Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during ...severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity ADCC assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9
NK cells. Consistently, Siglec-9
NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9
CD56
NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9
CD56
NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells.
One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9
NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.
Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this ...inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as β-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.
The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo , which may allow for immune-mediated clearance of these cells. However, Gal-9 also ...activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential 'double-edged sword' effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo .
We used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART).
Two independent cohorts of ART-suppressed HIV-infected BLT mice were treated with either recombinant Gal-9 or phosphate-buffered saline control. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Immunohistochemistry and HIV RNAscope were used to quantify CD4 + T, myeloid, and HIV RNA+ cells in tissues. T cell activation and exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays.
Gal-9 did not induce plasma markers of inflammation or T cell markers of activation/exhaustion in vivo . However, the treatment significantly increased levels of tissue-associated HIV DNA and RNA compared to controls ( P = 0.0007 and P = 0.011, respectively, for cohort I and P = 0.002 and P = 0.005, respectively, for cohort II). RNAscope validated the Gal-9 mediated induction of HIV RNA in tissue-associated myeloid cells, but not T cells.
Our study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.
The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a "risky" lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status ...(SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index BMI ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adult Vaccination Greenberg, Grant M; Koshy, Princy A; Hanson, Mary Jane S
American family physician,
11/2022, Volume:
106, Issue:
5
Journal Article
Peer reviewed
Adult vaccination rates are low in the United States, despite clear benefits for reducing morbidity and mortality. Vaccine science is evolving rapidly, and family physicians must maintain familiarity ...with the most recent guidelines. The recommended adult immunization schedule is updated annually by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention. All eligible patients should receive SARS-CoV-2 vaccines according to the current guidelines. Adults without contraindications should also receive an annual influenza vaccine. Hepatitis A vaccine is recommended for adults with specific risk factors. All pregnant patients, adults younger than 60 years, and those 60 years and older who have risk factors should receive a hepatitis B vaccine. A 15- or 20-valent pneumococcal conjugate vaccine is recommended for all patients who are 65 years and older. Patients who receive 15-valent pneumococcal conjugate vaccine should receive a dose of 23-valent pneumococcal polysaccharide vaccine one year later. Adults 19 to 64 years of age should receive a pneumococcal vaccination if they have medical risk factors. A single dose of measles, mumps, and rubella vaccine is recommended for adults without presumptive immunity, and additional doses are recommended for patients with HIV and postdelivery for pregnant patients who are not immune to rubella. A tetanus and diphtheria toxoids booster is recommended every 10 years. For pregnant patients and those in close contact with young infants, a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine should be administered. The human papillomavirus vaccine is recommended for all people through 26 years of age. Herpes zoster vaccine is indicated for all adults 50 years and older. .
Malaysia deforested 6.3 million hectares since independence; 91% of which occurred before Malaysia pledged, at the Earth Summit in 1992, to maintain a minimum 50% of its terrestrial area under forest ...cover. However, under economic and population pressure, Sarawak—the largest contributing state to the country’s current forest cover of 54.8%—shows continuing deforestation even after 1992. This paper reviews land use policies underpinned by economic development and environmental protection considerations, land rights issues that complicate land use planning, and legislation that regulates land use change. The objective is to investigate the adequacy of existing policies and legislation in governing forest cover in Sarawak and to recommend improvement measures. If the Sarawak Land Use Policy that allocates seven million hectares for forest is realized, Malaysia’s forest cover would drop to 53%, assuming other states maintain their forests. It is recommended that legislation governing the designation of permanent forest and conversion of forest for other land use to be strengthened, civil society to be enlisted to enhance knowledge level, and carbon credit production to be promoted as alternative land use that keeps forests standing. With these measures, it is hopeful that Malaysia’s aspirations regarding forest cover can be achieved.
Probiotics are live microorganisms that confer a health benefit to the host when administered in adequate amounts. This definition links probiotic efficacy to microbial viability. The current gold ...standard assay for probiotic potency is enumeration using classical microbiology plating-based procedures, yielding results in colony-forming units (CFU). One drawback to plating-based procedures is high variability due to intrinsic and extrinsic uncertainties. These uncertainties make comparison between analytical procedures challenging. In this article, we provide tools to reduce measurement uncertainty and strengthen the reliability of probiotic enumerations by using analytical procedure lifecycle management (APLM). APLM is a tool that uses a step-by-step process to define procedure performance based on the concept that the reportable value (final CFU result) must be fit for its intended use. Once the procedure performance is defined, the information gathered through APLM can be used to evaluate and compare procedures. Here, we discuss the theory behind applying APLM and give practical information about its application to CFU enumeration procedures for probiotics using a simulated example and data set. Data collected in a manufacturer’s development laboratory is included to support application of the concept. Implementation of APLM can lead to reduced variability by identifying specific factors (e.g., the dilution step) with significant impact on the variability and providing insights to procedural modifications that lead to process improvement. Understanding and control of the analytical procedure is improved by using these tools. The probiotics industry can confidently apply the information and analytical results generated to make decisions about processes and formulation, including overage requirements. One benefit of this approach is that companies can reduce overage costs. More reliable procedures for viable cell count determinations will improve the quality evaluation of probiotic products, and hence manufacturing procedures, while ensuring that products deliver clinically demonstrated beneficial doses.
Carbon pricing is widely recognized as an effective policy instrument for climate change mitigation. Carbon pricing have been imposed in 39 developed countries and eight middle-income countries. ...Eight more middle-income countries are considering its implementation. As experiences from industrialized countries may not be relevant to developing countries, this literature review fills a knowledge gap by collating the impacts of carbon pricing in developing economies to facilitate cross-learning. Some developing countries still have distortionary subsidies in place, while others are going through environmental fiscal reforms to nudge their societies and economies towards greenhouse gases emission reduction. Various studies demonstrated that safeguards introduced with carbon pricing could help firms to transition while maintaining the motivation to innovate to stay competitive. At the household level, given different energy consumption patterns, carbon pricing in developing economies is not necessarily regressive, especially for rural population. Aggregate impacts to employment rate and gross domestic product change over time as the economy restructures towards decarbonization. A well-designed carbon pricing policy package with revenue recycling mechanisms tailored to the socioeconomic circumstances of the country could achieve multiple dividends of economic growth, increased employment, improved equality, national debt reduction or accomplishment of other sustainable development goals.
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