors in NAFLD progression. Two-sample Mendelian randomization (MR) analysis was conducted to examine the association between plasma proteins and NAFLD. Colocalization analysis determined the shared causal variants between the identified proteins and NAFLD. The MR analysis was applied separately to proteins, risk factors, and NAFLD. Mediator shares were computed by detecting the correlations among these elements. Phenome-wide association studies (phewas) were utilized to assess the safety implications of targeting these proteins. Among 1,834 cis-protein quantitative trait loci (cis-pQTLs), after-FDR correction revealed correlations between the plasma levels of four gene-predicted proteins (CSPG3, CILP2, Apo-E, and GCKR) and NAFLD. Colocalization analysis indicated shared causal variants for CSPG3 and GCKR in NAFLD (posterior probability > 0.8). Out of the 22 risk factors screened for MR analysis, only 8 showed associations with NAFLD (p ≤ 0.05), while 4 linked to CSPG3 and GCKR. The mediator shares for these associations were calculated separately. Additionally, reverse MR analysis was performed on the pQTLs, risk factors, and NAFLD, which exhibited a causal relationship with forward MR analysis. Finally, phewas summarized the potential side effects of associated-targeting proteins, including CSPG3 and GCKR. Our research emphasized the potential therapeutic targets for NAFLD and provided modifiable risk factors for preventing NAFLD.

RNA-binding protein QKI promotes the progression of HCC by interacting with long non-coding RNA EGOT.

BACKGROUND: RNA-binding proteins are revealed to play important roles during the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanisms of RNA-binding protein Quaking (QKI) in the expression and role of long non-coding RNAs (lncRNAs) in HCC cells remain not well understood. METHODS: Cell Counting Kit-8, wound-healing, Transwell and colony-forming assays were performed to evaluate the effects of QKI and lncRNA EGOT on proliferation and migration of HCC cells. Tumor growth of HCC was analyzed using a mouse xenograft model. Immunoprecipitation (RIP) assay was used to investigate the interaction between QKI and EGOT. RESULTS: The expression of QKI was significantly upregulated in HCC tissues and the higher QKI level was significantly associated with a poorer prognosis. Overexpression of QKI promoted the proliferation, migration, and colony-forming ability of HCC cells in vitro and tumor growth of HCC in vivo. Mechanistically, QKI protein could bind to EGOT RNA and increase its expression. Inhibition of EGOT attenuated the effects of QKI on the malignant phenotypes of HCC cells. In addition, both QKI and EGOT could activate the SAPK/JNK signaling pathway in HCC cells. CONCLUSIONS: Our findings indicated that QKI exerted promotive effects on the malignant phenotypes of HCC through its interaction with EGOT.

A general strategy for all-solid-state batteries with agglomeration-free and high conductivity achieved by improving the interface compatibility of fillers and polymer matrix.

Composite solid electrolytes (CSEs) composed of polymer matrix and inorganic fillers show considerable potential for applications in all-solid-state lithium (Li) metal batteries. However, challenges such as fillers agglomeration and low lithium ion transference number (tLi+) remain significant obstacles to the practical application of CSEs. Herein, a general strategy of graft polymerization on the fillers surface to modulate the interface compatibility with the polymer matrix is proposed, and CSEs are prepared to verify the feasibility. The microstructure and composition of the surface coating of the fillers are analyzed, with subsequent studies of the fillers distribution within the CSEs confirming the improved interface compatibility. The enhancement of interface compatibility facilitates uniform dispersion of fillers, thereby greatly improving the utilization of fillers. CSEs exhibits high ionic conductivity (0.163 mS·cm-1 at 30 °C) and tLi+ (0.77), which gives the battery excellent rate performance and cycle stability. Therefore, chemical grafting of polymer onto the fillers surface to enhance the interface compatibility with the polymer matrix represents a promising strategy for the practical application of solid-state batteries.

[A new cucurbitane glycoside from Picrorhiza scrophulariiflora].

