Pathogenic features and clinical characteristics of acute community-acquired lower respiratory tract infections.

Objective: To investigate the pathogen distribution and clinical characteristics of acute community-acquired lower respiratory tract infections (CALRTIs). Methods: This was a retrospective study. The clinical data of 218 patients with CALRTIs admitted to Baoding No.1 Central Hospital from December 2021 to December 2022 were retrospectively collected and were divided into two groups according to the results of polymerase chain reaction(PCR) testing using a nasopharyngeal swab: streptococcus pneumoniae positive group(observation group) and non-streptococcus pneumoniae positive group(control group). Clinical symptoms, blood gas analysis indicators were compared between the two groups. Results: Haemophilus influenzae and Staphylococcus aureus, as well as virus and atypical pathogen infection, were the predominant pathogenic bacteria in both groups. No statistically significant differences were observed in the positive rates of sputum smear, sputum culture, respiratory virus detection and atypical pathogen detection between the two groups(P>0.05). However, the control group had a higher detection rate of gram-positive bacteria, gram-negative bacteria and Legionella pneumophila in sputum smears than the observation group, with a statistically significant difference(P<0.05). One death occurred in each group, with no significant difference in mortality and six in each group left the hospital or were transferred due to deterioration, with no significant difference in improved discharge rates. Conclusion: Acute community-acquired lower respiratory tract infections(CALRTIs) take bacteria, viruses and atypical pathogens as its leading pathogenic bacteria. In the treatment of patients with acute CALRTIs, early pathogenic examination should be performed to assist in guiding antibiotic therapy for rapid control, early recovery and ameliorated clinical outcomes.

PfEMP1 and var genes - Still of key importance in Plasmodium falciparum malaria pathogenesis and immunity.

The most severe form of malaria, caused by infection with Plasmodium falciparum parasites, continues to be an important cause of human suffering and poverty. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of clonally variant antigens, which mediates the adhesion of infected erythrocytes to the vascular endothelium in various tissues and organs, is a central component of the pathogenesis of the disease and a key target of the acquired immune response to malaria. Much new knowledge has accumulated since we published a systematic overview of the PfEMP1 family almost ten years ago. In this chapter, we therefore aim to summarize research progress since 2015 on the structure, function, regulation etc. of this key protein family of arguably the most important human parasite. Recent insights regarding PfEMP1-specific immune responses and PfEMP1-specific vaccination against malaria, as well as an outlook for the coming years are also covered.

Cytosolic serpins act in a cytoprotective feedback loop that limits ESX-1-dependent death of Mycobacterium marinum-infected macrophages.

Serine protease inhibitors (serpins) constitute the largest family of protease inhibitors expressed in humans, but their role in infection remains largely unexplored. In infected macrophages, the mycobacterial ESX-1 type VII secretion system permeabilizes internal host membranes and causes leakage into the cytosol of host DNA, which induces type I interferon (IFN) production via the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) surveillance pathway, and promotes infection in vivo. Using the Mycobacterium marinum infection model, we show that ESX-1-mediated type I IFN signaling in macrophages selectively induces the expression of serpina3f and serpina3g, two cytosolic serpins of the clade A3. The membranolytic activity of ESX-1 also caused leakage of cathepsin B into the cytosol where it promoted cell death, suggesting that the induction of type I IFN comes at the cost of lysosomal rupture and toxicity. However, the production of cytosolic serpins suppressed the protease activity of cathepsin B in this compartment and thus limited cell death, a function that was associated with increased bacterial growth in infected mice. These results suggest that cytosolic serpins act in a type I IFN-dependent cytoprotective feedback loop to counteract the inevitable toxic effect of ESX-1-mediated host membrane rupture. IMPORTANCE: The ESX-1 type VII secretion system is a key virulence determinant of pathogenic mycobacteria. The ability to permeabilize host cell membranes is critical for several ESX-1-dependent virulence traits, including phagosomal escape and induction of the type I interferon (IFN) response. We find that it comes at the cost of lysosomal leakage and subsequent host cell death. However, our results suggest that ESX-1-mediated type I IFN signaling selectively upregulates serpina3f and serpina3g and that these cytosolic serpins limit cell death caused by cathepsin B that has leaked into the cytosol, a function that is associated with increased bacterial growth in vivo. The ability to rupture host membranes is widespread among bacterial pathogens, and it will be of interest to evaluate the role of cytosolic serpins and this type I IFN-dependent cytoprotective feedback loop in the context of human infection.

From pathogenesis to antigens: the key to shaping the future of TB vaccines.

