Toxicity of methylmercury (MeHg) to wildlife and humans results from its binding to cysteine residues of proteins, forming MeHg-cysteinate (MeHgCys) complexes that hinder biological functions. ...MeHgCys complexes can be detoxified in vivo, yet how this occurs is unknown. We report that MeHgCys complexes are transformed into selenocysteinate Hg(Sec)4 complexes in multiple animals from two phyla (a waterbird, freshwater fish, and earthworms) sampled in different geographical areas and contaminated by different Hg sources. In addition, high energy-resolution X-ray absorption spectroscopy (HR-XANES) and chromatography-inductively coupled plasma mass spectrometry of the waterbird liver support the binding of Hg(Sec)4 to selenoprotein P and biomineralization of Hg(Sec)4 to chemically inert nanoparticulate mercury selenide (HgSe). The results provide a foundation for understanding mercury detoxification in higher organisms and suggest that the identified MeHgCys to Hg(Sec)4 demethylation pathway is common in nature.
Assessing wetland vulnerability to chronic and episodic physical drivers is fundamental for establishing restoration priorities. We synthesized multiple data sets from E.B. Forsythe National Wildlife ...Refuge, New Jersey, to establish a wetland vulnerability metric that integrates a range of physical processes, anthropogenic impact and physical/biophysical features. The geospatial data are based on aerial imagery, remote sensing, regulatory information, and hydrodynamic modeling; and include elevation, tidal range, unvegetated to vegetated marsh ratio (UVVR), shoreline erosion, potential exposure to contaminants, residence time, marsh condition change, change in salinity, salinity exposure and sediment concentration. First, we delineated the wetland complex into individual marsh units based on surface contours, and then defined a wetland vulnerability index that combined contributions from all parameters. We applied principal component and cluster analyses to explore the interrelations between the data layers, and separate regions that exhibited common characteristics. Our analysis shows that the spatial variation of vulnerability in this domain cannot be explained satisfactorily by a smaller subset of the variables. The most influential factor on the vulnerability index was the combined effect of elevation, tide range, residence time, and UVVR. Tide range and residence time had the highest correlation, and similar bay-wide spatial variation. Some variables (e.g., shoreline erosion) had no significant correlation with the rest of the variables. The aggregated index based on the complete dataset allows us to assess the overall state of a given marsh unit and quickly locate the most vulnerable units in a larger marsh complex. The application of geospatially complete datasets and consideration of chronic and episodic physical drivers represents an advance over traditional point-based methods for wetland assessment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although the use of airborne molecules as infochemicals is common in terrestrial plants, it has not been shown to occur in an ecologically relevant context in marine seaweeds. Like terrestrial ...plants, intertidal plants spend part of their lives emersed at low tide and release volatile organic compounds (VOCs) into the air when they are grazed or physiologically stressed. We hypothesized seaweeds could use airborne VOCs as infochemicals and respond to them by upregulating a keystone defensive metabolite, dimethylsulfoniopropionate (DMSP). We conducted laboratory and field experiments in which Ulva fenestrata was exposed to airborne dimethyl sulfide (DMS), a volatile antiherbivore and antioxidant metabolite released when the seaweed is grazed or physiologically stressed. In the laboratory, U. fenestrata exposed to DMS had 43-48% higher DMSP concentrations, relative to controls, 6-9 days after exposure. In the field, U. fenestrata 1 m downwind of DMS emitters had 19% higher DMSP concentrations than upwind seaweeds after 11 days. To our knowledge, this is the first demonstration of a marine plant using an airborne molecule released when damaged to elicit defensive responses. Our study suggests that the ability to detect airborne compounds has evolved multiple times or before the divergence of terrestrial plants and green algae.
Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T ...cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation
. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage
. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage
. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4
T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.
DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association ...between methylation at individual CpG sites and health outcomes. Although blood methylation may act as a peripheral marker of common disease states, previous EWAS have typically focused only on individual conditions and have had limited power to discover disease-associated loci. This study examined the association of blood DNA methylation with the prevalence of 14 disease states and the incidence of 19 disease states in a single population of over 18,000 Scottish individuals.
