Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors.

Receptor guanylyl cyclases (GCs) are single membrane spanning, multidomain enzymes, that synthesize cGMP in response to natriuretic peptides or other ligands. They are evolutionarily conserved from sea urchins to humans and regulate diverse physiologies. Most family members are phosphorylated on four to seven conserved serines or threonines at the beginning of their kinase homology domains. This review describes studies that demonstrate that phosphorylation and dephosphorylation are required for activation and inactivation of these enzymes, respectively. Phosphorylation sites in GC-A, GC-B, GC-E and sea urchin receptors are discussed as are mutant receptors that mimic the dephosphorylated, inactive or phosphorylated, active forms of GC-A and GC-B, respectively. A salt bridge model is described that explains why phosphorylation is required for enzyme activation. Potential kinases, phosphatases and ATP regulation of GC receptors are also discussed. Critically, knock-in mice with glutamate substitutions for receptor phosphorylation sites are described. The inability of opposing signaling pathways to inhibit cGMP synthesis in mice where GC-A or GC-B cannot be dephosphorylated demonstrates the necessity of receptor dephosphorylation in vivo. Cardiac hypertrophy, oocyte meiosis, long bone growth/achondroplasia, and bone density are regulated by GC phosphorylation, but additional processes are likely to be identified in the future.

Nature exposure and mental health during the COVID-19 pandemic: A Navigation Guide systematic review with meta-analysis.

Prior reviews have highlighted that nature exposure was a valuable coping strategy enhancing mental health during the COVID-19 pandemic. However, no existing reviews have determined the quality of evidence and risk of bias of the empirical studies supporting this claim. To address this gap, we employed a Navigation Guide systematic review and meta-analysis approach to investigate associations between nature exposure and mental health during the pandemic. Searches in PubMed, Web of Science, Scopus, CINAHL, and PsycInfo retrieved relevant articles published between January 1, 2020, and March 4, 2024. We used the Navigation Guide methodology to assess the risk of bias and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessments to evaluate the overall quality of evidence. Our search retrieved 113 studies that met the inclusion criteria and reported diverse types of exposure, including nature availability, nature visit frequency, green space accessibility, and green space type, alongside associations with 12 mental health outcomes. Meta-analyses found access to gardens was associated with lower odds of depression [(Pooled odds ratio [OR] = 0.71, 95%CI = 0.61, 0.82), I2 = 0%, n = 3] and anxiety [(Pooled OR = 0.73, 95%CI = 0.63, 0.84), I2 = 0%, n = 3]. Increased time in green spaces was associated with lower level of stress [(Pooled Corr = -0.11, 95%CI = -0.17, -0.05), I2 = 0%, n = 2]. Higher frequency of visits to nature was associated with improved mental well-being [(Pooled standardized beta = 0.10, 95%CI = 0.07, 0.14), I2 = 0%, n = 2] and general mental health [(Pooled standardized beta = 0.11, 95%CI = 0.03-0.38), I2 = 82%, n = 2]. However, the number of pooled studies was small and the overall quality of evidence was "very low" for all outcomes, and high levels of bias were observed (26% of studies had high, 71% probably high). Nonetheless, given the trends in the results, nature-based solutions emphasizing exposure to gardens and green spaces near the home may have promoted psychological resilience during this public health crisis.

Place attachment mediates links between pro-environmental attitudes and behaviors among visitors to Mt. Bukhan National Park, South Korea.

Introduction: Efforts to understand visitors' participation in pro-environmental behaviors (PEB) are important for protected area management. Previous research in nature-based recreation settings suggests environmental attitudes may affect PEB, and that these relationships might be mediated by different dimensions of place attachment (place identity and place dependence). Methods: We used structural equation modeling to test the mediating effect of hikers' place attachment in the relationship between environmental attitudes and PEBs that occur within (on-site) and outside a protected area (off-site): Mt. Bukhan National Park in South Korea. Results: Results showed that cognitive (environmental knowledge) and affective (environmental sensitivity) components of environmental attitudes were significant predictors for place attachment. Place identity was linked to off-site PEB, while place dependence was a key antecedent for both off-site and on-site PEBs. Discussion: Our findings could help researchers and practitioners better understand how place attachment forms and how it can impact outdoor recreationists' behavior, ultimately helping to promote PEBs and facilitate sustainable management goals.

