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BACKGROUND: Moral injury is a potentially debilitating outcome of exposure to events involving transgressions against an individual's moral code. It is often observed in the context of PTSD; however, treatments that do not differentiate the two are often ineffective for moral injury, suggesting different mechanisms contribute to the conditions. The most widely accepted model of moral injury proposes an important role for self-discrepancy processes in generating and maintaining event-related distress, but this has yet to be examined. METHODS: This study recruited 172 adults online who had been exposed to a potentially morally injurious event in the previous 5 years. Participants completed measures of event-related distress, PTSD, depression, and anxiety, as well as a self-discrepancy task involving subjective representations of their ideal, ought, and feared selves. RESULTS: Multiple regression analyses found a small but significant relationship between self-discrepancy and event-related distress, with higher levels of ought self-discrepancy independently predicting higher event-related distress scores. CONCLUSIONS: This study provides the first empirical evidence of the relationship between self-discrepancy and moral injury. We identified the ought self as a domain of self-discrepancy salient to moral injury, further differentiating moral injury from PTSD.

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CpG site methylation patterns have potential to improve differentiation of high-grade screening-detected cervical abnormalities. We assessed CpG differential methylation (DM) and differential variability (DV) in high-grade (CIN2+) vs. low-grade (≤CIN1) lesions. In ≤CIN1 (n=117) and CIN2+ (n=31) samples, cervical sample DNA underwent testing with Illumina HumanMethylation arrays. We assessed DM and DV of CpG methylation M values among nine cervical cancer-associated genes. We fit CpG-specific linear models and estimated empirical Bayes standard errors and false discovery rates (FDR). An exploratory epigenome-wide association study (EWAS) aimed to detect novel DM and DV CpGs (FDR<0.05) and Gene Ontology (GO) term enrichment. Compared to ≤CIN1, CIN2+ exhibited greater methylation at CCNA1 Cluster 1 (M value difference 0.24; 95% CI 0.04, 0.43) and RARB Cluster 2 (0.16; 95% CI 0.05, 0.28), and lower methylation at CDH1 Cluster 1 (-0.15; 95% CI -0.26, -0.04). CIN2+ exhibited lower variability at CDH1 Cluster 2 (variation difference -0.24; 95% CI -0.41, -0.05) and FHIT Cluster 1 (-0.30; 95% CI -0.50, -0.09). EWAS detected 3,534 DM and 270 DV CpGs. Forty-four GO terms were enriched with DM CpGs related to transcriptional, structural, developmental, and neuronal processes. Methylation patterns may help triage screening-detected cervical abnormalities and inform US screening algorithms.

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Multivariable Mendelian randomization allows simultaneous estimation of direct causal effects of multiple exposure variables on an outcome. When the exposure variables of interest are quantitative omic features, obtaining complete data can be economically and technically challenging: the measurement cost is high, and the measurement devices may have inherent detection limits. In this paper, we propose a valid and efficient method to handle unmeasured and undetectable values of the exposure variables in a one-sample multivariable Mendelian randomization analysis with individual-level data. We estimate the direct causal effects with maximum likelihood estimation and develop an expectation-maximization algorithm to compute the estimators. We show the advantages of the proposed method through simulation studies and provide an application to the Hispanic Community Health Study/Study of Latinos, which has a large amount of unmeasured exposure data.

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Circulating metabolite levels partly reflect the state of human health and diseases, and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single study analyses. Leveraging the rich metabolomics resources generated by the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally-diverse samples. We provided recommendations for outlier and imputation handling to process metabolite data, as well as a general analytical framework. We further performed a pooled analysis following our practical recommendations and discovered 1,778 independent loci associated with 667 metabolites. Among 108 novel locus - metabolite pairs, we detected not only novel loci within previously implicated metabolite associated genes, but also novel genes (such as GAB3 and VSIG4 located in the X chromosome) that have putative roles in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, including well-known metabolic genes such as FADS2 , D2HGDH , SUGP1 , UTG2B17 , strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

