Development of T cell antigen-based human coronavirus vaccines against nAb-escaping SARS-CoV-2 variants.

Currently approved vaccines have been successful in preventing the severity of COVID-19 and hospitalization. These vaccines primarily induce humoral immune responses; however, highly transmissible and mutated variants, such as the Omicron variant, weaken the neutralization potential of the vaccines, thus, raising serious concerns about their efficacy. Additionally, while neutralizing antibodies (nAbs) tend to wane more rapidly than cell-mediated immunity, long-lasting T cells typically prevent severe viral illness by directly killing infected cells or aiding other immune cells. Importantly, T cells are more cross-reactive than antibodies, thus, highly mutated variants are less likely to escape lasting broadly cross-reactive T cell immunity. Therefore, T cell antigen-based human coronavirus (HCoV) vaccines with the potential to serve as a supplementary weapon to combat emerging SARS-CoV-2 variants with resistance to nAbs are urgently needed. Alternatively, T cell antigens could also be included in B cell antigen-based vaccines to strengthen vaccine efficacy. This review summarizes recent advancements in research and development of vaccines containing T cell antigens or both T and B cell antigens derived from proteins of SARS-CoV-2 variants and/or other HCoVs based on different vaccine platforms.

Unveiling the mycobiota: The fungal frontier of human health.

The microbiota and its effect on health has been extensively studied over the past decade. In many studies, the term microbiota has become synonymous with the bacterial component of the microbiota. Other microbes in the microbiota, such as viruses and fungi, have been neglected until recently. This special issue provides some background on the mycobiota and explores the role of gut fungi in human diseases such as cancer, metabolic diseases, and infection by Clostridiodes difficile, and describes the incidence of fungal infections in transplant patients. The mycobiota, once overlooked, now garners increasing attention.

Hirsutella sinensis polysaccharides and Parabacteroides goldsteinii reduce lupus severity in imiquimod-treated mice.

BACKGROUND: The incidence of autoimmune diseases is increasing in developed countries, possibly due to the modern Western diet and lifestyle. We showed earlier that polysaccharides derived from the medicinal fungus Hirsutella sinensis produced anti-inflammatory, anti-diabetic and anti-obesity effects by modulating the gut microbiota and increasing the abundance of the commensal Parabacteroides goldsteinii in mice fed with a high-fat diet. METHODS: We examined the effects of the prebiotics, H. sinensis polysaccharides, and probiotic, P. goldsteinii, in a mouse model of imiquimod-induced systemic lupus erythematosus. RESULTS: The fungal polysaccharides and P. goldsteinii reduced markers of lupus severity, including the increase of spleen weight, proteinuria, and serum levels of anti-DNA auto-antibodies and signal transducer and activator of transcription 4 (STAT4). Moreover, the polysaccharides and P. goldsteinii improved markers of kidney and liver functions such as creatinine, blood urea nitrogen, glomerulus damage and fibrosis, and serum liver enzymes. However, the prebiotics and probiotics did not influence gut microbiota composition, colonic histology, or expression of tight junction proteins in colon tissues. CONCLUSIONS: Our results indicate that H. sinensis polysaccharides and the probiotic P. goldsteinii can reduce lupus markers in imiquimod-treated mice. These prebiotics and probiotics may therefore be added to other interventions conducive of a healthy lifestyle in order to counter autoimmune diseases.

Frankincense (Boswellia serrata) Extract Effects on Growth and Biofilm Formation of Porphyromonas gingivalis, and Its Intracellular Infection in Human Gingival Epithelial Cells.