Exploring the Geospatial Relationship Between COVID-19 Positivity and Income in Mixed Urban-Rural Population.

The COVID-19 pandemic has had a deep influence on American life in general and on the American economy in particular. However, the burden of the pandemic has not been distributed equally among members of a population based on their social-determinants-of-health. The purpose of this study was to investigate whether the median income was associated with COVID-19 total number of tests and positivity rate in Boone County, Missouri during the pandemic. We analyzed the geospatial data using three heat maps showing the Census tract-wise COVID-19 positivity rate, Census tract-wise median income, and Census tract-wise total number of COVID-19 tests to highlight our study findings. Our study results support the hypothesis that individuals with lower median income tend to have a lower total number of COVID-19 tests and higher COVID-19 positivity rates in Boone County, Missouri. The Pearson correlation coefficient between the positivity rate and median income is -0.324.

The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Smile Restoration of a Dental Anxiety Patient Using Same-Day Chairside CAD/CAM and Esthetic Zirconia.

This clinical case study describes the smile restoration of a 33-year-old female patient who exhibited severe dental anxiety, multiple cavities, discoloration, and a fractured tooth. The patient's complex dental history and anxiety-driven treatment preferences posed challenges that were met with a minimally invasive strategy. The case involved meticulous diagnosis, leveraging advanced diagnostic wax-ups, and a comprehensive treatment plan. Esthetic zirconia material was utilized to enable the preservation of tooth structure while achieving visually appealing and functional outcomes, and CAD/CAM technology facilitated same-day restorations with superior marginal fit, aided by the precision of a digital intraoral scanner. The patient's dental anxiety strongly influenced the treatment approach, leading to the integration of smile enhancement alongside caries treatment. The use of a single cement and bond product simplified the final cementation process, while the versatility of the zirconia CAD/CAM material allowed for fabrication of various restoration types with minimal tooth reduction. This streamlined workflow expedited treatment, which was especially crucial for the anxious patient undergoing sedation.

Novel enhancers of guanylyl cyclase-A activity acting via allosteric modulation.

BACKGROUND AND PURPOSE: Guanylyl cyclase-A (GC-A), activated by endogenous atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), plays an important role in the regulation of cardiovascular and renal homeostasis and is an attractive drug target. Even though small molecule modulators allow oral administration and longer half-life, drug targeting of GC-A has so far been limited to peptides. Thus, in this study we aimed to develop small molecular activators of GC-A. EXPERIMENTAL APPROACH: Hits were identified through high-throughput screening and optimized by in silico design. Cyclic GMP was measured in QBIHEK293A cells expressing GC-A, GC-B or chimerae of the two receptors using AlphaScreen technology. Binding assays were performed in membrane preparations or whole cells using 125 I-ANP. Vasorelaxation was measured in aortic rings isolated from Wistar rats. KEY RESULTS: We have identified small molecular allosteric enhancers of GC-A, which enhanced ANP or BNP effects in cellular systems and ANP-induced vasorelaxation in rat aortic rings. The mechanism of action appears novel and not mediated through previously described allosteric binding sites. In addition, the selectivity and activity depend on a single amino acid residue that differs between the two similar receptors GC-A and GC-B. CONCLUSION AND IMPLICATIONS: We describe a novel allosteric binding site on GC-A, which can be targeted by small molecules to enhance ANP and BNP effects. These compounds will be valuable tools in further development and proof-of-concept of GC-A enhancement for the potential use in cardiovascular therapy.

Demographic and Time Trend Analysis of COVID-19 Test Results of Boone County, Missouri.

The COVID-19 pandemic has had deep influence on American life. However, the burden of the pandemic has not been distributed equally among members of a population based on their demographic features. The purpose of this study was to investigate whether sex, age, race, and religion were associated with COVID-19 positivity rates in Boone County, Missouri over a 22-month period (March 15, 2020 to December 2, 2021) of the pandemic. We analyzed the data using age distribution histograms, two-way delta tables, and trend analysis graphs to highlight our study findings. We evaluated those graphs with each demographic feature across a collection of defined epochs of key events, such as vaccine release, Delta variant, vaccine boosters, and initial Omicron variant. Our results supported the hypothesis that males and minority races such as Black or African Americans and All-Other are more likely to have a higher COVID-19 positivity rate across our defined epochs.