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Obesity and poverty disproportionally affect African American persons. Epigenetic mechanisms could partially explain the association between socioeconomic disadvantage and body mass index (BMI). We examined the extent to which epigenetic mechanisms mediate the effect of socioeconomic status (SES) on BMI. Using data from African American adults from the Atherosclerosis Risk in Communities (ARIC) Study (n = 2664, mean age = 57 years), education, income, and occupation were used to create a composite SES score at visit 1 (1987-1989). We conducted two methylation-wide association analyses to identify associations between SES (visit 1), BMI and cytosine-phosphate-guanine (CpG) sites measured at a subsequent visit (1990-1995). We then utilized structural equation modeling (SEM) to test whether identified sites mediated the association between earlier SES and BMI in sex-stratified models adjusted for demographic and risk factor covariates. Independent replication and meta-analyses were conducted using the Jackson Heart Study (JHS, n = 874, mean age 51 years, 2000-2004). Three CpG sites near MAD1L1, KDM2B, and SOCS3 (cg05095590, cg1370865, and cg18181703) were suggestively associated (P-value < 1.3×10-5) in ARIC and at array-wide significance (P-value < 1.3×10-7) in a combined meta-analysis of ARIC with JHS. SEM of these three sites revealed significant indirect effects in females (P-value < 5.8×10-3), each mediating 7%-20% of the total effect of SES on BMI. Nominally significant indirect effects were observed for two sites near MAD1L1 and KDM2B in males (P-value < 3.4×10-2), mediating -17 and -22% of the SES-BMI effect. These results provide further evidence that epigenetic modifications may be a potential pathway through which SES may "get under the skin" and contribute to downstream health disparities.

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BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Asunto(s)

Citocromo P-450 CYP1B1 , Secuenciación del Exoma , Exoma , Glaucoma , Humanos , Glaucoma/genética , Glaucoma/congénito , Citocromo P-450 CYP1B1/genética , Femenino , Masculino , Secuenciación del Exoma/métodos , Estados Unidos , Exoma/genética , Mutación/genética , Predisposición Genética a la Enfermedad , Lactante , Recién Nacido

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Motivation: Deep generative models have the potential to overcome difficulties in sharing individual-level genomic data by producing synthetic genomes that preserve the genomic associations specific to a cohort while not violating the privacy of any individual cohort member. However, there is significant room for improvement in the fidelity and usability of existing synthetic genome approaches. Results: We demonstrate that when combined with plentiful data and with population-specific selection criteria, deep generative models can produce synthetic genomes and cohorts that closely model the original populations. Our methods improve fidelity in the site-frequency spectra and linkage disequilibrium decay and yield synthetic genomes that can be substituted in downstream local ancestry inference analysis, recreating results with .91 to .94 accuracy. Availability: The model described in this paper is freely available at github.com/rlaboulaye/clonehort .

RESUMEN

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Asunto(s)

Hematopoyesis Clonal , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Periodontitis , Animales , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Ratones , Hematopoyesis Clonal/genética , Humanos , Periodontitis/genética , Periodontitis/patología , Mutación , Masculino , Femenino , Inflamación/genética , Inflamación/patología , Osteoclastos/metabolismo , Ratones Endogámicos C57BL , Adulto , Interleucina-17/metabolismo , Interleucina-17/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Hematopoyesis/genética , Osteogénesis/genética , Células Madre Hematopoyéticas/metabolismo , Resorción Ósea/genética , Resorción Ósea/patología , Persona de Mediana Edad

RESUMEN

Bioactive fatty acid-derived oxylipin molecules play key roles in mediating inflammation and oxidative stress, which underlie many chronic diseases. Circulating levels of fatty acids and oxylipins are influenced by both environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biological pathways. Thus, we performed a genome wide association study (GWAS) of n=81 fatty acids and oxylipins in n=11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years, standard deviation = 13.8 years). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Heritability estimates ranged from 0% to 47.9%, and 48 of the 81oxylipins and fatty acids were significantly heritable. Moreover, 40 (49.4%) of the 81 oxylipins and fatty acids had at least one genome-wide significant (p< 6.94E-11) variant resulting in 19 independent genetic loci involved in fatty acid and oxylipin synthesis, as well as downstream pathways. Four loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including the desaturase-encoding FADS and the OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with four or more fatty acids and oxylipins. The majority of the 15 remaining loci (87.5%) (lead variant MAF range = 0.03-0.45, mean = 0.23) were only associated with one oxylipin or fatty acid, demonstrating evidence of distinct genetic effects. Finally, while most loci identified in two-degree-of-freedom tests were previously identified in our main effects analyses, we also identified an additional rare variant (MAF = 0.002) near CARS2, a locus previously implicated in inflammation. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating future multi-omics work to characterize these compounds and elucidate their roles in disease pathways.

