A guide to chemokines and their receptors

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G‐protein coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behaviour, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many non‐leukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localisation and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarises the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focussing particularly on their ability to direct leukocyte migration

PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation

Crosstalk between the phosphatidylinositol 3-kinase (PI3K) and the transforming growth factor-β signalling pathways play an important role in regulating many cellular functions. However, the molecular mechanisms underpinning this crosstalk remain unclear. Here, we report that PI3K signalling antagonizes the Activin-induced definitive endoderm (DE) differentiation of human embryonic stem cells by attenuating the duration of Smad2/3 activation via the mechanistic target of rapamycin complex 2 (mTORC2). Activation of mTORC2 regulates the phosphorylation of the Smad2/3-T220/T179 linker residue independent of Akt, CDK and Erk activity. This phosphorylation primes receptor-activated Smad2/3 for recruitment of the E3 ubiquitin ligase Nedd4L, which in turn leads to their degradation. Inhibition of PI3K/mTORC2 reduces this phosphorylation and increases the duration of Smad2/3 activity, promoting a more robust mesendoderm and endoderm differentiation. These findings present a new and direct crosstalk mechanism between these two pathways in which mTORC2 functions as a novel and critical mediator

Stroke increases ischemia-related decreases in motor unit discharge rates

Following stroke, hyperexcitable sensory pathways, such as the group III/IV afferents that are sensitive to ischemia, may inhibit paretic motor neurons during exercise. We quantified the effects of whole leg ischemia on paretic vastus lateralis motor unit firing rates during submaximal isometric contractions. Ten chronic stroke survivors (>1 yr poststroke) and 10 controls participated. During conditions of whole leg occlusion, the discharge timings of motor units were identified from decomposition of high-density surface electromyography signals during repeated submaximal knee extensor contractions. Quadriceps resting twitch responses and near-infrared spectroscopy measurements of oxygen saturation as an indirect measure of blood flow were made. There was a greater decrease in paretic motor unit discharge rates during the occlusion compared with the controls (average decrease for stroke and controls, 12.3 ± 10.0% and 0.1 ± 12.4%, respectively; P < 0.001). The motor unit recruitment thresholds did not change with the occlusion (stroke: without occlusion, 11.68 ± 5.83%MVC vs. with occlusion, 11.11 ± 5.26%MVC; control: 11.87 ± 5.63 vs. 11.28 ± 5.29%MVC). Resting twitch amplitudes declined similarly for both groups in response to whole leg occlusion (stroke: 29.16 ± 6.88 vs. 25.75 ± 6.78 Nm; control: 38.80 ± 13.23 vs 30.14 ± 9.64 Nm). Controls had a greater exponential decline (lower time constant) in oxygen saturation compared with the stroke group (stroke time constant, 22.90 ± 10.26 min vs. control time constant, 5.46 ± 4.09 min; P < 0.001). Ischemia of the muscle resulted in greater neural inhibition of paretic motor units compared with controls and may contribute to deficient muscle activation poststroke. NEW & NOTEWORTHY Hyperexcitable inhibitory sensory pathways sensitive to ischemia may play a role in deficient motor unit activation post stroke. Using high-density surface electromyography recordings to detect motor unit firing instances, we show that ischemia of the exercising muscle results in greater inhibition of paretic motor unit firing rates compared with controls. These findings are impactful to neurophysiologists and clinicians because they implicate a novel mechanism of force-generating impairment poststroke that likely exacerbates baseline weakness

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

The effects of depression and use of antidepressive medicines during pregnancy on the methylation status of the IGF2 imprinted control regions in the offspring

