Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it ...is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.
Alterations in gene expression in the suicide brain have been reported and for several genes DNA methylation as an epigenetic regulator is thought to play a role. rRNA genes, that encode ribosomal ...RNA, are the backbone of the protein synthesis machinery and levels of rRNA gene promoter methylation determine rRNA transcription.
We test here by sodium bisulfite mapping of the rRNA promoter and quantitative real-time PCR of rRNA expression the hypothesis that epigenetic differences in critical loci in the brain are involved in the pathophysiology of suicide. Suicide subjects in this study were selected for a history of early childhood neglect/abuse, which is associated with decreased hippocampal volume and cognitive impairments. rRNA was significantly hypermethylated throughout the promoter and 5' regulatory region in the brain of suicide subjects, consistent with reduced rRNA expression in the hippocampus. This difference in rRNA methylation was not evident in the cerebellum and occurred in the absence of genome-wide changes in methylation, as assessed by nearest neighbor.
This is the first study to show aberrant regulation of the protein synthesis machinery in the suicide brain. The data implicate the epigenetic modulation of rRNA in the pathophysiology of suicide.
Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory ...syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUbLys48 products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUbLys48 activity-based probe. SARS PLpro binds diUbLys48 in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUbLys48 chains is predicated on contacts in the S2 site and enhanced by an S1-S1′ preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUbLys48 specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections.
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•A Lys48 linkage-specific diubiquitin activity-based probe selectively labels SARS PLpro•The structure of a diUbLys48∼SARS PLpro complex reveals an extended di-Ub conformation•S2-S1 and S1-S1′ interactions make SARS PLpro specific for K48-linked polyubiquitin•SARS PLpro recognizes Lys48-linked polyUb chains and ISG15 via distinct manners
Békés et al. present a high-resolution crystal structure of a SARS virus PLpro∼diUbLys48 complex that reveals an extended conformation of the Lys48-linked diUb unit and shows the biochemical basis for SARS PLpro’s preference for Lys48-linked polyUb chains.
Rural populations have a higher prevalence of obesity and poor access to weight loss programs. Effective models for treating obesity in rural clinical practice are needed.
To compare the Medicare ...Intensive Behavioral Therapy for Obesity fee-for-service model with 2 alternatives: in-clinic group visits based on a patient-centered medical home model and telephone-based group visits based on a disease management model.
Cluster randomized trial conducted in 36 primary care practices in the rural Midwestern US. Inclusion criteria included age 20 to 75 years and body mass index of 30 to 45. Participants were enrolled from February 2016 to October 2017. Final follow-up occurred in December 2019.
All participants received a lifestyle intervention focused on diet, physical activity, and behavior change strategies. In the fee-for-service intervention (n = 473), practice-employed clinicians provided 15-minute in-clinic individual visits at a frequency similar to that reimbursed by Medicare (weekly for 1 month, biweekly for 5 months, and monthly thereafter). In the in-clinic group intervention (n = 468), practice-employed clinicians delivered group visits that were weekly for 3 months, biweekly for 3 months, and monthly thereafter. In the telephone group intervention (n = 466), patients received the same intervention as the in-clinic group intervention, but sessions were delivered remotely via conference calls by centralized staff.
The primary outcome was weight change at 24 months. A minimum clinically important difference was defined as 2.75 kg.
Among 1407 participants (mean age, 54.7 SD, 11.8 years; baseline body mass index, 36.7 SD, 4.0; 1081 77% women), 1220 (87%) completed the trial. Mean weight loss at 24 months was -4.4 kg (95% CI, -5.5 to -3.4 kg) in the in-clinic group intervention, -3.9 kg (95% CI, -5.0 to -2.9 kg) in the telephone group intervention, and -2.6 kg (95% CI, -3.6 to -1.5 kg) in the in-clinic individual intervention. Compared with the in-clinic individual intervention, the mean difference in weight change was -1.9 kg (97.5% CI, -3.5 to -0.2 kg; P = .01) for the in-clinic group intervention and -1.4 kg (97.5% CI, -3.0 to 0.3 kg; P = .06) for the telephone group intervention.
Among patients with obesity in rural primary care clinics, in-clinic group visits but not telephone-based group visits, compared with in-clinic individual visits, resulted in statistically significantly greater weight loss at 24 months. However, the differences were small in magnitude and of uncertain clinical importance.
ClinicalTrials.gov Identifier: NCT02456636.
Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of ...an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged ≥ 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow-up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality.
Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk
. More than 60% of this effect is attributable to the ability of ...metformin to lower body weight in a sustained manner
. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show-in two independent randomized controlled clinical trials-that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
Background Group model building is a process of engaging stakeholders in a participatory modeling process to elicit their perceptions of a problem and explore concepts regarding the origin, ...contributing factors, and potential solutions or interventions to a complex issue. Recently, it has emerged as a novel method for tackling complex, long-standing public health issues that traditional intervention models and frameworks cannot fully address. However, the extent to which group model building has resulted in the adoption of evidence-based practices, interventions, and policies for public health remains largely unstudied. The goal of this systematic review was to examine the public health and healthcare applications of GMB in the literature and outline how it has been used to foster implementation and dissemination of evidence-based interventions. Methods We searched PubMed, Web of Science, and other databases through August 2022 for studies related to public health or health care where GMB was cited as a main methodology. We did not eliminate studies based on language, location, or date of publication. Three reviewers independently extracted data on GMB session characteristics, model attributes, and dissemination formats and content. Results Seventy-two studies were included in the final review. Majority of GMB activities were in the fields of nutrition (n = 19, 26.4%), health care administration (n = 15, 20.8%), and environmental health (n = 12, 16.7%), and were conducted in the United States (n = 29, 40.3%) and Australia (n = 7, 9.7%). Twenty-three (31.9%) studies reported that GMB influenced implementation through policy change, intervention development, and community action plans; less than a third reported dissemination of the model outside journal publication. GMB was reported to have increased insight, facilitated consensus, and fostered communication among stakeholders. Conclusions GMB is associated with tangible benefits to participants, including increased community engagement and development of systems solutions. Transdisciplinary stakeholder involvement and more rigorous evaluation and dissemination of GMB activities are recommended.