RESUMEN

Genome-wide association studies (GWAS) have identified numerous body mass index (BMI) loci. However, most underlying mechanisms from risk locus to BMI remain unknown. Leveraging omics data through integrative analyses could provide more comprehensive views of biological pathways on BMI. We analyzed genotype and blood gene expression data in up to 5,619 samples from the Framingham Heart Study (FHS). Using 3,992 single nucleotide polymorphisms (SNPs) at 97 BMI loci and 20,692 transcripts within 1 Mb, we performed separate association analyses of transcript with BMI and SNP with transcript (PBMI and PSNP, respectively) and then a correlated meta-analysis between the full summary data sets (PMETA). We identified transcripts that met Bonferroni-corrected significance for each omic, were more significant in the correlated meta-analysis than each omic, and were at least nominally associated with BMI in FHS data. Among 308 significant SNP-transcript-BMI associations, we identified seven genes (NT5C2, GSTM3, SNAPC3, SPNS1, TMEM245, YPEL3, and ZNF646) in five association regions. Using an independent sample of blood gene expression data, we validated results for SNAPC3 and YPEL3. We tested for generalization of these associations in hypothalamus, nucleus accumbens, and liver and observed significant (PMETA<0.05 & PMETA

RESUMEN

Targeted grazing to control undesirable plant species is increasingly of interest across a diversity of ecosystems, particularly as an alternative or complement to widely used herbicides. However, there are limited comprehensive evaluations of targeted grazing that evaluate both invasive species management effectiveness and potential negative effects on the ecosystem. Phragmites australis, a tall-statured, dense perennial invasive grass from Eurasia, is a pervasive problem in wetlands across the North American continent. As with many invasive species where management has historically relied on herbicides and resistance is a growing concern, land managers seek viable alternatives that have minimal negative ecosystem impacts. Grazing has been used for millennia to manage native Phragmites in Europe. Similarly, in its invasive range within North America, small-scale studies suggest Phragmites may be suppressed by grazers. Yet, the effectiveness of grazing at large scales and its effects on broader ecosystem properties remain largely unknown. We evaluated the influence of targeted grazing on vegetation, soil nutrients, and water nutrients over two years in large plots (∼300x the size of previous studies). We also tested the effects of mowing, a treatment that can be used to facilitate grazer access to large, dense Phragmites stands. In line with our predictions, we found that cattle grazing effectively suppressed invasive Phragmites over two years. Mowing reduced litter, and moderately reduced standing dead Phragmites, both of which suppress native plant germination in this system. However, these reductions in Phragmites were not accompanied by indications of native plant community recovery, as we had optimistically predicted. Despite the potential for grazing to reduce nutrient sequestration by plants and fertilize soils, we were surprised to find no clear negative effects of grazing on nutrient mobilization to groundwater or floodwater. Taken together, our findings indicate that targeted grazing, when implemented at broad scales over short time frames, is effective at achieving invasive plant management goals without sizable nutrient impacts. However, additional steps will be needed to achieve the restoration of diverse, robust native plant communities.

Asunto(s)

Especies Introducidas , Humedales , Animales , Poaceae , Ecosistema , Suelo , Herbivoria , Nutrientes

RESUMEN

Dominant X-linked diseases are uncommon due to female X chromosome inactivation (XCI). While random XCI usually protects females against X-linked mutations, Rett syndrome (RTT) is a female neurodevelopmental disorder caused by heterozygous MECP2 mutation. After 6-18 months of typical neurodevelopment, RTT girls undergo poorly understood regression. We performed longitudinal snRNA-seq on cerebral cortex in a construct-relevant Mecp2e1 mutant mouse model of RTT, revealing transcriptional effects of cell type, mosaicism, and sex on progressive disease phenotypes. Across cell types, we observed sex differences in the number of differentially expressed genes (DEGs) with 6x more DEGs in mutant females than males. Unlike males, female DEGs emerged prior to symptoms, were enriched for homeostatic gene pathways in distinct cell types over time, and correlated with disease phenotypes and human RTT cortical cell transcriptomes. Non-cell-autonomous effects were prominent and dynamic across disease progression of Mecp2e1 mutant females, indicating wild-type-expressing cells normalizing transcriptional homeostasis. These results improve understanding of RTT progression and treatment.