Frankincense is produced by Boswellia trees, which can be found throughout the Middle East and parts of Africa and Asia. Boswellia serrata extract has been shown to have anti-cancer, anti-inflammatory, and antimicrobial effects. Periodontitis is an oral chronic inflammatory disease that affects nearly half of the US population. We investigated the antimicrobial effects of B. serrata extract on two oral pathogens associated with periodontitis. Using the minimum inhibitory concentration and crystal violet staining methods, we demonstrated that Porphyromonas gingivalis growth and biofilm formation were impaired by treatment with B. serrata extracts. However, the effects on Fusobacterium nucleatum growth and biofilm formation were not significant. Using quantification of colony-forming units and microscopy techniques, we also showed that concentrations of B. serrata that were not toxic for host cells decreased intracellular P. gingivalis infection in human gingival epithelial cells. Our results show antimicrobial activity of a natural product extracted from Boswellia trees (B. serrata) against periodontopathogens. Thus, B. serrata has the potential for preventing and/or treating periodontal diseases. Future studies will identify the molecular components of B. serrata extracts responsible for the beneficial effects.

miRNAs mediate the impact of smoking on dental pulp stem cells via the p53 pathway.

Cigarette smoke changes the genomic and epigenomic imprint of cells. In this study, we investigated the biological consequences of extended cigarette smoke exposure on dental pulp stem cells (DPSCs) and the potential roles of miRNAs. DPSCs were treated with various doses of cigarette smoke condensate (CSC) for up to 6 weeks. Cell proliferation, survival, migration, and differentiation were evaluated. Cytokine and miRNA expression were profiled. The results showed that extended exposure to CSC significantly impaired the regenerative capacity of the DPSCs. Bioinformatic analysis showed that the cell cycle pathway, cancer pathways (small cell lung cancer, pancreatic, colorectal, and prostate cancer), and pathways for TNF, TGF-ß, p53, PI3K-Akt, mTOR, and ErbB signal transduction, were associated with altered miRNA profiles. In particular, 3 miRNAs has-miR-26a-5p, has-miR-26b-5p, and has-miR-29b-3p fine-tune the p53 and cell cycle signaling pathways to regulate DPSC cellular activities. The work indicated that miRNAs are promising targets to modulate stem cell regeneration and understanding miRNA-targeted genes and their associated pathways in smoking individuals have significant implications for disease control and prevention.

Multiple energy X-ray imaging of metal oxide particles inside gingival tissues.

BACKGROUND: Periodontal disease affects over 50% of the global population and is characterized by gingivitis as the initial sign. One dental health issue that may contribute to the development of periodontal disease is foreign body gingivitis (FBG), which can result from exposure to some kinds of foreign metal particles from dental products or food. OBJECTIVE: We design a novel, portable, affordable, multispectral X-ray and fluorescence optical microscopic imaging system dedicated to detecting and differentiating metal oxide particles in dental pathological tissues. A novel denoising algorithm is applied. We verify the feasibility and optimize the performance of the imaging system with numerical simulations. METHODS: The designed imaging system has a focused X-ray tube with tunable energy spectra and thin scintillator coupled with an optical microscope as detector. A simulated soft tissue phantom is embedded with 2-micron thick metal oxide discs as the imaged object. GATE software is used to optimize the systematic parameters such as energy bandwidth and X-ray photon number. We have also applied a novel denoising method, Noise2Sim with a two-layer UNet structure, to improve the simulated image quality. RESULTS: The use of an X-ray source operating with an energy bandwidth of 5 keV, X-ray photon number of 108, and an X-ray detector with a 0.5 micrometer pixel size in a 100 by 100-pixel array allowed for the detection of particles as small as 0.5 micrometer. With the Noise2Sim algorithm, the CNR has improved substantially. A typical example is that the Aluminum (Al) target's CNR is improved from 6.78 to 9.72 for the case of 108 X-ray photons with the Chromium (Cr) source of 5 keV bandwidth. CONCLUSIONS: Different metal oxide particles were differentiated using Contrast-to-Noise ratio (CNR) by utilizing four different X-ray spectra.

Lifestyle interventions to delay senescence.

Senescence is a condition of cell cycle arrest that increases inflammation and contributes to the development of chronic diseases in the aging human body. While several compounds described as senolytics and senomorphics produce health benefits by reducing the burden of senescence, less attention has been devoted to lifestyle interventions that produce similar effects. We describe here the effects of exercise, nutrition, caloric restriction, intermittent fasting, phytochemicals from natural products, prebiotics and probiotics, and adequate sleep on senescence in model organisms and humans. These interventions can be integrated within a healthy lifestyle to reduce senescence and inflammation and delay the consequences of aging.