Chemical constituents from the ethanol extract of Picrorhiza scrophulariiflora were isolated and purified by column chromatography. Their structures were identified by HR-MS, 1D and 2D-NMR, and their cytotoxicity was assessed by CCK-8 assay. Four compounds were isolated and identified as follows: 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosterol-5,25-diene-22-one(1), 2ß-D-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,24-diene-22-one(2), 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5-ene-22-one(3) and 25-acetoxy-2ß-glucosyloxy-3ß,16α,20ß-trihydroxy-9-methyl-19-norlanosta-5,23-(E)-diene-22-one(4). Compound 1 represents a new cucurbitane glycoside. The half inhibitory concentrations of the 4 compounds exceeded 100 µmol·L~(-1) against four tumor cell lines, indicating no significant cytotoxicity.

Lycopene Protects against Atrazine-Induced Kidney STING-Dependent PANoptosis through Stabilizing mtDNA via Interaction with Sam50/PHB1.

Atrazine (ATR) is a widely used herbicide worldwide that can cause kidney damage in humans and animals by accumulation in water and soil. Lycopene (LYC), a carotenoid with numerous biological activities, plays an important role in kidney protection due to its potent antioxidant and anti-inflammatory effects. The current study sought to investigate the role of interactions between mtDNA and the cGAS-STING signaling pathway in LYC mitigating PANoptosis and inflammation in kidneys induced by ATR exposure. In our research, 350 mice were orally administered LYC (5 mg/kg BW/day) and ATR (50 or 200 mg/kg BW/day) for 21 days. Our results reveal that ATR exposure induces a decrease in mtDNA stability, resulting in the release of mtDNA into the cytoplasm through the mPTP pore and the BAX pore and the mobilization of the cGAS-STING pathway, thereby inducing renal PANoptosis and inflammation. LYC can inhibit the above changes caused by ATR. In conclusion, LYC inhibited ATR exposure-induced histopathological changes, renal PANoptosis, and inflammation by inhibiting the cGAS-STING pathway. Our results demonstrate the positive role of LYC in ATR-induced renal injury and provide a new therapeutic target for treating renal diseases in the clinic.

Self-sacrificing-induced defect enhances the oxidase-like activity of MnOOH for total antioxidant capacity evaluation.

Nanozymes is a kind of nanomaterials with enzyme catalytic properties. Compared with natural enzymes, nanozymes merge the advantages of both nanomaterials and natural enzymes, which is highly important in applications such as biosensing, clinical diagnosis, and food inspection. In this study, we prepared ß-MnOOH hexagonal nanoflakes with a high oxygen vacancy ratio by utilizing SeO2 as a sacrificial agent. The defect-rich MnOOH hexagonal nanoflakes demonstrated excellent oxidase-like activity, catalyzing the oxidation substrate in the presence of O2, thereby rapidly triggering a color reaction. Consequently, a colorimetric sensing platform was constructed to assess the total antioxidant capacity in commercial beverages. The strategy of introducing defects in situ holds great significance for the synthesis of a series of high-performance metal oxide nanozymes, driving the development of faster and more efficient biosensing and analysis methods.

Melatonin Mitigates Atrazine-Induced Renal Tubular Epithelial Cell Senescence by Promoting Parkin-Mediated Mitophagy.

The accumulation of senescent cells in kidneys is considered to contribute to age-related diseases and organismal aging. Mitochondria are considered a regulator of cell senescence process. Atrazine as a triazine herbicide poses a threat to renal health by disrupting mitochondrial homeostasis. Melatonin plays a critical role in maintaining mitochondrial homeostasis. The present study aims to explore the mechanism by which melatonin alleviates atrazine-induced renal injury and whether parkin-mediated mitophagy contributes to mitigating cell senescence. The study found that the level of parkin was decreased after atrazine exposure and negatively correlated with senescent markers. Melatonin treatment increased serum melatonin levels and mitigates atrazine-induced renal tubular epithelial cell senescence. Mechanistically, melatonin maintains the integrity of mitochondrial crista structure by increasing the levels of mitochondrial contact site and cristae organizing system, mitochondrial transcription factor A (TFAM), adenosine triphosphatase family AAA domain-containing protein 3A (ATAD3A), and sorting and assembly machinery 50 (Sam50) to prevent mitochondrial DNA release and subsequent activation of cyclic guanosine 5'-monophosphate-adenosine 5'-monophosphate synthase pathway. Furthermore, melatonin activates Sirtuin 3-superoxide dismutase 2 axis to eliminate the accumulation of reactive oxygen species in the kidney. More importantly, the antisenescence role of melatonin is largely determined by the activation of parkin-dependent mitophagy. These results offer novel insights into measures against cell senescence. Parkin-mediated mitophagy is a promising drug target for alleviating renal tubular epithelial cell senescence.