Tuberculosis (TB) remains one of the gravest global health challenges. Mycobacterium tuberculosis (M. tuberculosis), the causative agent, employs sophisticated immune evasion and pathogenesis strategies. Its capability to thrive within immune cells and incite robust inflammatory responses prolongs infection and dissemination. Mycobacterial advanced adaptations facilitate navigation through the human immune system and present a variable antigenic profile throughout different infection stages. Investigating these strategies unfolds targeted approaches to effective vaccine development against TB. This review delves into the most advanced and exhaustive insights into the immune evasion tactics and pathogenic processes of M. tuberculosis across various infection stages. The knowledge distilled from this analysis holds the promise of guiding the creation of innovative TB vaccines and translating theoretical groundwork into practical immunological defenses.

Hepatic microcirculatory disturbance in liver diseases: intervention with traditional Chinese medicine.

The liver, a complex parenchymal organ, possesses a distinctive microcirculatory system crucial for its physiological functions. An intricate interplay exists between hepatic microcirculatory disturbance and the manifestation of pathological features in diverse liver diseases. This review updates the main characteristics of hepatic microcirculatory disturbance, including hepatic sinusoidal capillarization, narrowing of sinusoidal space, portal hypertension, and pathological angiogenesis, as well as their formation mechanisms. It also summarized the detection methods for hepatic microcirculation. Simultaneously, we have also reviewed the characteristics of microcirculatory disturbance in diverse liver diseases such as acute liver failure, hepatic ischemia-reperfusion injury, viral hepatitis, non-alcoholic fatty liver disease, hepatic fibrosis, hepatic cirrhosis, and hepatocellular carcinoma. Finally, this review also summarizes the advancement in hepatic microcirculation attributed to traditional Chinese medicine (TCM) and its active metabolites, providing novel insights into the application of TCM in treating liver diseases.

Research progress of T cell autophagy in autoimmune diseases.

T cells, as a major lymphocyte population involved in the adaptive immune response, play an important immunomodulatory role in the early stages of autoimmune diseases. Autophagy is a cellular catabolism mediated by lysosomes. Autophagy maintains cell homeostasis by recycling degraded cytoplasmic components and damaged organelles. Autophagy has a protective effect on cells and plays an important role in regulating T cell development, activation, proliferation and differentiation. Autophagy mediates the participation of T cells in the acquired immune response and plays a key role in antigen processing as well as in the maintenance of T cell homeostasis. In autoimmune diseases, dysregulated autophagy of T cells largely influences the pathological changes. Therefore, it is of great significance to study how T cells play a role in the immune mechanism of autoimmune diseases through autophagy pathway to guide the clinical treatment of diseases.

Isolation and identification of a novel porcine-related recombinant mammalian orthoreovirus type 3 strain from cattle in Guangxi Province, China.

The Mammalian orthoreovirus (MRV) infects various mammals, including humans, and is linked to gastrointestinal, respiratory, and neurological diseases. A recent outbreak in Liuzhou, Guangxi, China, led to the isolation of a new MRV strain, GXLZ2301, from fecal samples. This strain replicates in multiple cell lines and forms lattice-like structures. Infected cells exhibit single-cell death and syncytia formation. The virus's titers peaked at 107.2 TCID50/0.1 mL in PK-15 and BHK cells, with the lowest at 103.88 TCID50/0.1 mL in A549 cells. Electron microscopy showed no envelope with a diameter of about 70 nm. Genetic analysis revealed GXLZ2301 as a recombinant strain with gene segments from humans, cows, and pigs, similar to type 3 MRV strains from Italy (2015-2016). Pathogenicity tests indicated that while the bovine MRV strain did not cause clinical symptoms in mice, it caused significant damage to the gut, lungs, liver, kidneys, and brain. The emergence of this MRV strain may pose a threat to the health of animals and humans, and it is recommended that its epidemiology and recombination be closely monitored.

Exploring the role of NLRP3 inflammasome in diabetic nephropathy and the advancements in herbal therapeutics.

Diabetic nephropathy (DN), a prevalent complication of diabetes mellitus (DM), is clinically marked by progressive proteinuria and a decline in glomerular filtration rate. The etiology and pathogenesis of DN encompass a spectrum of factors, including hemodynamic alterations, inflammation, and oxidative stress, yet remain incompletely understood. The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a critical component of the body's innate immunity, plays a pivotal role in the pathophysiology of DN by promoting the release of inflammatory cytokines, thus contributing to the progression of this chronic inflammatory condition. Recent studies highlight the involvement of the NLRP3 inflammasome in the renal pathology associated with DN. This article delves into the activation pathways of the NLRP3 inflammasome and its pathogenic implications in DN. Additionally, it reviews the therapeutic potential of traditional Chinese medicine (TCM) in modulating the NLRP3 inflammasome, aiming to provide comprehensive insights into the pathogenesis of DN and the current advancements in TCM interventions targeting NLRP3 inflammatory vesicles. Such insights are expected to lay the groundwork for further exploration into TCM-based treatments for DN.