Correction: Mononuclear-macrophages but not neutrophils act as major infiltrating anti-leptospiral phagocytes during leptospirosis.

[This corrects the article DOI: 10.1371/journal.pone.0181014.].

Cigarette smoking exposure disrupts the regenerative potential of dental pulp stem cells.

INTRODUCTION: Smoking is known to alter the regenerative and immunomodulatory properties of many types of mesenchymal stem cells (MSCs). This study investigates the impact of cigarette smoke exposure on the regenerative potential of dental pulp stem cells (DPSCs). METHODS: DPSCs were treated with various doses of cigarette smoke condensate (CSC) or nicotine. Cell proliferation and survival were evaluated by a water-soluble tetrazolium salt (WST-1) and a survival assay. DPSC migration, cytokine expression, mutagenesis, and the signaling pathway were also measured during CSC and nicotine treatment. RESULTS: Low concentrations of CSC and nicotine did not impair cell proliferation, but higher concentrations reduced cell proliferation. CSC and nicotine could impede DPSC survival and migration in a dose-dependent manner. In addition, the cytokine secretion expression profile was altered with CSC or nicotine treatments. In particular, secretion of IL-6, TNF-α, and IL-10 significantly increased, while TGF-ß1 levels showed different patterns after exposure to CSC or nicotine, as shown by ELISA and quantitative PCR. Nicotine treatment increased AKT (also known as protein kinase B) and extracellular signal-regulated kinase (ERK) phosphorylation. Finally, CSC induced higher levels of mutagenicity than nicotine, as shown by the Ames test. CONCLUSIONS: These findings suggest that cigarette smoke exposure alters the regenerative abilities of DPSCs in various ways. Future studies are warranted to further characterize the underlying molecular mechanisms of smoking-mediated damage to DPSCs, which will guide the personalized stem cell treatment plan for smoking patients.

The role of NOD-like receptors in innate immunity.

The innate immune system in vertebrates and invertebrates relies on conserved receptors and ligands, and pathways that can rapidly initiate the host response against microbial infection and other sources of stress and danger. Research into the family of NOD-like receptors (NLRs) has blossomed over the past two decades, with much being learned about the ligands and conditions that stimulate the NLRs and the outcomes of NLR activation in cells and animals. The NLRs play key roles in diverse functions, ranging from transcription of MHC molecules to initiation of inflammation. Some NLRs are activated directly by their ligands, while other ligands may have indirect effects on the NLRs. New findings in coming years will undoubtedly shed more light on molecular details involved in NLR activation, as well as the physiological and immunological outcomes of NLR ligation.

X-ray projection imaging of metal oxide particles inside gingival tissues.

There is increasing recognition that oral health affects overall health and systemic diseases. Nonetheless it remains challenging to rapidly screen patient biopsies for signs of inflammation or the pathogens or foreign materials that elicit the immune response. This is especially true in conditions such as foreign body gingivitis (FBG), where the foreign particles are often difficult to detect. Our long term goal is to establish a method to determine if the inflammation of the gingival tissue is due to the presence of a metal oxide, with emphasis on elements that were previously reported in FBG biopsies, such as silicon dioxide, silica, and titanium dioxide whose persistent presence can be carcinogenic. In this paper, we proposed to use multiple energy X-ray projection imaging to detect and to differentiate different metal oxide particles embedded inside gingival tissues. To simulate the performance of the imaging system, we have used GATE simulation software to mimic the proposed system and to obtain images with different systematic parameters. The simulated parameters include the X-ray tube anode metal, the X-ray spectra bandwidth, the X-ray focal spot size, the X-ray photon number, and the X-ray dector pixel. We have also applied the de-noising algorithm to obtain better Contrast-to-noise ratio (CNR). Our results indicate that it is feasible to detect metal particles as small as 0.5 micrometer in diameter when we use a Chromium anode target with an energy bandwidth of 5 keV, an X-ray photon number of 10^8, and an X-ray detector with a pixel size of 0.5 micrometer and 100 by 100 pixels. We have also found that different metal particles could be differentiated from the CNR at four different X-ray anodes and spectra. These encouraging initial results will guide our future imaging system design.

