Line Of Defense Research Articles

Significance of host antimicrobial peptides in the pathogenesis and treatment of acne vulgaris

Acne vulgaris (AV) is a chronic inflammatory condition of the pilosebaceous units characterized by multiple immunologic, metabolic, hormonal, genetic, psycho-emotional dysfunctions, and skin microbiota dysbiosis. The latter is manifested by a decreased population (phylotypes, i.e., genetically distinct bacterial subgroups that play different roles in skin health and disease) diversity of the predominant skin bacterial commensal - Cutinbacterium acnes. Like in other dysbiotic disorders, an elevated expression of endogenous antimicrobial peptides (AMPs) is a hallmark of AV. AMPs, such as human β-defensins, cathelicidin LL-37, dermcidin, or RNase-7, due to their antibacterial and immunomodulatory properties, function as the first line of defense and coordinate the host-microbiota interactions. Therefore, AMPs are potential candidates for pharmaceutical prophylaxis or treating this condition. This study outlines the current knowledge regarding the importance of AMPs in AV pathomechanism in light of recent transcriptomic studies. In particular, their role in improving the tight junctions (TJs) skin barrier by activating the fundamental cellular proteins, such as PI3K, GSK-3, aPKC, and Rac1, is discussed. We hypothesized that the increased expression of AMPs and their patterns in AV act as a compensatory mechanism to protect the skin with an impaired permeability barrier. Therefore, AMPs could be key determinants in regulating AV development and progression, linking acne-associated immune responses and metabolic factors, like insulin/IGF-1 and PI3K/Akt/mTOR/FoxO1 signaling pathways or glucotoxicity. Research and development of anti-acne AMPs are also addressed.

STING exerts antiviral innate immune response by activating pentose phosphate pathway

BackgroundThe innate immune system serves as the host’s first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.MethodsMetabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.ResultsIn this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.ConclusionOur findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.

The cGAS-STING pathway in ischemia-reperfusion injury in acute cerebral infarction: a new therapeutic opportunities?

The innate immune response is the body's first line of defense against external pathogens and endogenous damage signals. The cGAS-STING pathway is a crucial component of the innate immune response, playing a key role in initiating antiviral and anti-infective immune responses by recognizing cytosolic DNA. Acute cerebral infarction is one of the leading causes of death and disability worldwide, with the primary treatment approach being the restoration of blood flow to ischemic brain tissue. However, reperfusion injury remains a significant challenge during treatment. The overactivation of the cGAS-STING pathway and its association with ischemia-reperfusion injury have been confirmed in numerous studies. This article will systematically elucidate the mechanisms of the cGAS-STING pathway, its role in ischemia-reperfusion injury in acute cerebral infarction, the current research status of cGAS-STING inhibitors, and the application of nanomaterials in this context, evaluating the therapeutic potential of this pathway.

The Fortifications of the Late Scythian Settlement at Konsulivske

Konsulivske belongs to the group of Late Scythian hillforts located in the lower Dnipro area. Since 2015, a Ukrainian–Polish archaeological team has been carrying out the investigation of the site. The article presents the results of these studies focused on fortifications of the citadel and the main line of defence.

The clinical significance of open vs. minimally invasive surgical approaches in the management of thymic epithelial tumors and myasthenia gravis

Though advancements have been made in the pharmacologic treatment of myasthenia gravis (MG), surgical resection is not only an option as a last line of defense for those patients who do not respond to medical therapy but also remains vital for those with thymic epithelial tumors (TET). While prior studies have shown the potential superiority of minimally invasive approaches via robotic- and video-assisted thoracoscopic surgery (RATS/VATS) for thymectomy compared to open surgery, in the setting of malignancies, this outcome delineation is controversial. As RATS/VATS may be associated with less post-operative complications in the treatment of TET, some surgeons argue that the open approach is necessary for complete resection (R0 resection) and to prevent potential seeding of the malignancy. In this review article, we will compare the efficacy and implications of the different surgical approaches and techniques themselves in performing a thymectomy for autoimmune and oncologic pathologies.

