The circadian system, that is ubiquitous across species, generates ∼24 h rhythms in virtually all biological processes, and allows them to anticipate and adapt to the 24 h day/night cycle, thus ...ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular (CV) events, and controlled laboratory studies demonstrate a circadian influence on key markers of CV function and risk. Furthermore, circadian misalignment, that is typically experienced by shift workers as well as by individuals who experience late eating, (social) jet lag, or circadian rhythm sleep–wake disturbances, increases CV risk factors. Therefore, understanding the mechanisms by which the circadian system regulates CV function, and which of these are affected by circadian disruption, may help to develop intervention strategies to mitigate CV risk.
Adverse CV events, including myocardial infarction, arrhythmias, and stroke, show time-of-day variations. Underlying factors may include circadian system control over a plethora of markers associated with CV function.Our modern lifestyle, which includes shiftwork, jet lag, and disturbed sleep, has been associated with increased CV risk.Misalignment of the endogenous circadian timing system and behavioral/environmental cycles can adversely impact on CV function in both animal models and human studies. These mechanistic insights may help to explain why some aspects of our modern lifestyle can increase CV risk.Circadian disruption may play a role in the onset and development of CV disease, and treatments aimed at mitigating circadian disruption may diminish CV risk.
The term ‘therapeutic landscapes’ was first coined by health geographer, Wilbert Gesler, in 1992 to explore why certain environments seem to contribute to a healing sense of place. Since then, the ...concept and its applications have evolved and expanded as researchers have examined the dynamic material, affective and socio-cultural roots and routes to experiences of health and wellbeing in specific places. Drawing on a scoping review of studies of these wider therapeutic landscapes published between 2007 and 2016, this paper explores how, where, and to what benefit the ‘therapeutic landscapes’ concept has been applied to date, and how such applications have contributed to its critical evolution as a relevant and useful concept in health geography. Building on themes included in two earlier (1999, 2007) edited volumes on Therapeutic Landscapes, we summarise the key themes identified in the review, broadly in keeping with the core material, social, spiritual and symbolic dimensions of the concept initially posited by Gesler. Through this process, we identify strengths and limitations of the concept and its applications, as well as knowledge gaps and promising future directions for work in this field, reflecting critically on its value within health geography and its potential contribution to wider interdisciplinary discussions and debates around ‘healthy’ spaces, places, and related practices.
•A scoping review of the therapeutic landscapes literature published since 2007.•Therapeutic landscapes remain a lively field of inquiry across health geography.•Offers in-depth insights into experiential, embodied and emotional geographies.•Promotes awareness of place as simultaneously therapeutic and exclusionary.
Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. ...Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.
Prognosis in Parkinson's disease (PD) remains poorly understood due to a lack of unbiased data on the natural history of treated PD. The CamPaIGN study has been the first to prospectively track ...disease evolution from diagnosis in an unselected population-representative incident cohort. We now report the 10-year follow-up data, focusing on three key irreversible milestones: postural instability (Hoehn and Yahr 3), dementia and death.
The cohort was collected between December 2000 and 2002. Those meeting diagnostic criteria (n=142) were followed-up until 1 January 2012. Clinical, neuropsychological and genetic testing were performed. Progression to key milestones was evaluated using Kaplan-Meier and Cox regression survival analyses.
At 10 years, 55% had died, 68% had postural instability and 46% dementia. 23% had a good outcome at 10 years (surviving free of dementia/postural instability). Death rate was comparable with the UK population (standardised mortality ratio 1.29 (0.97-1.61)). Death certificates indicated PD was a substantial contributor in only 20%, with pneumonia being the commonest cause of death. Age, non-tremor-dominant motor phenotype and comorbidity predicted earlier postural instability. Baseline predictors of dementia were age, motor impairment, 'posterior-cortical' cognitive deficits and MAPT genotype.
(1) outlook in PD is heterogeneous, with most dying or developing dementia or postural instability by 10 years from diagnosis, but a quarter still doing well, with preserved mobility and intact cognition; (2) death is not directly related to PD in the majority; (3) baseline clinical and genetic variables are predictive of outcome and may be helpful in selecting patients for clinical trials.