Greenness and equity: Complex connections between intra-neighborhood contexts and residential tree planting implementation.

Associations between neighborhood greenness and socioeconomic status (SES) are established, yet intra-neighborhood context and SES-related barriers to tree planting remain unclear. Large-scale tree planting implementation efforts are increasingly common and can improve human health, strengthen climate adaptation, and ameliorate environmental inequities. Yet, these efforts may be ineffective without in-depth understanding of local SES inequities and barriers to residential planting. We recruited 636 residents within and surrounding the Oakdale Neighborhood of Louisville, Kentucky, USA, and evaluated associations of individual and neighborhood-level sociodemographic indicators with greenness levels at multiple scales. We offered no-cost residential tree planting and maintenance to residents within a subsection of the neighborhood and examined associations of these sociodemographic indicators plus baseline greenness levels with tree planting adoption among 215 eligible participants. We observed positive associations of income with Normalized Difference Vegetation Index (NDVI) and leaf area index (LAI) within all radii around homes, and within yards of residents, that varied in strength. There were stronger associations of income with NDVI in front yards but LAI in back yards. Among Participants of Color, associations between income and NDVI were stronger than with Whites and exhibited no association with LAI. Tree planting uptake was not associated with income, education, race, nor employment status, but was positively associated with lot size, home value, lower population density, and area greenness. Our findings reveal significant complexity of intra-neighborhood associations between SES and greenness that could help shape future research and equitable greening implementation. Results show that previously documented links between SES and greenspace at large scales extend to residents' yards, highlighting opportunities to redress greenness inequities on private property. Our analysis found that uptake of no-cost residential planting and maintenance was nearly equal across SES groups but did not redress greenness inequity. To inform equitable greening, further research is needed to evaluate culture, norms, perceptions, and values affecting tree planting acceptance among low-SES residents.

The Role of Remote Sensing and Geospatial Analysis for Understanding COVID-19 Population Severity: A Systematic Review.

Remote sensing (RS), satellite imaging (SI), and geospatial analysis have established themselves as extremely useful and very diverse domains for research associated with space, spatio-temporal components, and geography. We evaluated in this review the existing evidence on the application of those geospatial techniques, tools, and methods in the coronavirus pandemic. We reviewed and retrieved nine research studies that directly used geospatial techniques, remote sensing, or satellite imaging as part of their research analysis. Articles included studies from Europe, Somalia, the USA, Indonesia, Iran, Ecuador, China, and India. Two papers used only satellite imaging data, three papers used remote sensing, three papers used a combination of both satellite imaging and remote sensing. One paper mentioned the use of spatiotemporal data. Many studies used reports from healthcare facilities and geospatial agencies to collect the type of data. The aim of this review was to show the use of remote sensing, satellite imaging, and geospatial data in defining features and relationships that are related to the spread and mortality rate of COVID-19 around the world. This review should ensure that these innovations and technologies are instantly available to assist decision-making and robust scientific research that will improve the population health diseases outcomes around the globe.

Antimicrobial resistance from a One Health perspective in Zambia: a systematic review.

BACKGROUND: Antimicrobial resistance (AMR) is widely acknowledged as a global health problem, yet its extent is not well evaluated, especially in low-middle income countries. It is challenging to promote policies without focusing on healthcare systems at a local level, therefore a baseline assessment of the AMR occurrence is a priority. This study aimed to look at published papers relating to the availability of AMR data in Zambia as a means of establishing an overview of the situation, to help inform future decisions. METHODS: PubMed, Cochrane Libraries, Medical Journal of Zambia and African Journals Online databases were searched from inception to April 2021 for articles published in English in accordance with the PRISMA guidelines. Retrieval and screening of article was done using a structured search protocol with strict inclusion/exclusion criteria. RESULTS: A total of 716 articles were retrieved, of which 25 articles met inclusion criteria for final analysis. AMR data was not available for six of the ten provinces of Zambia. Twenty-one different isolates from the human health, animal health and environmental health sectors were tested against 36 antimicrobial agents, across 13 classes of antibiotics. All the studies showed a degree of resistance to more than one class of antimicrobials. Majority of the studies focused on antibiotics, with only three studies (12%) highlighting antiretroviral resistance. Antitubercular drugs were addressed in only five studies (20%). No studies focused on antifungals. The most common organisms tested, across all three sectors, were Staphylococcus aureus, with a diverse range of resistance patterns found; followed by Escherichia coli with a high resistance rate found to cephalosporins (24-100%) and fluoroquinolones (20-100%). CONCLUSIONS: This review highlights three important findings. Firstly, AMR is understudied in Zambia. Secondly, the level of resistance to commonly prescribed antibiotics is significant across the human, animal, and environmental sectors. Thirdly, this review suggests that improved standardization of antimicrobial susceptibility testing in Zambia could help to better delineate AMR patterns, allow comparisons across different locations and tracking of AMR evolution over time.