A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.

Through two decades of research and development, adoptive cell therapies (ACTs) have revolutionized treatment for hematologic malignancies. Many of the seven US Food and Drug Administration (FDA)-approved products are proven to be a curative last line of defense against said malignancies. The ACTs, known more commonly as chimeric antigen receptor (CAR) T-cells, utilize engineered lymphocytes to target and destroy cancer cells in a patient-specific, major histocompatibility complex (MHC)-independent manner, acting as "living drugs" that adapt to and surveil the body post-treatment. Despite their efficacy, CAR T-cell therapies present unique challenges in preclinical safety assessment. The safety and pharmacokinetics of CAR T-cells are influenced by numerous factors including donor and recipient characteristics, product design, and manufacturing processes that are not well-predicted by existing in vitro and in vivo preclinical safety models. The CAR therapy-mediated toxicities in clinical settings primarily arise from unintended targeting of non-tumor cells, potential tumorigenicity, and severe immune activation syndromes like cytokine release syndrome and immune effector cell-associated neurotoxicity. Addressing these issues necessitates a deep understanding of CAR target expression in normal tissues, inclusive of the spatial microanatomical distribution, off-target screening, and a deep understanding CAR cell manufacturing practices and immunopathology.

Advanced MicroRNA delivery for lung inflammatory therapy: surfactant protein A controls cellular internalisation and degradation of extracellular vesicles

IntroductionAlveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular...

Epstein-Barr virus and immunity.

The Epstein-Barr virus has infected the vast majority of the world's population. EBV is the most common herpes virus in the human population. In childhood, viral infection is either asymptomatic or can lead to infectious mononucleosis. In a small proportion of latently infected people, especially in immunosuppressed patients, EBV causes lymphoid and epithelial malignancies and a number of autoimmune diseases, including one of the causes of the development of multiple sclerosis. Innate immunity is the first line of antiviral defense, which EBV evades using a number of strategies to achieve successful infection. EBV disrupts the innate immune signaling pathways activated by Toll-like, RIG-I-like, NOD-like and AIM2-like receptors, as well as cyclic GMP-AMP synthetase. EBV also antagonizes interferon production and signaling, including the TBK1-IRF3 and JAK-STAT pathways. Through differential modulation of proviral and antiviral mechanisms of action of caspases and other cellular life cycle regulators at different stages of infection, EBV actively interferes with apoptotic and inflammatory pathways to continue effective infection. By turning the activation of innate immunity to its advantage by triggering a pro-inflammatory reaction and proteolytic cleavage of caspases that exhibit proviral activity, the virus establishes latency or enters the lytic reactivation phase, which contributes to the development of serious life-threatening diseases, including oncogenesis. The outcome of EBV infection is regulated by a subtle interaction between innate, adaptive immunity, and viral replication. In the absence of licensed preventive vaccines, immunocorrection and antiviral therapy are the only possible ways to combat the virus and prevent diseases associated with it. Understanding the mechanisms of action of certain EBV genes involved in the life cycle at different stages of infection will help in the future to find the right approach to the development of preventive and therapeutic drugs against EBV.

Local Electric Field-Incorporated In-Situ Copper Ions Eliminating Pathogens and Antibiotic Resistance Genes in Drinking Water