Data from ten sources comprising 3,851 flocks were modelled to identify variation in levels of mortality in laying hens. The predicted increase with age was curvilinear with significant variation ...between the seven breed categories. Mortality was higher in loose housing systems than in cages and variable within system, confirming previous reports. Cumulative mortality (CM) was higher in flocks with intact beaks (χ2 = 6.03; df 1; p = 0.014) than in those with trimmed beaks. Most data were available for free-range systems (2,823 flocks), where producer recorded CM at 60-80 weeks of age averaged 10% but with a range from 0% to 69.3%. Life cycle assessment showed that the main effect of increased levels of hen mortality is to increase the relative contribution of breeding overheads, so increasing environmental burdens per unit of production. Reducing CM to levels currently achieved by the 1st quartile could reduce flock greenhouse gas emissions by as much as 25%. Concurrently this would enhance hen welfare and better meet the expectation of egg consumers. More research to understand the genetic x environment interaction and detailed records of the causes of mortality is required so that improved genotypes can be developed for different systems and different breeds can be better managed within systems.
Human milk is a complex fluid comprised of myriad substances, with one of the most abundant substances being a group of complex carbohydrates referred to as human milk oligosaccharides (HMOs). There ...has been some evidence that HMO profiles differ in populations, but few studies have rigorously explored this variability.
We tested the hypothesis that HMO profiles differ in diverse populations of healthy women. Next, we examined relations between HMO and maternal anthropometric and reproductive indexes and indirectly examined whether differences were likely related to genetic or environmental variations.
In this cross-sectional, observational study, milk was collected from a total of 410 healthy, breastfeeding women in 11 international cohorts and analyzed for HMOs by using high-performance liquid chromatography.
There was an effect of the cohort (
< 0.05) on concentrations of almost all HMOs. For instance, the mean 3-fucosyllactose concentration was >4 times higher in milk collected in Sweden than in milk collected in rural Gambia (mean ± SEM: 473 ± 55 compared with 103 ± 16 nmol/mL, respectively;
< 0.05), and disialyllacto-
-tetraose (DSLNT) concentrations ranged from 216 ± 14 nmol/mL (in Sweden) to 870 ± 68 nmol/mL (in rural Gambia) (
< 0.05). Maternal age, time postpartum, weight, and body mass index were all correlated with several HMOs, and multiple differences in HMOs e.g., lacto-
-neotetrose and DSLNT were shown between ethnically similar (and likely genetically similar) populations who were living in different locations, which suggests that the environment may play a role in regulating the synthesis of HMOs.
The results of this study support our hypothesis that normal HMO concentrations and profiles vary geographically, even in healthy women. Targeted genomic analyses are required to determine whether these differences are due at least in part to genetic variation. A careful examination of sociocultural, behavioral, and environmental factors is needed to determine their roles in this regard. This study was registered at clinicaltrials.gov as NCT02670278.
The membranes of the first protocells on the early Earth were likely self-assembled from fatty acids. A major challenge in understanding how protocells could have arisen and withstood changes in ...their environment is that fatty acid membranes are unstable in solutions containing high concentrations of salt (such as would have been prevalent in early oceans) or divalent cations (which would have been required for RNA catalysis). To test whether the inclusion of amino acids addresses this problem, we coupled direct techniques of cryoelectron microscopy and fluorescence microscopy with techniques of NMR spectroscopy, centrifuge filtration assays, and turbidity measurements. We find that a set of unmodified, prebiotic amino acids binds to prebiotic fatty acid membranes and that a subset stabilizes membranes in the presence of salt and Mg2+. Furthermore, we find that final concentrations of the amino acids need not be high to cause these effects; membrane stabilization persists after dilution as would have occurred during the rehydration of dried or partially dried pools. In addition to providing a means to stabilize protocell membranes, our results address the challenge of explaining how proteins could have become colocalized with membranes. Amino acids are the building blocks of proteins, and our results are consistent with a positive feedback loop in which amino acids bound to self-assembled fatty acid membranes, resulting in membrane stabilization and leading to more binding in turn. High local concentrations of molecular building blocks at the surface of fatty acid membranes may have aided the eventual formation of proteins.