The effects of nitrogen and straw management on global warming potential (GWP) and greenhouse gas intensity (GHGI) in a winter wheat–summer maize double-cropping system on the North China Plain were ...investigated. We measured nitrous oxide (N2O) emissions and studied net GWP (NGWP) and GHGI by calculating the net exchange of CO2 equivalent (CO2-eq) from greenhouse gas emissions, agricultural inputs and management practices, as well as changes in soil organic carbon (SOC), based on a long-term field experiment established in 2006. The field experiment includes six treatments with three fertilizer N levels (zero N (control), optimum and conventional N) and straw removal (i.e. N0, Nopt and Ncon) or return (i.e. SN0, SNopt and SNcon). Optimum N management (Nopt, SNopt) saved roughly half of the fertilizer N compared to conventional agricultural practice (Ncon, SNcon), with no significant effect on grain yields. Annual mean N2O emissions reached 3.90 kg N2O-N ha−1 in Ncon and SNcon, and N2O emissions were reduced by 46.9% by optimizing N management of Nopt and SNopt. Straw return increased annual mean N2O emissions by 27.9%. Annual SOC sequestration was 0.40–1.44 Mg C ha−1 yr−1 in plots with N application and/or straw return. Compared to the conventional N treatments the optimum N treatments reduced NGWP by 51%, comprising 25% from decreasing N2O emissions and 75% from reducing N fertilizer application rates. Straw return treatments reduced NGWP by 30% compared to no straw return because the GWP from increments of SOC offset the GWP from higher emissions of N2O, N fertilizer and fuel after straw return. The GHGI trends from the different nitrogen and straw management practices were similar to the NGWP. In conclusion, optimum N and straw return significantly reduced NGWP and GHGI and concomitantly achieved relatively high grain yields in this important winter wheat–summer maize double-cropping system.
Acute allergic symptoms are caused by allergen-induced crosslinking of allergen-specific immunoglobulin E (IgE) bound to Fc-epsilon receptors on effector cells. Desensitization with allergen-specific ...immunotherapy (SIT) has been used for over a century, but the dominant protective mechanism remains unclear. One consistent observation is increased allergen-specific IgG, thought to competitively block allergen binding to IgE. Here we show that the blocking potency of the IgG response to Cat-SIT is heterogeneous. Next, using two potent, pre-selected allergen-blocking monoclonal IgG antibodies against the immunodominant cat allergen Fel d 1, we demonstrate that increasing the IgG/IgE ratio reduces the allergic response in mice and in cat-allergic patients: a single dose of blocking IgG reduces clinical symptoms in response to nasal provocation (ANCOVA, p = 0.0003), with a magnitude observed at day 8 similar to that reported with years of conventional SIT. This study suggests that simply augmenting the blocking IgG/IgE ratio may reverse allergy.
Aims
Methicillin‐sensitive and methicillin‐resistant Staphylococcus aureus (MSSA and MRSA, respectively) in the nostrils of dogs and workers at an animal shelter were cultured. Staphylococcal toxin ...genes were analysed to identify potential health concerns.
Methods and Results
Samples were obtained from 441 dogs and 9 workers. The respective isolation rates of S. aureus and MRSA were 49·0% (216/441) and 1·6% (7/441) for shelter dogs and 44·4% (4/9) and 33·3% (3/9) for workers, respectively. Isolation of S. aureus in summer (61·9%) and in adult dogs (59·2%) were significantly higher than those in winter (35·8%) and in juvenile dogs (33·3%) (P < 0·001), respectively. The predominant enterotoxin genotypes and combination profiles of S. aureus were (sea, seb, seg, sei, sem, sen, seo, seu) and (sea, sea‐seb, and seg‐sei‐sem‐sen‐seo‐seu), respectively, and 20% of isolates carried food poisoning‐associated enterotoxins. The se profiles in shelter dogs were different from those in general pet dogs and their owners. MRSA isolates were identified as SCCmec IV and VII, and they shared se combination profiles of (sec‐seg‐sei‐sel‐sem‐sen‐seo‐seu) and (seb‐sek‐seq). MRSA in this shelter had similar microbiological characteristics as those reported in CA‐MRSA ST59 in humans.
Conclusions
Human health‐associated bacteria and food poisoning‐related toxin genes were identified. Further evaluations of health concerns in animal shelters are necessary.
Significance and Impact of the Study
This is the first study to focus on se prevalence and MRSA characteristics in an animal shelter in Taiwan. The MRSA characteristics determined in this study were similar to those of CA‐MRSA strains isolated from communities in the past, indicating potential health risks in cities.
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