RESUMEN

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Asunto(s)

Aberraciones Cromosómicas , Hematopoyesis Clonal , Mosaicismo , Humanos , Hematopoyesis Clonal/genética , Masculino , Femenino , Estudio de Asociación del Genoma Completo , Janus Quinasa 2/genética , Telomerasa/genética , Telomerasa/metabolismo , Pérdida de Heterocigocidad , Estudios Transversales , Mutación , Persona de Mediana Edad , Células Madre Hematopoyéticas/metabolismo , Polimorfismo de Nucleótido Simple , Anciano

RESUMEN

Predicting how biological communities assemble in restored ecosystems can assist in conservation efforts, but most research has focused on plants, with relatively little attention paid to soil microbial organisms that plants interact with. Arbuscular mycorrhizal (AM) fungi are an ecologically significant functional group of soil microbes that form mutualistic symbioses with plants and could therefore respond positively to plant community restoration. To evaluate the effects of plant community restoration on AM fungi, we compared AM fungal abundance, species richness, and community composition of five annually cultivated, conventionally managed agricultural fields with paired adjacent retired agricultural fields that had undergone prairie restoration 5-9 years prior to sampling. We hypothesized that restoration stimulates AM fungal abundance and species richness, particularly for disturbance-sensitive taxa, and that gains of new taxa would not displace AM fungal species present prior to restoration due to legacy effects. AM fungal abundance was quantified by measuring soil spore density and root colonization. AM fungal species richness and community composition were determined in soils and plant roots using DNA high-throughput sequencing. Soil spore density was 2.3 times higher in restored prairies compared to agricultural fields, but AM fungal root colonization did not differ between land use types. AM fungal species richness was 2.7 and 1.4 times higher in restored prairies versus agricultural fields for soil and roots, respectively. The abundance of Glomeraceae, a disturbance-tolerant family, decreased by 25% from agricultural to restored prairie soils but did not differ in plant roots. The abundance of Claroideoglomeraceae and Diversisporaceae, both disturbance-sensitive families, was 4.6 and 3.2 times higher in restored prairie versus agricultural soils, respectively. Species turnover was higher than expected relative to a null model, indicating that AM fungal species were gained by replacement. Our findings demonstrate that restoration can promote a relatively rapid increase in the abundance and diversity of soil microbial communities that had been degraded by decades of intensive land use, and community compositional change can be predicted by the disturbance tolerance of soil microbial taxonomic and functional groups.

Asunto(s)

Pradera , Micorrizas , Microbiología del Suelo , Micorrizas/fisiología , Biodiversidad , Simbiosis , Restauración y Remediación Ambiental , Conservación de los Recursos Naturales , Agricultura

RESUMEN

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38 465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program (with varying sample size by trait, where the minimum sample size was n = 737 for MMP-1). We identified 22 distinct single-variant associations across 6 traits-E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin-that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

Asunto(s)

Biomarcadores , Estudio de Asociación del Genoma Completo , Inflamación , Medicina de Precisión , Secuenciación Completa del Genoma , Humanos , Medicina de Precisión/métodos , Inflamación/genética , Estudio de Asociación del Genoma Completo/métodos , Secuenciación Completa del Genoma/métodos , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Predisposición Genética a la Enfermedad , Femenino , Interleucina-6/genética

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OBJECTIVE: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

Asunto(s)

Diabetes Mellitus Tipo 1 , Veteranos , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiología , Masculino , Persona de Mediana Edad , Veteranos/estadística & datos numéricos , Femenino , Adulto , Anciano , Predisposición Genética a la Enfermedad , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiología , Factores de Riesgo

RESUMEN

Parkinson's disease (PD) is a chronic, age-related, progressive multisystem disease associated with neuroinflammation and immune dysfunction. This review discusses the methodological approaches used to study the changes in central and peripheral immunity in PD, the advantages and limitations of the techniques, and their applicability to humans. Although a single animal model cannot replicate all pathological features of the human disease, neuroinflammation is present in most animal models of PD and plays a critical role in understanding the involvement of the immune system (IS) in the pathogenesis of PD. The IS and its interactions with different cell types in the central nervous system (CNS) play an important role in the pathogenesis of PD. Even though culture models do not fully reflect the complexity of disease progression, they are limited in their ability to mimic long-term effects and need validation through in vivo studies. They are an indispensable tool for understanding the interplay between the IS and the pathogenesis of this disease. Understanding the immune-mediated mechanisms may lead to potential therapeutic targets for the treatment of PD. We believe that the development of methodological guidelines for experiments with animal models and PD patients is crucial to ensure the validity and consistency of the results.