Neonatal gastrointestinal (GI) bacterial community structure may be related to bacterial communities of the mother, including those of her milk. However, very little is known about the diversity in ...and relationships among complex bacterial communities in mother-infant dyads.
Our primary objective was to assess whether microbiomes of milk are associated with those of oral and fecal samples of healthy lactating women and their infants.
Samples were collected 9 times from day 2 to 6 mo postpartum from 21 healthy lactating women and their infants. Milk was collected via complete breast expression, oral samples via swabs, and fecal samples from tissue (mothers) and diapers (infants). Microbiomes were characterized using high-throughput sequencing of the 16S ribosomal RNA (rRNA) gene. Alpha and beta diversity indices were used to compare microbiomes across time and sample types. Membership and composition of microbiomes were analyzed using nonmetric multidimensional scaling and canonical correlation analysis (CCA). The contribution of various bacterial communities of the mother-infant dyad to both milk and infant fecal bacterial communities were estimated using SourceTracker2.
Bacterial community structures were relatively unique to each sample type. The most abundant genus in milk and maternal and infant oral samples was Streptococcus (47.1% ± 2.3%, 53.9% ± 1.3%, and 69.1% ± 1.8%, respectively), whereas Bacteroides were predominant in maternal and infant fecal microbiomes (22.9% ± 1.3% and 21.4% ± 2.4%, respectively). The milk microbiome was more similar to the infant oral microbiome than the infant fecal microbiome. However, CCA suggested strong associations between the complex microbial communities of milk and those of all other sample types collected.
These findings suggest complex microbial interactions between breastfeeding mothers and their infants and support the hypothesis that variation in the milk microbiome may influence the infant GI microbiome.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in ...the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro4.5decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Carriers of mutations in the glucocerebrosidase gene (GBA) are at increased risk of developing Parkinson's disease. The frequency of GBA mutations in unselected Parkinson's disease populations has ...not been established. Furthermore, no previous studies have investigated the influence of GBA mutations on the natural history of Parkinson's disease using prospective follow-up. We studied DNA from 262 cases who had been recruited at diagnosis into one of two independent community-based incidence studies of Parkinson's disease. In 121 cases, longitudinal data regarding progression of motor disability and cognitive function were derived from follow-up assessments conducted every 18 months for a median of 71 months. Sequencing of the GBA was performed after two-stage polymerase chain reaction amplification. The carrier frequency of genetic variants in GBA was determined. Baseline demographic and clinical variables were compared between cases who were either GBA mutation carriers, polymorphism carriers or wild-type homozygotes. Cox regression analysis was used to model progression to major motor (Hoehn and Yahr stage 3), and cognitive (dementia) end-points in cases followed longitudinally. We show that in a representative, unselected UK Parkinson's disease population, GBA mutations are present at a frequency of 3.5%. This is higher than the prevalence of other genetic mutations currently associated with Parkinson's disease and indicates that GBA mutations make an important contribution to Parkinson's disease encountered in the community setting. Baseline clinical characteristics did not differ significantly between cases with and without GBA sequence variants. However, the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers. We also show that carriers of polymorphisms in GBA which are not generally considered to increase Parkinson's disease risk are at significantly increased risk of progression to Hoehn and Yahr stage 3 (3.2, P = 0.004). Our results indicate that genetic variation in GBA has an important impact on the natural history of Parkinson's disease. To our knowledge, this is the first time a genetic locus has been shown to influence motor progression in Parkinson's disease. If confirmed in further studies, this may indicate that GBA mutation status could be used as a prognostic marker in Parkinson's disease. Elucidation of the molecular mechanisms that underlie this effect will further our understanding of the pathogenesis of the disease and may in turn suggest novel therapeutic strategies.
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