Potential Roles of Long Non-coding RNAs in the Pathogenesis of Periodontitis: Inflammation Response, Immune Infiltration, Collagen Fibers Synthesis, and Bone Remodeling.

BACKGROUND: It is evident that long non-coding RNAs (lncRNAs) are implicated in the pathogenesis of periodontitis. However, the detailed functional mechanisms remain unknown. OBJECTIVE: This study aimed to elucidate the pathogenic mechanisms of lncRNAs in periodontitis by investigating their regulation of protein-coding gene expression. METHOD: Human Gingival Fibroblasts-1 (HGF-1) were stimulated with 5 µg/mL of Lipopolysaccharide (LPS) for 24 hours to construct the periodontitis cell model. qRTPCR and western blot analyses were carried out to determine mRNA and protein levels of genes induced by LPS or involved in the inflammatory response. Cytokine levels and inflammatory proteins were assayed using ELISA. Transcriptome sequencing and analysis were conducted to reveal the expression signatures of lncRNAs. DESeq2 (v1.4.5) was used to analyze differentially expressed genes. Gene function enrichment was carried out using Phyper. AnimalTFDB v3.0 was used to analyze transcription factors involved in the pathogenesis of periodontitis. Prot\ein domains and families of the target proteins were identified based on the Pfam protein family database. RESULTS: In LPS-treated HGF-1 cells, we detected the secretion of TNF-α and IL-1ß, along with the production of MDA and ROS, indicating that LPS significantly triggered inflammatory responses and oxidative stress in HGF-1 cells. A total of 15,295 lncRNAs were detected in both the control (ConT) and LPS-treated groups. We selected 10 significantly differentially co-expressed lncRNA-coding genes (MIR222HG, SNHG15, SNHG12, URS00005F6AA3, URS00009C153E, URS0000D57D7F, URS00019A4688, URS00019AF240, URS00019C6526, and URS0001A00B79) as potential biomarkers for diagnosing the progression of periodontitis. An interaction network consisting of 2 lncRNA- encoding genes (MIR222HG and SNHG15) and protein-encoding genes (CBX5, NUPR1, CHAC1, and MAB21L3) may be involved in the pathogenesis of periodontitis. The ceRNA network analysis revealed the differentially expressed lncRNAs to be involved in inflammatory response, immune infiltration, collagen fiber synthesis, and bone remodeling in LPS-induced periodontitis. CONCLUSION: This study has identified pivotal molecules implicated in the pathogenesis of periodontitis, including those involved in inflammation regulation, collagen fiber synthesis, and bone remodeling. Our findings may contribute to explaining how lncRNAs participate in the pathological process of periodontitis.

Multi-Drug Resistance and Breast Cancer Progression via Toll-Like Receptors (TLRs) Signaling.

Toll-like receptors (TLRs) are essential receptors involved in inflammation and innate immunity. Various types of cancer cells, as well as innate immune cells, express TLRs. There is mounting proof that TLRs are critical to the development and spread of cancer as well as metabolism. In breast cancer, up-regulated levels of TLRs have been linked to the aggressiveness of the diseases, worse treatment outcomes, and the emergence of therapeutic resistance. Patients with advanced non-resectable, recurring, and metastatic breast cancer currently have few available treatment choices. An intriguing new strategy is an innate immunity-mediated anticancer immunotherapy, either used alone or in conjunction with existing treatments. In fact, several TLR agonists and antagonists have been used in clinical studies for anti-cancer immunotherapy. Consequently, TLRs serve as critical targets for controlling the course of breast cancer and treatment resistance in addition to being implicated in immune responses against pathogen infection and cancer immunology. In this review, we deliver an overview of the most current findings on TLR involvement in the development of breast cancer and treatment resistance.

Current status of Merkel cell carcinoma: Epidemiology, pathogenesis and prognostic factors.