Background/Objectives: Pathogen inactivation and harmful gene destruction from water just before drinking is the last line of defense to protect people from waterborne diseases. However, commonly used disinfection methods, such as chlorination, ultraviolet irradiation, and membrane filtration, experience several challenges such as continuous chemical dosing, the spread of antibiotic resistance genes (ARGs), and intensive energy consumption. Methods: Here, we perform a simultaneous elimination of pathogens and ARGs in drinking water using local electric fields and in-situ generated trace copper ions (LEF-Cu) without external chemical dosing. A 100-μm thin copper wire placed in the center of a household water pipe can generate local electric fields and trace copper ions near its surface after an external low voltage is applied. Results: The local electric field rapidly damages the outer structure of microorganisms through electroporation, and the trace copper ions can effectively permeate the electroporated microorganisms, successfully damaging their nucleic acids. The LEF-Cu disinfection system achieved complete inactivation (>6 log removal) of Escherichia coli O157:H7, Pseudomonas aeruginosa PAO1, and bacteriophage MS2 in drinking water at 2 V for 2 min, with low energy consumption (10−2 kWh/m3). Meanwhile, the system effectively damages both intracellular (0.54~0.64 log) and extracellular (0.5~1.09 log) ARGs and blocks horizontal gene transfer. Conclusions: LEF-Cu disinfection holds promise for preventing horizontal gene transfer and providing safe drinking water for household applications.

Adaptation of the in vivo respiratory burst assay for fathead minnow larvae (Pimephales promelas).

Initial innate immune responses such as the respiratory burst response of phagocytes present the first line of defense in response to exposure to pathogens. Several respiratory burst assays have been developed in mammals, cell cultures, and whole zebrafish embryos as a reliable indicator of the innate immune response of a host, and these assays are being used to screen various environmental contaminants for their immunotoxic potential. While zebrafish are a common laboratory fish used in toxicology studies geared towards human health effects, fathead minnows are commonly used as an ecotoxicological indicator species for North America. In this technical note, we describe how we adapted the zebrafish in vivo respiratory burst assay for use in fathead minnow larvae. This assay provides promising expansion of using in vivo respiratory burst responses in different species of larval fish for future comparative immunotoxicity assays, as well as laying the groundwork for studies that can better define the development of the innate and adaptive immune responses of fathead minnow larvae.

Study on Plugging Process Parameters and Mechanism of Large-Scale Plugging Experimental Device for Blowout Preventer Stack

Summary The blowout preventer (BOP) stack is the last line of defense for well control (pressure control of the wellbore), and the failure of its sealing components will cause serious well control accidents. At present, there is a lack of suitable experimental device to verify the feasibility of the emergency rescue method proposed for the early seal failure of the BOP stack by pumping plugging particles. However, it is costly, risky, and time-consuming to build and implement a large-scale plugging experimental model for BOP stack with ultrahigh pressure (70 MPa) and large displacement. Therefore, based on this device, this paper establishes a large-scale plugging experimental model of BOP stack by using computational fluid dynamics-discrete element method (CFD-DEM). The volume flow rate is used as the evaluation index to analyze the influence of the shape, size, concentration, and pump displacement of the plugging particle on the plugging efficiency, and the plugging parameters of the experimental device are researched and selected. The results show that the plugging particles can be divided into four stages—particle pumping, particle diffusion, particle bridging, and particle accumulation. The 5-mm spherical particle has the best plugging efficiency for the largest dimension of flange connection seal failure. The particle concentration and pump displacement affect the bridging time of particles but have no obvious effect on the plugging efficiency. A pump displacement of 2.4 m3/min and 5-mm spherical particles with 25% concentration were selected for emergency plugging of the experimental device. This study not only reduces the cost and risk of large-scale plugging experimental device for BOP stack but also further promotes the feasibility study of emergency rescue of BOP seal failure.

Adaptation in human immune cells residing in tissues at the frontline of infections

Human immune cells are under constant evolutionary pressure, primarily through their role as first line of defence against pathogens. Most studies on immune adaptation are, however, based on protein-coding genes without considering their cellular context. Here, using data from the Human Cell Atlas, we infer the gene adaptation rate of the human immune landscape at cellular resolution. We find abundant cell types, like progenitor cells during development and adult cells in barrier tissues, to harbour significantly increased adaptation rates. We confirm the adaptation of tissue-resident T and NK cells in the adult lung located in compartments directly facing external challenges, such as respiratory pathogens. Analysing human iPSC-derived macrophages responding to various challenges, we find adaptation in early immune responses. Together, our study suggests host benefits to control pathogen spread at early stages of infection, providing a retrospect of forces that shaped the complexity, architecture, and function of the human body.