Proline inhibits postharvest physiological deterioration of cassava by improving antioxidant capacity.

Cassava (Manihot esculenta Crantz), a crucial global tuber crop, encounters significant economic losses attributed to postharvest physiological deterioration (PPD). The PPD phenomenon in cassava is closely related to the accumulation of reactive oxygen species (ROS), and amino acids play a pivotal role in regulating signaling pathways and eliminating ROS. In this study, the storage performance of eight cassava varieties were conducted. Cassava cultivar SC5 showed the best storage performance among the eight cassava varieties, but the edible cassava cultivar SC9 performed much worse. Comparative analysis of free amino acids was conducted in eight cassava varieties, revealing changes in proline, aspartic acid, histidine, glutamic acid, threonine, and serine. Exogenous supplementation of these six amino acids was performed to inhibit PPD of SC9. Proline was confirmed as the key amino acid for inhibiting PPD. Treatment with optimal exogenous proline of 5 g/L resulted in a 17.9% decrease in the deterioration rate compared to untreated cassava. Accompanied by a decrease in H2O2 content and an increase in catalase, superoxide dismutase and ascorbate peroxidase activity. Proline treatment proved to be an effective approach to alleviate cell oxidative damage, inhibit PPD in cassava, and prolong shelf life.

Oxidized sodium alginate hydrogel-mouse nerve growth factor sustained release system promotes repair of peripheral nerve injury.

In recent years, mouse nerve growth factor (mNGF) has emerged as an important biological regulator to repair peripheral nerve injury, but its systemic application is restricted by low efficiency and large dosage requirement. These limitations prompted us to search for biomaterials that can be locally loaded. Oxidized sodium alginate hydrogel (OSA) exhibits good biocompatibility and physicochemical properties, and can be loaded with drugs to construct a sustained-release system that can act locally on nerve injury. Here, we constructed a sustained-release system of OSA-mouse nerve growth factor (mNGF), and investigated the loading and release of the drug through Fourier transform infrared spectroscopy and drug release curves. In vitro and in vivo experiments showed that OSA-mNGF significantly promoted the biological activities of RSC-96 cells and facilitated the recovery from sciatic nerve crush injury in rats. This observation may be attributed to the additive effect of OSA on promoting Schwann cell biological activities or its synergistic effect of cross-activating phosphoinositide 3-kinase (PI3K) through extracellular signal regulated kinase (ERK) signaling. Although the specific mechanism of OSA action needs to be explored in the future, the current results provide a valuable preliminary research basis for the clinical application of the OSA-mNGF sustained-release system for nerve repair.

Maintaining ideal cardiovascular health is associated with higher serum anti-aging protein klotho in the middle-aged and older populations.