Increasing reliability of axially compressed cylinders through stiffness tailoring and optimization.

The capabilities of the rapid tow shearing (RTS) process are explored to reduce the well-known imperfection sensitivity of axially compressed cylindrical shells. RTS deposits curvilinear carbon fibre tapes with a fibre-angle-thickness coupling that enables the in situ manufacturing of embedded rings and stringers. By blending the material's elastic modulus and wall thickness smoothly across the cylindrical surface, the load paths can be redistributed favourably with a minimal-design approach that contains part count and weight while ameliorating imperfection sensitivity. A genetic algorithm that incorporates realistic manufacturing imperfections and axial stiffness penalty is used to maximize the 99.9% reliability load of straight fibre (SF) and RTS cylinders. The axial stiffness penalty ensures that reliability does not come at the expense of stiffness. The first-order second-moment method is used to calculate statistical moments that enable an estimate of the 99.9% reliability load. Due to the fibre-angle-thickness coupling of RTS, buckling data are normalized by mass and thickness. Compared to a quasi-isotropic laminate, which corresponds to the optimal eight-layer design for a perfect cylinder, the optimized SF and RTS laminates have a 6% and 8% greater 99.9% normalized reliability load. By relaxing the axial stiffness penalty, the performance benefit can be increased such that SF and RTS cylinders exceed the 99.9% normalized reliability load of an eight-layer quasi-isotropic laminate by 23% and 37%, respectively. Both improvements (with and without penalty functions) stem largely from a reduction in the variance of the buckling-load distribution, thereby demonstrating the potential of fibre-steered cylinders in reducing the imperfection sensitivity of cylindrical shells. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'.

Beyond "bluespace" and "greenspace": A narrative review of possible health benefits from exposure to other natural landscapes.

Numerous studies have highlighted the physical and mental health benefits of contact with nature, typically in landscapes characterized by plants (i.e., "greenspace") and water (i.e., "bluespace"). However, natural landscapes are not always green or blue, and the effects of other landscapes are worth attention. This narrative review attempts to overcome this limitation of past research. Rather than focusing on colors, we propose that natural landscapes are composed of at least one of three components: (1) plants (e.g., trees, flowering plants, grasses, sedges, mosses, ferns, and algae), (2) water (e.g., rivers, canals, lakes, and oceans), and/or (3) rocks and minerals, including soil. Landscapes not dominated by plants or liquid-state water include those with abundant solid-state water (e.g., polar spaces) and rocks or minerals (e.g., deserts and caves). Possible health benefits of solid-state water or rock/mineral dominated landscapes include both shorter-term (e.g., viewing images) and longer-term (e.g., living in these landscapes) exposure durations. Reported benefits span improved emotional and mental states and medical treatment resources for respiratory conditions and allergies. Mechanisms underlying the health benefits of exposure consist of commonly discussed theories in the "greenspace" and "bluespace" literature (i.e., instoration and restoration) as well as less discussed pathways in that literature (i.e., post-traumatic growth, self-determination, supportive environment theory, and place attachment). This is the first review to draw attention to the potential salutogenic value of natural landscapes beyond "greenspace" and "bluespace." It is also among the first to highlight the limitations and confusion that result from classifying natural landscapes using color. Since the extant literature on natural landscapes - beyond those with abundant plants or liquid-state water - is limited in regard to quantity and quality, additional research is needed to understand their restorative potential and therapeutic possibilities.

The complex relationship between greenspace and well-being in children with and without autism.