Role of neutrophils in the pathogenesis of Post Kala-azar Dermal Leishmaniasis (PKDL).

Post Kala-azar Dermal Leishmaniasis (PKDL) is a dermal sequel of visceral leishmaniasis (VL), poses a significant threat to the success of ongoing kala-azar elimination program, due to its potential role in sustaining transmission cycles and complicating disease management strategies. In VL, neutrophils have been identified as the 'first line of defence', having multiple roles in disease pathogenesis, but their role in PKDL, if any, still remains elusive; presenting a critical gap in knowledge, and was the aim of this study. In a cohort of PKDL patients, CD66b+ neutrophils were quantified in skin biopsies, followed by immunostaining of FFPE sections to identify activated neutrophils (CD66b+/CD64+) and degranulated (CD66b+/MPO+), along with expression of neutrophil elastase (NE), matrix metalloprotease 9 (MMP9) and collagen I. Plasma levels of neutrophil chemo-attractants CXCL8/1/2/5, CCL2 and 20 and cytokines, (IL-6, IFN-γ, IL-4, IL-10, TNF-α, IL-17 and IL-22, 23) were evaluated by a multiplex assay, while lesional expression of IL-8, IL-10 and IL-17 was evaluated by immunohistochemistry. As compared to healthy individuals (control skin samples), PKDL cases at the lesional sites had an increased number of activated CD66b+ neutrophils (positive for CD64+, MPO+ and NE+). The plasma levels of neutrophil chemo-attractants, pro-inflammatory and regulatory cytokines were raised as was circulating and lesional IL-8, along with an enhanced lesional expression of IL-10 and IL-17A. An increase in circulatory and lesional MMP9 was accompanied by decreased collagen I, suggesting disintegration of matrix integrity. Taken together, in PKDL, activated neutrophils possibly contribute towards modulating the lesional landscape. Understanding this involvement of neutrophils in patients with PKDL, particularly in the absence of an animal model, could offer better understanding of the disease pathogenesis and provide insights into novel therapeutic strategies for the ongoing elimination program.

The Role of Pharmacists in Minimizing the Risk Inherent in Unbundled Telehealth Services: A 12-Month Retrospective Case Study

Pharmacists have often been viewed as the last line of defence against prescription errors in traditional care models. Although a large number of chronic care patients are using telehealth services to increase their access to continuous care, researchers have yet to investigate prescription safety in such settings in Australia. The absence of this literature is particularly concerning in the context of the Australian Government’s admission in a 2024 report that the national health system has not adequately addressed the World Health Organization’s ‘Medication without harm’ objective. One of the report’s key findings was that knowledge on digital direct-to-consumer services is insufficient. A defining feature of some of these services is their unbundling of the pharmacy component, which logically increases the risk for prescription errors. This study analyzed the frequency of which the Cloud pharmacy network intercepted prescription errors in an unbundled digital sexual dysfunction service for men. Investigators found that Cloud pharmacists were responsible for intercepting 22 (5.31%) the 414 prescribing errors observed in the Pilot Australia service in 2023, including 12 (8.05%) of the 149 prescription errors for premature ejaculation (PE) patients and 10 (3.77%) of the 265 errors for erectile dysfunction (ED) patients. Seven of the errors intercepted by Cloud pharmacists were of high or medium severity, including four drug contraindications, two cases of inadequate patient history reviews, and one case of inadequate counselling. This study also appears to be the first to provide digital prescribing error rate data in an Australian sexual healthcare setting, observing an error rate of 0.86% from 30,649 ED prescriptions, 1.13% from the 13,154 PE prescriptions, and a total prescription error rate of 0.95% (414 out of 43,792 prescriptions). These findings demonstrate the vital role of pharmacists in intercepting prescribing errors in unbundled telehealth services. Possible implications of these findings include the allocation of additional resources across the pharmacy sector and the establishment of regulatory safety standards for unbundled telehealth services.