Interactions between silica and titanium nanoparticles and oral and gastrointestinal epithelia: Consequences for inflammatory diseases and cancer.

Engineered nanoparticles (NPs) composed of elements such as silica and titanium, smaller than 100 nm in diameter and their aggregates, are found in consumer products such as cosmetics, food, antimicrobials and drug delivery systems, and oral health products such as toothpaste and dental materials. They may also interact accidently with epithelial tissues in the intestines and oral cavity, where they can aggregate into larger particles and induce inflammation through pathways such as inflammasome activation. Persistent inflammation can lead to precancerous lesions. Both the particles and lesions are difficult to detect in biopsies, especially in clinical settings that screen large numbers of patients. As diagnosis of early stages of disease can be lifesaving, there is growing interest in better understanding interactions between NPs and epithelium and developing rapid imaging techniques that could detect foreign particles and markers of inflammation in epithelial tissues. NPs can be labelled with fluorescence or radioactive isotopes, but it is challenging to detect unlabeled NPs with conventional imaging techniques. Different current imaging techniques such as synchrotron radiation X-ray fluorescence spectroscopy are discussed here. Improvements in imaging techniques, coupled with the use of machine learning tools, are needed before diagnosis of particles in biopsies by automated imaging could move usefully into the clinic.

Association between Periodontal Disease and Cognitive Impairment in Adults.

INTRODUCTION: Periodontitis is a severe oral infection that can contribute to systemic inflammation. A large body of evidence suggests a role for systemic inflammation in the initiation of neurodegenerative disease. This systematic review synthesized data from observational studies to investigate the association between periodontitis and neuroinflammation in adults. METHODS AND MATERIALS: A systematic literature search of PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed for studies published from the date of inception up to September 2021. Search terms for the exposure "oral disease" and outcome "dementia", "neuroinflammation" and "cognitive decline" were used. Study selection and data extraction were independently undertaken by two reviewers. The final eligible articles were included only if the exposure is periodontitis and the outcome is cognitive impairment or dementia or a topic related to this condition, and if the study was conducted in an adult population. The quality and risk of bias were assessed by Newcastle Ottawa Scale (NOS). Qualitative synthesis was used to narratively synthesize the results. Six cohort studies, three cross-sectional studies, and two case-control studies met the inclusion criteria. These eleven studies were only narratively synthesized. Meta-analysis was not performed due to the methodological heterogeneity of the studies. RESULTS: The results of included studies show that chronic periodontitis patients with at least eight years of exposure are at higher risk of developing cognitive decline and dementia. Oral health measures such as gingival inflammation, attachment loss, probing depth, bleeding on probing, and alveolar bone loss are associated with cognitive impairment. The reduction of epidermal growth factor (EGF), interleukin 8 (IL-8), interferon γ-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) in addition to over expression of interleukin 1-ß (IL-1ß) are significant in patients suffering from cognitive decline with pre-existing severe periodontitis. CONCLUSIONS: All the included studies show evidence of an association between periodontitis and cognitive impairment or dementia and Alzheimer's disease pathology. Nonetheless, the mechanisms responsible for the association between periodontitis and dementia are still unclear and warrant further investigation.

Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming.

The nucleotide-binding and oligomerization domain, leucine-rich repeats, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1ß secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC-itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases.

Influence of electromagnetic fields on the circadian rhythm: Implications for human health and disease.