Greenspace (defined here as canopy coverage) positively correlates with improved well-being in typically developing individuals, but this relationship has not been established in children with autism spectrum disorder (ASD). To investigate this relationship, the current study merged data from the National Survey of Children's Health (2012) with the National Land Cover Database. Across typically developing children, children with ASD, and non-autistic children with special healthcare needs (CSHCN), greenspace unexpectedly negatively correlated with well-being. Further, compared with typically developing children, children with ASD or CSHCN status had lower well-being. Interestingly, typically developing children with conduct problems displayed an unexpected negative relationship (i.e. as greenspace increased whereas well-being decreased), though those without conduct problems showed no relationship. Children with ASD displayed no relationship between greenspace independent of conduct problems. CSHCN displayed non-significant trends suggesting mild positive relationships between greenspace and well-being. These data indicate the relationship between greenspace and well-being is more complex than expected and may depend on the diagnostic traits of the population studied.

Ethnic and National Differences in Congenital Adrenal Hyperplasia Incidence: A Systematic Review and Meta-Analysis.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions. OBJECTIVES: This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH. METHODS: PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types. RESULTS: This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient. CONCLUSIONS: This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.

Epitope-tagged and phosphomimetic mouse models for investigating natriuretic peptide-stimulated receptor guanylyl cyclases.

The natriuretic peptide receptors NPR1 and NPR2, also known as guanylyl cyclase A and guanylyl cyclase B, have critical functions in many signaling pathways, but much remains unknown about their localization and function in vivo. To facilitate studies of these proteins, we developed genetically modified mouse lines in which endogenous NPR1 and NPR2 were tagged with the HA epitope. To investigate the role of phosphorylation in regulating NPR1 and NPR2 guanylyl cyclase activity, we developed mouse lines in which regulatory serines and threonines were substituted with glutamates, to mimic the negative charge of the phosphorylated forms (NPR1-8E and NPR2-7E). Here we describe the generation and applications of these mice. We show that the HA-NPR1 and HA-NPR2 mice can be used to characterize the relative expression levels of these proteins in different tissues. We describe studies using the NPR2-7E mice that indicate that dephosphorylation of NPR2 transduces signaling pathways in ovary and bone, and studies using the NPR1-8E mice that indicate that the phosphorylation state of NPR1 is a regulator of heart, testis, and adrenal function.

Vicinal glutamates are better phosphomimetics: Phosphorylation is required for allosteric activation of guanylyl cyclase-A.

Multisite phosphorylation of guanylyl cyclase (GC)-A, also known as NPR-A or NPR1, is required for receptor activation by natriuretic peptides (NPs) because alanine substitutions for the first four GC-A phosphorylation sites produce an enzyme that cannot be stimulated by NPs. In contrast, single Glu substitutions for the first six chemically identified GC-A phosphorylation sites to mimic the negative charge of phosphate produced an enzyme that is activated by NPs but had an elevated Michaelis constant (Km), resulting in low activity. Here, we show that vicinal (double adjacent) Glu substitutions for the same sites to mimic the two negative charges of phosphate produced a near wild type (WT) enzyme with a low Km. Unlike the enzyme with single glutamate substitutions, the vicinally substituted enzyme did not require the functionally identified Ser-473-Glu substitution to achieve WT-like activity. Importantly, the negative charge associated with either phosphorylation or glutamate substitutions was required for allosteric activation of GC-A by ATP. We conclude that vicinal Glu substitutions are better phosphomimetics than single Glu substitutions and that phosphorylation is required for allosteric activation of GC-A in the absence and presence of NP. Finally, we suggest that the putative functionally identified phosphorylation sites, Ser-473 in GC-A and Ser-489 in GC-B, are not phosphorylation sites at all.

A Case of Recurrent Epiploic Appendagitis Treated With Conservative Management.

Epiploic appendagitis is a rare and commonly misdiagnosed cause of acute abdominal pain. Treatment for the initial presentation of epiploic appendagitis is conservative management with anti-inflammatory medications. There is no consensual treatment algorithm for recurrent appendagitis as some studies recommend conservative management and others recommend surgical excision. This case report will cover a patient who presented with recurrent epiploic appendagitis and was treated with conservative management.

Correction: Psychological impacts from COVID-19 among university students: Risk factors across seven states in the United States.

[This corrects the article DOI: 10.1371/journal.pone.0245327.].