Forecasting the relative abundance of Aedes vector populations to enhance situational awareness for mosquito control operations.

Aedes-borne diseases represent a major public health threat and mosquito control operations represent a key line of defense. Improving the real-time awareness of mosquito control authorities by providing reliable forecasts of the relative abundance of mosquito vectors could greatly enhance control efforts. To this aim, we developed an analytical tool that forecasts Aedes aegypti relative abundance 1 to 4 weeks ahead. Forecasts were validated against mosquito surveillance data (2,760 data points) collected over multiple years in four jurisdictions in the US. The symmetric absolute percentage error was in the range 0.43-0.69, and the 90% interquantile range of the forecasts had a coverage of 83-92%. Our forecasts consistently outperformed a reference "naïve" model for all analyzed study sites, forecasting horizon, and for periods with medium/high Ae. aegypti activity. The developed tool can be instrumental to address the need for evidence-based decision making.

Experiences of women living with cervical cancer in Ghana: challenges and coping strategies

BackgroundCervical cancer is a leading cause of morbidity and mortality among women globally. The condition is both preventable and treatable yet remains a leading cause of cancer death in Ghana. This study aims to explore the unique experiences of women living with cervical cancer with a focus on the challenges and coping strategies.MethodsThe study employed a qualitative approach with an exploratory, descriptive design. This study was conducted among women with cervical cancer aged 18 years and above who have been diagnosed with the disease for at least 3 months. A total of 16 participants were purposively sampled based on the eligibility criteria and individually interviewed using a semi-structured guide. The six-step technique for qualitative analysis by Braun and Clarke guided data analysis.ResultsMost participants resorted to self-medication, over-the-counter drugs and herbal preparations as a first line of defense against the disease. The presence of cervical cancer affected participants’ physical and mental well-being. Other challenges included financial burden and frequent equipment breakdowns which affected patients’ treatment. Participants adopted different coping strategies such as taking blood tonic, increased rest and sleep, spiritual prayers and recreational activities. Family members, friends, the church and health workers provided support in the area of finance, advice, meal preparation and house chores, prayers and counseling to participants.ConclusionsCervical cancer affects the quality of life of many women and their significant others. The condition puts a lot of financial burden on its victims and there is the need for a system to reduce the burden on patients. It is recommended that the treatment of cervical cancer should be covered by the National Health Insurance Scheme to ease the financial burden on patients. There is a need for expansion of access to cervical cancer treatment across the country to reduce patients’ burden and relieve the pressure on the few pieces of equipment at the current treatment centres.

Expression of two CD83 homologs in macrophage subpopulations isolated from the brain and kidney of ginbuna crucian carp

There are numerous fish diseases that affect the central nervous system. However, few studies have investigated the immune cells and immunological responses of fish brains. Meanwhile, microglial cells, as the brain's first line of defense, play a vital role in neuroimmunology. Furthermore, CD83 is a co-stimulatory protein that regulates immunological responses and the activation of dendritic cells and macrophages. Although CD83 expression has been linked to the initial activation of microglia in various disease scenarios in mammals, its role in teleost microglial biology remains unclear. In a recent investigation, we discovered that Ginbuna crucian carp (Gb) contains two CD83 homologs (GbCD83 and GbCD83-L). In this study, we used modified procedures of mouse-based macrophage culture from the brain and kidney to identify that GbCD83-L is highly expressed by the brain microglia-like cells and kidney-resident macrophages (KRMs) at both the protein and gene levels. Interestingly, GbCD83-L was considerably elevated in the microglia-like cells and KRMs after 24 h of lipopolysaccharide stimulation. These findings provide the first evidence of CD83 as a potential marker for active microglia and KRMs in teleosts, thus making it a crucial regulator in fish neuroimmunology and a candidate for future immunomodulatory applications in aquaculture.

Effects of intranasal administration with a symbiotic strain of Bacillus velezensis NSV2 on nasal cavity mucosal barrier in lambs.