OBJECTIVES: Maintaining ideal cardiovascular health (CVH) is believed to have potential anti-aging benefits. The American Heart Association (AHA) recently updated the "Life's Essential 8 (LE8)" metrics to measure ideal CVH, but its connection with the anti-aging protein klotho is still unclear. We aimed to explore the relationship between ideal cardiovascular health and serum anti-aging protein klotho in a nationally representative US middle-aged and older population. DESIGN: A cross-sectional study. SETTING: The National Health and Nutrition Examination Survey (2007-2016). PARTICIPANTS: A total of 9457 middle-aged and older participants. MEASUREMENTS: Ideal CVH scores and their components were defined according to the guidelines set by the AHA. Serum klotho detected by enzyme-linked immunosorbent assay. Weighted multivariable linear regression and restricted cubic spline were employed to examine the association between CVH score and klotho. Subgroup analyses were conducted, stratified by age (40-59 and 60-79), sex (Male and Female), race (Mexican American, non-Hispanic White, non-Hispanic Black, and Others) and chronic kidney disease (Yes and No) in fully adjusted models. RESULTS: A total of 9457 middle-aged and older participants were included in this study, with a mean age of 55.27 ± 0.17 years. The mean serum klotho level in the population was 849.33 ± 5.39 pg/mL. After controlling for potential confounders, the LE8 score showed a positive correlation with serum klotho levels (ß: 1.32; 95% CI 0.73, 1.91), and a non-linear dose-response relationship was observed. Furthermore, we also discovered a positive relationship between health behaviors score and health factors score and serum klotho levels (ß: 0.48; 95% CI 0.07, 0.88 and ß: 1.05; 95% CI 0.54, 1.56, respectively), particularly a stronger correlation between health factors and serum klotho. In the subgroup analysis, we observed a significant interaction between LE8 score and sex and race. (P for interaction <0.05). CONCLUSIONS: LE8 and its subscale scores were positively associated with serum klotho levels in the middle-aged and older populations. Promoting the maintenance of ideal CVH can contribute to delaying the aging process.

Soil microbial community are more sensitive to ecological regions than cropping systems in alpine annual grassland of the Qinghai-Tibet Plateau.

Introduction: Modern agriculture emphasizes the design of cropping systems using ecological function and production services to achieve sustainability. The functional characteristics of plants (grasses vs. legumes) affect changes in soil microbial communities that drive agroecosystem services. Information on the relationship between legume-grass mixtures and soil microorganisms in different ecological zones guides decision-making toward eco-friendly and sustainable forage production. However, it is still poorly understood how cropping patterns affect soil microbial diversity in alpine grasslands and whether this effect varies with altitude. Methods: To fill this gap in knowledge, we conducted a field study to investigate the effects of growing oats (Avena sativa L.), forage peas (Pisum sativum L.), common cornflower (Vicia sativa L.), and fava beans (Vicia faba L.) in monocultures and mixtures on the soil microbial communities in three ecological zones of the high alpine zone. Results: We found that the fungal and bacterial community structure differed among the cropping patterns, particularly the community structure of the legume mixed cropping pattern was very different from that of monocropped oats. In all ecological zones, mixed cropping significantly (p < 0.05) increased the α-diversity of the soil bacteria and fungi compared to oat monoculture. The α-diversity of the soil bacteria tended to increase with increasing elevation (MY [2,513 m] < HZ [2,661 m] < GN [3,203 m]), while the opposite was true for fungi (except for the Chao1 index in HZ, which was the lowest). Mixed cropping increased the abundance of soil fungi and bacteria across ecological zones, particularly the relative abundances of Nitrospira, Nitrososphaera, Phytophthora, and Acari. Factors affecting the bacterial community structure included the cropping pattern, the ecological zone, water content, nitrate-nitrogen, nitrate reductase, and soil capacity, whereas factors affecting fungal community structure included the cropping pattern, the ecological zone, water content, pH, microbial biomass nitrogen, and catalase. Discussion: Our study highlights the variation in soil microbial communities among different in alpine ecological regions and their resilience to cropping systems. Our results also underscore that mixed legume planting is a sustainable and effective forage management practice for the Tibetan Plateau.

Genome-wide characterization of TCP family and their potential roles in abiotic stress resistance of oat (Avena sativa L.).