Living organisms have evolved within the natural electromagnetic fields (EMFs) of the earth which comprise the global atmospheric electrical circuit, Schumann resonances (SRs) and the geomagnetic field. Research suggests that the circadian rhythm, which controls several physiological functions in the human body, can be influenced by light but also by the earth's EMFs. Cyclic solar disturbances, including sunspots and seasonal weakening of the geomagnetic field, can affect human health, possibly by disrupting the circadian rhythm and downstream physiological functions. Severe disruption of the circadian rhythm increases inflammation which can induce fatigue, fever and flu-like symptoms in a fraction of the population and worsen existing symptoms in old and diseased individuals, leading to periodic spikes of infectious and chronic diseases. Possible mechanisms underlying sensing of the earth's EMFs involve entrainment via electrons and electromagnetic waves, light-dependent radical pair formation in retina cryptochromes, and paramagnetic magnetite nanoparticles. Factors such as electromagnetic pollution from wireless devices, base antennas and low orbit internet satellites, shielding by non-conductive materials used in shoes and buildings, and local geomagnetic anomalies may also affect sensing of the earth's EMFs by the human body and contribute to circadian rhythm disruption and disease development.

Infection of the oral cavity with SARS-CoV-2 variants: Scope of salivary diagnostics.

Coronaviruses, including SARS-CoV-2, have caused pandemics in the past two decades. The most prevalent SARS-CoV-2 variants of concern can re-infect individuals who have been previously infected with other variants or had protection from vaccines targeting the original SARS-CoV-2 variant. Given the high risk of transmission of coronavirus via aerosols produced during dental procedures, it is important to understand the future risk of coronavirus infection for oral health professionals and to diagnose quickly early stages of outbreaks. Testing of saliva for coronavirus may be the least invasive and most convenient method for following the outbreak at the individual and community level. This review will describe strategies for diagnosis of coronavirus in saliva.

Role of TRAIL-R in Primary and Secondary Genital and Respiratory Chlamydia muridarum Infections in Mice.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor (TRAIL-R) suppresses inflammation and could therefore affect the course of Chlamydia infections and their long-term sequelae. Wild-type (WT) and TRAIL-R-/- C57BL/6 mice were inoculated vaginally with Chlamydia muridarum; the course of the infection was followed with vaginal cultures and the presence of hydrosalpinx determined. To evaluate the role of TRAIL-R following a secondary infection, the mice were vaginally reinfected. WT and TRAIL-R-/- male mice were also infected and reinfected in the respiratory tract, and the course of the diseases and the infections were followed. Following the primary and secondary vaginal infection, no significant differences in vaginal shedding or hydrosalpinx formation were observed between the WT and TRAIL-R-/- mice. The WT and TRAIL-R-/- mice mounted antibody responses in serum and vaginal washes that were not significantly different. After the primary and secondary intranasal infections of the male mice, changes in body weight were determined, and no significant differences were observed between the WT and TRAIL-R-/- mice. Ten days after the primary and the secondary infections, the weight of the lungs and number of C. muridarum inclusion forming units (IFU) were determined. The lungs of the WT mice weighed less compared with the TRAIL-R-/- mice following a primary infection but not after a secondary infection. No differences in the number of C. muridarum IFU in the lungs were observed between the two groups of mice. In conclusion, despite playing a role in inflammation cell-signaling pathways in vitro, TRAIL-R does not appear to play a major role in the susceptibility, clinical outcomes, or long-term sequelae of C. muridarum infections in vivo. IMPORTANCE TNF-related apoptosis-inducing ligand receptor (TRAIL-R) is involved in suppressing inflammatory responses. Bacterial pathogens such as Chlamydia spp. elicit inflammatory responses in humans following genital, ocular, and respiratory infections. The inflammatory responses are important to control the spread of Chlamydia. However, in certain instances, these inflammatory responses can produce long-term sequelae, including fibrosis. Fibrosis, or scarring, in the genital tract, eye, and respiratory system results in functional deficiencies, including infertility, blindness, and chronic obstructive lung disease, respectively. The goal of this study was to determine if mice deficient in TRAIL-R infected in the genital and respiratory tracts with Chlamydia spp. suffer more or less severe infections, infertility, or lung diseases than wild-type mice. Our results show no differences between the immune responses, infection severity, and long-term sequelae between TRAIL-R knockout and wild-type animals following a genital or a respiratory infection with Chlamydia.