The nasal mucosa is composed of multiple layers of barrier structures and is the first line of defense against infection by respiratory pathogenic microorganisms. A large number of commensal microorganisms are present in the nasal mucosa that mediate and regulate nasal mucosal barrier function. The objective of this research was to investigate the effects of commensal microorganisms on the nasal mucosal barrier. The results revealed that the strain of Bacillus velezensis (B. velezensis) NSV2 from the nasal cavity has good probiotic abilities to resist Pasteurella multocida, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Lambs were subsequently administered intranasally with B. velezensis NSV2 at 3, 12, 21, and 26 days old, respectively. For the microbial barrier, although B. velezensis NSV2 reduces the diversity of nasal microbiota, it significantly increased the relative abundance of beneficial bacteria in the nasal cavity, and reduced the abundance of potential pathogenic bacteria. For the mucus barrier, the number of goblet cells in the nasal mucosa significantly increased after B. velezensis NSV2 treatment. For the immune barrier, B. velezensis NSV2 also significantly increased the number of IgA+ B cells, CD3+ T cells and dendritic cells in the nasal mucosa, as well as the mRNA expression of interleukin (IL) 6, IL11, CCL2, and CCL20 (P < 0.05). The protein level of CCL20 also significantly raised in nasal washings (P < 0.05). Moreover, the heat-inactivated and culture products of B. velezensis NSV2 also drastically induced the expression of CCL20 in nasal mucosa explants (P < 0.05), but lower than that of the live bacteria. This study demonstrated that a symbiotic strain of B. velezensis NSV2 could improve the nasal mucosal barrier, and emphasized the important role of nasal symbiotic microbiota.

Ultrasound of Lateral Epicondylitis.

Clinical findings are generally sufficient to make the diagnosis of lateral epicondylitis of the elbow. Ultrasound (US), in conjunction with standard radiography, is a simple and cost-effective way to confirm the diagnosis, and it is also useful for eliminating most differential diagnoses and guiding treatment.US analysis of the muscle bodies and tendon laminae of the lateral epicondyle muscles, starting distally at the wrist and extending up to the lateral epicondyle, assists in understanding the complex fibrous architecture of the proximal tendons inserting on the lateral epicondyle. Pain when the US probe passes over an area of hypoechoic tendinosis, hyperemia in Doppler mode, and an intratendinous split are the signs to look for in patients. US helps guide needling or injection by targeting pathologic areas.Other examinations (computed tomography arthrogram and magnetic resonance imaging) are used as a second line of defense, particularly in cases of bone or joint pathology.

The role of chorion integrity on the bioaccumulation and toxicity of selenium nanoparticles in Japanese medaka (Oryzias latipes)

Selenium nanoparticles (nano-Se) have a wide range of biomedical and agricultural applications. However, there is little information on the potential toxicity of nano-Se once it enters the environment, particularly in fish. The first line of defense from contaminants that embryonic fish have is the chorion, but the degree to which the chorion protects the developing embryo is unknown. Japanese medaka (Oryzias latipes) embryos were exposed to nano-Se in a wide range of concentrations (0.1-400 µM). The importance of chorion integrity was evaluated by exposing embryos to 16 nm nano-Se under four degrees of dechorionation: intact, roughened, partially-dechorionated, fully-dechorionated. Then, effects of particle size on embryos and larvae were determined using four sizes of nano-Se particles (16, 25-50, 50, 100 nm). The results showed that nano-Se exposure reduced survival, development, and hatching. Nano-Se was observed to adsorb on the chorion, with the amount decreasing with increased degree of dechorionation. Toxicity increased with increasing degree of dechorionation, and smaller-sized nano-Se crossed intact chorion more readily and resulted in higher toxicity than larger ones. In larvae, nano-Se accumulated on the skin and was more toxic compared to embryos. This study demonstrated the importance of the chorion in protecting developing embryos and effects of nanoparticle size on its bioavailability and subsequent toxicity.