The TCP gene family members play multiple functions in plant growth and development and were named after the first three family members found in this family, TB1 (TEOSINTE BRANCHED 1), CYCLOIDEA (CYC), and Proliferating Cell Factor 1/2 (PCF1/2). Nitrogen (N) is a crucial element for forage yield; however, over-application of N fertilizer can increase agricultural production costs and environmental stress. Therefore, the discovery of low N tolerance genes is essential for the genetic improvement of superior oat germplasm and ecological protection. Oat (Avena sativa L.), is one of the world's staple grass forages, but no genome-wide analysis of TCP genes and their roles in low-nitrogen stress has been performed. This study identified the oat TCP gene family members using bioinformatics techniques. It analyzed their phylogeny, gene structure analysis, and expression patterns. The results showed that the AsTCP gene family includes 49 members, and most of the AsTCP-encoded proteins are neutral or acidic proteins; the phylogenetic tree classified the AsTCP gene family members into three subfamilies, and each subfamily has different conserved structural domains and functions. In addition, multiple cis-acting elements were detected in the promoter of the AsTCP genes, which were associated with abiotic stress, light response, and hormone response. The 49 AsTCP genes identified from oat were unevenly distributed on 18 oat chromosomes. The results of real-time quantitative polymerase chain reaction (qRT-PCR) showed that the AsTCP genes had different expression levels in various tissues under low nitrogen stress, which indicated that these genes (such as AsTCP01, AsTCP03, AsTCP22, and AsTCP38) played multiple roles in the growth and development of oat. In conclusion, this study analyzed the AsTCP gene family and their potential functions in low nitrogen stress at the genome-wide level, which lays a foundation for further analysis of the functions of AsTCP genes in oat and provides a theoretical basis for the exploration of excellent stress tolerance genes in oat. This study provides an essential basis for future in-depth studies of the TCP gene family in other oat genera and reveals new research ideas to improve gene utilization.

Increased Cyclic Guanosine Monophosphate and Interleukin-1Beta Is Activated by Mitochondrial Dysfunction and Associated With Heart Failure in Atrial Fibrillation Patients.

Background: This study aimed to identify the association of cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator interferon genes (cGAS-STING) pathway with heart failure (HF) in atrial fibrillation (AF) patients. Methods: We prospectively enrolled 106 AF patients without evidence of HF. The serum levels of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) and interleukin (IL)-1ß were measured by enzyme-linked immunoassay (ELISA). To determine the underlying mechanism, we supplemented the complex I inhibitor rotenone and the specific cGAS inhibitor RU.521 in neonatal rat ventricular cardiomyocytes. Results: During 18-month follow-up, serum concentrations of 2'3'-cGAMP (baseline 51.82 ± 11.34 pg/mL vs. follow-up 124.50 ± 75.83 pg/mL, Ppaired t < 0.01) and IL-1ß (baseline 436.07 ± 165.82 vs. follow-up 632.48 ± 119.25 ng/mL, Ppaired t < 0.01) were substantially upregulated in AF patients with HF as compared with those without HF. Furthermore, serum 2'3'-cGAMP and IL-1ß levels at 18-month follow-up were independently associated with the occurrence of HF in AF patients. Inhibition of cGAS by RU.521 effectively reversed the upregulation of 2'3'-cGAMP and STING phosphorylation induced by mitochondrial dysfunction, accompanied with inhibition of nod-like receptor protein 3 (NLRP3) inflammasome, IL-1ß and IL-18 secretion. Conclusions: Induction of mitochondrial dysfunction causes an upregulation of 2'3'-cGAMP and activation of NLRP3 inflammasome through cGAS-STING pathway in cardiomyocytes.

Mesenchymal stem cells promote ovarian reconstruction in mice.