Merkel cell carcinoma (MCC) is an extremely rare cutaneous neuroendocrine cancer, with an incidence approximately 40 times lower than that of malignant melanoma; however, its significantly inferior survival rate compared to melanoma establishes MCC as the most lethal form of skin cancer. In recent years, a substantial body of literature has demonstrated a gradual increase in the incidence of MCC. Although the two factors that contribute to MCC, ultraviolet radiation and Merkel cell polyomavirus infection, have been well established, the specific pathogenesis of this disease remains unclear. Additionally, considering the high lethality and recurrence rates of MCC, as well as the absence of specific antitumor drugs, it is crucial to elucidate the factors that can accurately predict patients' outcomes. In this review, we summarized the significant advancements in the epidemiological characteristics, pathogenesis, and the factors that influence patient prognosis of MCC to enhance clinical practices and public health efforts.

Approaches based on natural products and miRNAs in pituitary adenomas: unveiling therapeutic intervention.

Pituitary adenomas (PAs) are tumors originating in the pituitary gland, a small gland located at the base of the brain. They are the most common type of pituitary tumor, affecting approximately 1 in 10 people over their lifetime. Common symptoms include headaches, vision problems, hormonal imbalances, and weight changes. Treatment options depend on the type and size of the adenoma and may consist of medication, surgery, radiation therapy, or a combination. PAs are typically benign and slow-growing, but they can cause significant health issues if left untreated. Proper diagnosis and management by an experienced multidisciplinary team is important for achieving the best outcomes. Natural compounds like celastrol, curcumin, quercetin, apigenin, resveratrol, epigallocatechin gallate (EGCG), and genistein have shown the ability to inhibit cell growth, promote cell death, and suppress hormone activity in pituitary tumor cells, suggesting their potential as alternative or complementary treatments for PAs. MicroRNAs (miRNAs) are a kind of tiny RNA molecules that do not code for proteins and have a vital function in controlling gene expression. These 21-23 nucleotide-long molecules regulate gene expression by binding to complementary sequences in mRNA molecules, leading to mRNA degradation. miRNAs participate in a wide range of biological activities, including apoptosis, metastasis, differentiation, and proliferation. The research indicates that miRNAs play a crucial role in the pathogenesis, therapeutic approaches, diagnosis, and prognosis of PAs. This review article will provide a comprehensive analysis of the current understanding of the efficacy of naturally derived anti-cancer agents in the treatment of PAs. Furthermore, the study provides a comprehensive assessment of the miRNAs in PAs, their role in the development of PAs, and their potential application in the treatment of the condition.

The Role of Transforming Growth Factor-ß (TGF-ß) in Asthma and Chronic Obstructive Pulmonary Disease (COPD).

Asthma and chronic obstructive pulmonary disease (COPD) represent chronic inflammatory respiratory disorders that, despite having distinct pathophysiological underpinnings, both feature airflow obstruction and respiratory symptoms. A critical component in the pathogenesis of each condition is the transforming growth factor-ß (TGF-ß), a multifunctional cytokine that exerts varying influences across these diseases. In asthma, TGF-ß is significantly involved in airway remodeling, a key aspect marked by subepithelial fibrosis, hypertrophy of the smooth muscle, enhanced mucus production, and suppression of emphysema development. The cytokine facilitates collagen deposition and the proliferation of fibroblasts, which are crucial in the structural modifications within the airways. In contrast, the role of TGF-ß in COPD is more ambiguous. It initially acts as a protective agent, fostering tissue repair and curbing inflammation. However, prolonged exposure to environmental factors such as cigarette smoke causes TGF-ß signaling malfunction. Such dysregulation leads to abnormal tissue remodeling, marked by excessive collagen deposition, enlargement of airspaces, and, thus, accelerated development of emphysema. Additionally, TGF-ß facilitates the epithelial-to-mesenchymal transition (EMT), a process contributing to the phenotypic alterations observed in COPD. A thorough comprehension of the multifaceted role of TGF-ß in asthma and COPD is imperative for elaborating precise therapeutic interventions. We review several promising approaches that alter TGF-ß signaling. Nevertheless, additional studies are essential to delineate further the specific mechanisms of TGF-ß dysregulation and its potential therapeutic impacts in these chronic respiratory diseases.

Murine Models of Secondary Cytokine Storm Syndromes.