Asunto(s)

Modelos Animales de Enfermedad , Enfermedad de Parkinson , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/etiología , Animales , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/patología

RESUMEN

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

Asunto(s)

Proteína C-Reactiva , Metilación de ADN , Humanos , Proteína C-Reactiva/genética , Epigénesis Genética , ADN , Inflamación/genética , Estudio de Asociación del Genoma Completo , Islas de CpG , Péptidos y Proteínas de Señalización Intracelular/genética

RESUMEN

BACKGROUND: Land uses such as crop production, livestock grazing, mining, and urban development have contributed to degradation of drylands worldwide. Loss of big sagebrush (Artemisia tridentata) on disturbed drylands across the western U.S. has prompted massive efforts to re-establish this foundational species. There has been growing interest in avoiding the severe limitations experienced by plants at the seed and seedling stages by instead establishing plants from containerized greenhouse seedlings ("tubelings"). In some settings, a potential alternative approach is to transplant larger locally-collected plants ("wildlings"). We compared the establishment of mountain big sagebrush (A. tridentata ssp. vaseyana) from tubelings vs. wildlings in southeastern Idaho. A mix of native and non-native grass and forb species was drill-seeded in a pasture previously dominated by the introduced forage grass, smooth brome (Bromus inermis). We then established 80 m x 80 m treatment plots and planted sagebrush tubelings (n = 12 plots, 1200 plants) and wildlings (n = 12 plots, 1200 plants). We also established seeded plots (n = 12) and untreated control plots (n = 6) for long-term comparison. We tracked project expenses in order to calculate costs of using tubelings vs. wildlings as modified by probability of success. RESULTS: There was high (79%) tubeling and low (10%) wildling mortality within the first year. Three years post-planting, chance of survival for wildlings was significantly higher than that of tubelings (85% and 14% respectively). Despite high up-front costs of planting wildlings, high survival rates resulted in their being < 50% of the cost of tubelings on a per-surviving plant basis. Additionally, by the third year post-planting 34% of surviving tubelings and 95% of surviving wildlings showed evidence of reproduction (presence / absence of flowering stems), and the two types of plantings recruited new plants via seed (3.7 and 2.4 plants, respectively, per surviving tubeling/wildling). CONCLUSIONS: Our results indicate that larger plants with more developed root systems (wildlings) may be a promising avenue for increasing early establishment rates of sagebrush plants in restoration settings. Our results also illustrate the potential for tubelings and wildlings to improve restoration outcomes by "nucleating" the landscape via recruitment of new plants during ideal climate conditions.

Asunto(s)

Artemisia , Plantones , Plantones/crecimiento & desarrollo , Idaho , Conservación de los Recursos Naturales/métodos

RESUMEN

Microbial community structure and function were assessed in the organic and upper mineral soil across a ~4000-year dune-based chronosequence at Big Bay, New Zealand, where total P declined and the proportional contribution of organic soil in the profile increased with time. We hypothesized that the organic and mineral soils would show divergent community evolution over time with a greater dependency on the functionality of phosphatase genes in the organic soil layer as it developed. The structure of bacterial, fungal, and phosphatase-harbouring communities was examined in both horizons across 3 dunes using amplicon sequencing, network analysis, and qPCR. The soils showed a decline in pH and total phosphorus (P) over time with an increase in phosphatase activity. The organic horizon had a wider diversity of Class A (phoN/phoC) and phoD-harbouring communities and a more complex microbiome, with hub taxa that correlated with P. Bacterial diversity declined in both horizons over time, with enrichment of Planctomycetes and Acidobacteria. More complex fungal communities were evident in the youngest dune, transitioning to a dominance of Ascomycota in both soil horizons. Higher phosphatase activity in older dunes was driven by less diverse P-mineralizing communities, especially in the organic horizon.

Asunto(s)

Microbiota , Suelo , Suelo/química , Fósforo/análisis , Bosque Lluvioso , Bacterias/genética , Microbiota/genética , Minerales , Monoéster Fosfórico Hidrolasas/genética , Microbiología del Suelo