BACKGROUND: Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex cryopreservation is a good choice to preserve female fertility before cancer treatment. Following the remission of the disease, the thawed ovarian tissue can be transplanted back and restore fertility of the patient. However, there is a risk to reintroduce cancer cells in the body and leads to the recurrence of cancer. Given the low success rate of current in vitro culture techniques for obtaining mature oocytes from primordial follicles, an artificial ovary with primordial follicles may be a good way to solve this problem. METHODS: In the study, we established an artificial ovary model based on the participation of mesenchymal stem cells (MSCs) to evaluate the effect of MSCs on follicular development and oocyte maturation. P2.5 mouse ovaries were digested into single cell suspensions and mixed with bone marrow derived mesenchymal stem cells (BM-MSCs) at a 1:1 ratio. The reconstituted ovarian model was then generated by using phytohemagglutinin. The phenotype and mechanism studies were explored by follicle counting, immunohistochemistry, immunofluorescence, in vitro maturation (IVM), in vitro fertilization (IVF), real-time quantitative polymerase chain reaction (RT-PCR), and Terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL) assay. RESULTS: Our study found that the addition of BM-MSCs to the reconstituted ovary can enhance the survival of oocytes and promote the growth and development of follicles. After transplanting the reconstituted ovaries under kidney capsules of the recipient mice, we observed normal folliculogenesis and oocyte maturation. Interestingly, we found that BM-MSCs did not contribute to the formation of follicles in ovarian aggregation, nor did they undergo proliferation during follicle growth. Instead, the cells were found to be located around growing follicles in the reconstituted ovary. When theca cells were labeled with CYP17a1, we found some overlapped staining with green fluorescent protein(GFP)-labeled BM-MSCs. The results suggest that BM-MSCs may participate in directing the differentiation of theca layer in the reconstituted ovary. CONCLUSIONS: The presence of BM-MSCs in the artificial ovary was found to promote the survival of ovarian cells, as well as facilitate follicle formation and development. Since the cells didn't proliferate in the reconstituted ovary, this discovery suggests a potential new and safe method for the application of MSCs in clinical fertility preservation by enhancing the success rate of cryo-thawed ovarian tissues after transplantation.

Folate-PEG-PROTAC Micelles for Enhancing Tumor-Specific Targeting Proteolysis In Vivo.

Proteolysis targeting chimeras (PROTACs) technology is rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting, and low efficacy in vivo. Herein, self-assembling micelles of FA-PEG-PROTAC are designed for cancer cell selective targeting and reductive-response proteolysis in tumor-bearing mice. FA-PEG-PROTAC is prepared by conjugating folic acid (FA)-PEG with EGFR-targeting PROTAC via a disulfide bond. The FA-PEG-PROTAC micelles, formed by self-assembling, are demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti-tumor efficacy in the mouse xenograft model compared to the traditional PROTACs. The strategy of applying self-assembled FA-PEG-PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but also broaden applications in the development of PROTAC-based drugs.

Epidemiology, pathogenesis, immune evasion mechanism and vaccine development of porcine Deltacoronavirus.

Coronaviruses have been identified as pathogens of gastrointestinal and respiratory diseases in humans and various animal species. In recent years, the global spread of new coronaviruses has had profound influences for global public health and economies worldwide. As highly pathogenic zoonotic viruses, coronaviruses have become the focus of current research. Porcine Deltacoronavirus (PDCoV), an enterovirus belonging to the family of coronaviruses, has emerged on a global scale in the past decade and significantly influenced the swine industry. Moreover, PDCoV infects not only pigs but also other species, including humans, chickens and cattles, exhibiting a broad host tropism. This emphasizes the need for in-depth studies on coronaviruses to mitigate their potential threats. In this review, we provided a comprehensive summary of the current studies on PDCoV. We first reviewed the epidemiological investigations on the global prevalence and distribution of PDCoV. Then, we delved into the studies on the pathogenesis of PDCoV to understand the mechanisms how the virus impacts its hosts. Furthermore, we also presented some exploration studies on the immune evasion mechanisms of the virus to enhance the understanding of host-virus interactions. Despite current limitations in vaccine development for PDCoV, we highlighted the inhibitory effects observed with certain substances, which offers a potential direction for future research endeavors. In conclusion, this review summarized the scientific findings in epidemiology, pathogenesis, immune evasion mechanisms and vaccine development of PDCoV. The ongoing exploration of potential vaccine candidates and the insights gained from inhibitory substances have provided a solid foundation for future vaccine development to prevent and control diseases associated with PDCoV.

Role of Type VI secretion system in pathogenic remodeling of host gut microbiota during Aeromonas veronii infection.