DNA methylation was assayed at 752,722 CpG sites in whole-blood samples from 18,413 volunteers in the family-structured, population-based cohort study Generation Scotland (age range 18 to 99 years). EWAS tested for cross-sectional associations between baseline CpG methylation and 14 prevalent disease states, and for longitudinal associations between baseline CpG methylation and 19 incident disease states. Prevalent cases were self-reported on health questionnaires at the baseline. Incident cases were identified using linkage to Scottish primary (Read 2) and secondary (ICD-10) care records, and the censoring date was set to October 2020. The mean time-to-diagnosis ranged from 5.0 years (for chronic pain) to 11.7 years (for Coronavirus Disease 2019 (COVID-19) hospitalisation). The 19 disease states considered in this study were selected if they were present on the World Health Organisation's 10 leading causes of death and disease burden or included in baseline self-report questionnaires. EWAS models were adjusted for age at methylation typing, sex, estimated white blood cell composition, population structure, and 5 common lifestyle risk factors. A structured literature review was also conducted to identify existing EWAS for all 19 disease states tested. The MEDLINE, Embase, Web of Science, and preprint servers were searched to retrieve relevant articles indexed as of March 27, 2023. Fifty-four of approximately 2,000 indexed articles met our inclusion criteria: assayed blood-based DNA methylation, had >20 individuals in each comparison group, and examined one of the 19 conditions considered. First, we assessed whether the associations identified in our study were reported in previous studies. We identified 69 associations between CpGs and the prevalence of 4 conditions, of which 58 were newly described. The conditions were breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes mellitus. We also uncovered 64 CpGs that associated with the incidence of 2 disease states (COPD and type 2 diabetes), of which 56 were not reported in the surveyed literature. Second, we assessed replication across existing studies, which was defined as the reporting of at least 1 common site in >2 studies that examined the same condition. Only 6/19 disease states had evidence of such replication. The limitations of this study include the nonconsideration of medication data and a potential lack of generalizability to individuals that are not of Scottish and European ancestry.
We discovered over 100 associations between blood methylation sites and common disease states, independently of major confounding risk factors, and a need for greater standardisation among EWAS on human disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. Objective The objective of ...this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. Methods OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate–dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. Results Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue ( P < .05). OSM levels were also increased in bronchoalveolar lavage fluid of allergic asthmatic patients after segmental allergen challenge and in esophageal biopsy specimens from patients with eosinophilic esophagitis. OSM stimulation of air-liquid interface cultures resulted in reduced barrier function, as measured by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran flux ( P < .05). Alterations in barrier function by OSM were reversible, and the viability of epithelial cells was unaffected. OSM levels in lysates of nasal polyps and uncinate tissue positively correlated with levels of α2 -macroglobulin, a marker of epithelial leak, in localized nasal secretions ( r = 0.4855, P < .05). Conclusions These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases.
Obesity is a modifiable risk factor for urinary incontinence. This study randomly assigned overweight and obese women with urinary incontinence to an intensive 6-month weight-loss program or to a ...structured education program. More intervention-group participants had clinically relevant reductions in the frequency of episodes of any incontinence, stress incontinence, and urge incontinence.
This study randomly assigned overweight and obese women with urinary incontinence to an intensive 6-month weight-loss intervention or to a structured education program. More intervention-group participants had clinically relevant reductions in the frequency of episodes of any incontinence, stress incontinence, and urge incontinence.
Urinary incontinence affects more than 13 million women in the United States and has been associated with profound adverse effects on quality of life
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,
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; an increased risk of falls, fractures,
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and nursing-home admissions
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; and more than $20 billion in estimated annual direct health care costs.
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Observational studies suggest that obesity is a strong risk factor for urinary incontinence,
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–
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and preliminary studies suggest that weight loss may have a beneficial effect on urinary incontinence in obese patients.
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Reductions in urinary incontinence have been observed in morbidly obese women who have had dramatic weight loss after bariatric . . .
Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by ...excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells.
This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD.
NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours.
This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13–induced attenuation of tPA expression in cultured cells (P < .01).
RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13–induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.
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Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition ...including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
Synopsis
This study extends recent research demonstrating that the veiled chameleon (Chamaeleo calyptratus) can produce and detect biotremors. Chameleons were paired in various social contexts: ...dominance (male–male; female–female C. calyptratus); courtship (male–female C. calyptratus); heterospecific (C. calyptratus + C. gracilis); and inter-size class dominance (adult + juvenile C. calyptratus). Simultaneous video and accelerometer recordings were used to monitor their behavior and record a total of 398 biotremors. Chamaeleo calyptratus produced biotremors primarily in conspecific dominance and courtship contexts, accounting for 84.7% of the total biotremors recorded, with biotremor production varying greatly between individuals. Biotremors were elicited by visual contact with another conspecific or heterospecific, and trials in which chameleons exhibited visual displays and aggressive behaviors were more likely to record biotremors. Three classes of biotremor were identified—hoots, mini-hoots, and rumbles, which differed significantly in fundamental frequency, duration, and relative intensity. Biotremor frequency decreased with increasing signal duration, and frequency modulation was evident, especially in hoots. Overall, the data show that C. calyptratus utilizes substrate-borne vibrational communication during conspecific and possibly heterospecific interactions.
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