Hemophagocytic lymphohistiocytosis (HLH) comprises a broad spectrum of life-threatening cytokine storm syndromes, classified into primary (genetic) or secondary (acquired) HLH. The latter occurs in a variety of medical conditions, including infections, malignancies, autoimmune and autoinflammatory diseases, acquired immunodeficiency, and metabolic disorders. Despite recent advances in the field, the pathogenesis of secondary HLH remains incompletely understood. Considering the heterogeneity of triggering factors and underlying diseases in secondary HLH, a large diversity of animal models has been developed to explore pivotal disease mechanisms. To date, over 20 animal models have been described that each recapitulates certain aspects of secondary HLH. This review provides a comprehensive overview of the existing models, highlighting relevant findings, discussing the involvement of different cell types and cytokines in disease development and progression, and considering points of interest toward future therapeutic strategies.

[The role of ozone in the pathogenesis of allergic rhinitis].

Allergic rhinitis （AR） is a nasal hypersensitivity disease that is influenced by environmental factors, genetic factors, and various inflammatory factors. The role and mechanisms of ozone, as a component of air pollution, in the pathogenesis of AR are not yet fully understood. This article provides a review of the impact of ozone on the epidemiology and pathology of AR, as well as its possible mechanisms, to provide new insights into the prevention and treatment of AR.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine.

Genome sequencing has revealed frequent mutations in Ras homolog family member A (RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma (PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Differential changes in mast cells with food reintroduction in children with Eosinophilic Esophagitis.

BACKGROUND: Intraepithelial mast cells (MC) are increased in Eosinophilic Esophagitis (EoE) and reduced with elimination of dietary antigens. Single food reintroduction can identify triggers of eosinophilia however it remains unknown the extent to which specific foods trigger intraepithelial mastocytosis. We hypothesized that specific foods drive different degrees of MC inflammation. METHODS: We previously reported a prospective pediatric EoE cohort treated with a 4-food elimination diet (4FED) with removal of soy, egg, wheat, milk. We retrieved unstained slides in which baseline, 4FED, and post-4FED diet reintroduction time points were available. Slides were stained with tryptase, and intraepithelial MCs were counted. Comparisons were made by stratifying patients by eosinophilia, basal cell hyperplasia (BCH), endoscopic abnormalities, and symptoms. Pearson correlation was assessed for MCs with eosinophilic, endoscopic and BCH severity, symptoms, and a novel mucosal activity score (MAS) combining endoscopic and histologic structural severity. RESULTS: Slides were available from 37 patients with at least 1 food reintroduced. MCs were significantly reduced with 4FED. Wheat led to increased intraepithelial MCs in the upper esophagus and with food-induced eosinophilia, while milk led to significantly increased MCs in the upper and lower esophagus and was significantly associated with patients with food-triggered eosinophilia, endoscopic abnormalities, BCH, and symptoms. MCs best correlated with the MAS during milk reintroduction. CONCLUSION: In children with EoE, MCs are reduced with 4FED. During milk reintroduction, significant increases in MCs were observed with all metrics of inflammation along with moderate correlation with structural mucosal activity that was not seen with other foods. This suggests milk exerts unique effects either directly or indirectly on MCs in the esophagus in EoE patients.

The molecular mechanisms that underlie IGHMBP2-related diseases.

Immunoglobulin Mu-binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot-Marie-Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2-related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2-related disease and highlight the most prominent ones.

The plasmid-encoded members of paralogous gene family 52 are dispensable to the enzootic cycle of Borrelia burgdorferi.

Lyme disease, the leading vector-borne disease in the United States and Europe, develops after infection with Borrelia burgdorferi sensu lato bacteria. Transmission of the spirochete from the tick vector to a vertebrate host requires global changes in gene expression that are controlled, in part, by the Rrp2/RpoN/RpoS alternative sigma factor cascade. Transcriptional studies defining the B. burgdorferi RpoS regulon have suggested that RpoS activates the transcription of paralogous family 52 (PFam52) genes. In strain B31, PFam52 genes (bbi42, bbk53, and bbq03) encode a set of conserved hypothetical proteins with >89% amino acid identity that are predicted to be surface-localized. Extensive homology among members of paralogous families complicates studies of protein contributions to pathogenicity as the potential for functional redundancy will obfuscate findings. Using a sequential mutagenesis approach, we generated clones expressing a single PFam52 paralog, as well as a strain deficient in all three. The single paralog expressing strains were used to confirm BBI42, BBK53, and BBQ03 surface localization and RpoS regulation. Surprisingly, the PFam52-deficient strain was able to infect mice and complete the enzootic cycle similar to the wild-type parental strain. Indeed, the presence of numerous pseudogenes that contain frameshifts or internal stop codons among the PFam52 genes suggests that they may be subjected to gene loss in B. burgdorferi's reduced genome. Alternatively, the lack of phenotype might reflect the limitations of the experimental mouse infection model.