Intestinal microbial disturbance is a direct cause of host disease. The bacterial Type VI secretion system (T6SS) often plays a crucial role in the fitness of pathogenic bacteria by delivering toxic effectors into target cells. However, its impact on the gut microbiota and host pathogenesis is poorly understood. To address this question, we characterized a new T6SS in the pathogenic Aeromonas veronii C4. First, we validated the secretion function of the core machinery of A. veronii C4 T6SS. Second, we found that the pathogenesis and colonization of A. veronii C4 is largely dependent on its T6SS. The effector secretion activity of A. veronii C4 T6SS not only provides an advantage in competition among bacteria in vitro, but also contributes to occupation of an ecological niche in the nutritionally deficient and anaerobic environment of the host intestine. Metagenomic analysis showed that the T6SS directly inhibits or eliminates symbiotic strains from the intestine, resulting in dysregulated gut microbiome homeostasis. In addition, we identified three unknown effectors, Tse1, Tse2, and Tse3, in the T6SS, which contribute to T6SS-mediated bacterial competition and pathogenesis by impairing targeted cell integrity. Our findings highlight that T6SS can remodel the host gut microbiota by intricate interplay between T6SS-mediated bacterial competition and altered host immune responses, which synergistically promote pathogenesis of A. veronii C4. Therefore, this newly characterized T6SS could represent a general interaction mechanism between the host and pathogen, and may offer a potential therapeutic target for controlling bacterial pathogens.

Comparison of Locking Plate Alone and Locking Plate Combined with 3D Printed Polymethylmethacrylate Augmentation in Treating Proximal Humerus Fractures in the Elderly.

BACKGROUND: Locking plates are widely used in open reduction internal fixation (ORIF) for proximal humeral fracture (PHF). However, the optimal surgical treatment of unstable, displaced PHF in elderly patients remains controversial. This study aimed to compare the radiological and clinical outcomes of surgical treatment of PHF in the elderly with locking plate (LP) alone and locking plate combined with 3D printed polymethylmethacrylate (PMMA) prosthesis augmentation (LP-PA). METHODS: From May 2015 to April 2021, a total of 97 patients aged ≥ 60 years with acute unstable PHF who underwent osteosynthesis with either LP (46 patients) or LP-PA (51 patients) were retrospectively analyzed. For the LP-PA group, a customized proximal humeral prosthesis made of PMMA cement was intra-operatively fabricated by a three-dimensional (3D) printed prototype mold for the humeral medial support. Radiological outcomes were analyzed by measuring the value of neck-shaft angle (NSA) and humeral head height (HHH). The clinical outcomes were evaluated using Constant-Murley Score (CMS), Disabilities of the Arm Shoulder and Hand (DASH) score, American Shoulder and Elbow Surgeons (ASES) score, and the shoulder range of motion (ROM). Pain was measured using a visual analogue scale (VAS). RESULTS: At the one-year follow-up, all fractures healed radiologically and clinically. The mean changes of NSA and HHH over the follow-up period were markedly smaller in the LP-PA group (3.8 ± 0.9° and 1.7 ± 0.3 mm) than those in the LP group (9.7 ± 2.1° and 3.2 ± 0.6 mm, both P < 0.0001). The LP-PA group also presented lower DASH score (17.1 ± 3.6), higher ASES score (89.5 ± 11.2) and better ROM in forward elevation (142 ± 26°) and external rotation (59 ± 11°) compared to the LP group (28.9 ± 4.8 for DASH score, P < 0.0001; 82.3 ± 9.0 for ASES score, P < 0.001; 129 ± 21° for forward elevation, P = 0.008; and 52 ± 9° for external rotation, P = 0.001). There was no significant difference in overall complication rate between the two groups, although the complication rate of screw perforation was higher in the LP-PA group (P = 0.172). CONCLUSIONS: For PHF in elderly patients, the combination of LP fixation and PMMA prosthesis augmentation effectively improved humeral head support and reduction maintenance, providing satisfactory outcomes both radiologically and clinically. This technique also reduced the incidence of screw perforation associated with plate fixation alone, making it a reasonable option to ensure satisfactory clinical outcomes.