In utero exposures to environmental factors may result in persistent epigenetic modifications affecting normal development and susceptibility to chronic diseases in later life. We explored the relationship between exposure of the growing fetus to maternal depression or antidepressants and DNA methylation at two differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Aberrant DNA methylation at the IGF2 and neighboring H19 DMRs has been associated with deregulated IGF2 expression, childhood cancers and several chronic diseases during adulthood. Our study population is comprised of pregnant mothers and their newborns (n = 436), as part of the Newborn Epigenetics Study (NEST). A standardized questionnaire was completed and medical record data were abstracted to ascertain maternal depression and antidepressive drug use. DMR methylation levels in umbilical cord blood leukocytes were quantified using pyrosequencing. From the 436 newborns, laboratory data were obtained for 356 individuals at the IGF2 DMRs, and for 411 individuals at the H19 DMRs; about half of each group was African American or Caucasian. While overall no association between depression and methylation profiles was found, we observed a significant hypermethylation of the H19 DMRs in newborns of African American (n = 177) but not Caucasian (n = 168) mothers who reported the use of antidepressive drugs during pregnancy (β = +6.89, p = 0.01). Of note, our data reveal a race-independent association between smoking during pregnancy and methylation at the IGF2 DMR (+3.05%, p = 0.01). In conclusion, our findings suggest a race-dependent response related to maternal use of antidepressants at one of the IGF2 DMRs in the offspring

Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States.

BACKGROUND: Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test. METHODS: A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05. RESULTS: At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP. CONCLUSIONS: Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs. IMPACT: Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines

Emerging technologies for the management of Type 1 diabetes in pregnancy

Purpose of Review: The purpose of the study is to discuss emerging technologies available in the management of type 1 diabetes in pregnancy. Recent Findings: The latest evidence suggests that continuous glucose monitoring (CGM) should be offered to all women on intensive insulin therapy in early pregnancy. Studies have additionally demonstrated the ability of CGM to help gain insight into specific glucose profiles as they relate to glycaemic targets and pregnancy outcomes. Despite new studies comparing insulin pump therapy to multiple daily injections, its effectiveness in improving glucose and pregnancy outcomes remains unclear. Sensor-integrated insulin delivery (also called artificial pancreas or closed-loop insulin delivery) in pregnancy has been demonstrated to improve time in target and performs well despite the changing insulin demands of pregnancy. Summary: Emerging technologies show promise in the management of type 1 diabetes in pregnancy; however, research must continue to keep up as technology advances. Further research is needed to clarify the role technology can play in optimising glucose control before and during pregnancy as well as to understand which women are candidates for sensor-integrated insulin delivery

A global disorder of imprinting in the human female germ line

Imprinted genes are expressed differently depending on whether they are carried by a chromosome of maternal or paternal origin. Correct imprinting is established by germline-specific modifications; failure of this process underlies several inherited human syndromes. All these imprinting control defects are cis-acting, disrupting establishment or maintenance of allele-specific epigenetic modifications across one contiguous segment of the genome. In contrast, we report here an inherited global imprinting defect. This recessive maternal-effect mutation disrupts the specification of imprints at multiple, non-contiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extra-embryonic tissue proliferates while development of the embryo is absent or nearly so. This disorder offers a genetic route to the identification of trans-acting oocyte factors that mediate maternal imprint establishment

Presentation and analysis of a worldwide database for lava dome collapse events: the Global Archive of Dome Instabilities (GLADIS)

Lava dome collapses generate hazardous pyroclastic flows, rockfalls and debris avalanches. Despite advances in understanding lava dome collapses and their resultant products, the conditions that occur prior to collapse are still poorly understood. Here we introduce the Global Archive of Dome Instabilities (GLADIS), a database that compiles worldwide historical dome collapses and their reported properties, including original dome volume (at the time of collapse), dome morphology, emplacement conditions, precursory activity, dome geometry and deposit characteristics. We determine the collapse magnitude for events where possible, using both absolute deposit volumes and relative collapse volume ratios (this being deposit volume as a proportion of original dome volume). We use statistical analysis to explore whether relationships exist between collapse magnitude and extrusion rate, dome growth style, original dome volume, and causal mechanism of collapse. We find that relative collapse magnitude is independent of both the extrusion rate and the original dome volume. Relative collapse volume ratio is dependent on dome growth style, where endogenous growth is found to precede the largest collapses (~75% original volume). Collapses that comprise a higher proportion (<50%) of original dome volume are particularly attributed to both gravitational loading and the development of gas overpressure, whilst collapses comprising a small proportion (<10%) of original dome volume are associated with the topography surrounding the dome, and variations in extrusion direction. By providing validation and/or source data, we intend these data on various dome growth and collapse events, and their associated mechanisms, to be the focus of future numerical modelling efforts, whilst the identified relationships with relative collapse volume ratios can inform collapse hazard assessment based on observations of a growing dome