Summary
In 1879 Paul Ehrlich published his technique for staining blood films and his method for differential blood cell counting using coal tar dyes and mentions the eosinophil for the first time. ...Eosin is a bright red synthetic dye produced by the action of bromine on fluorescein and stains basic proteins due to its acidic nature. It was discovered in 1874 by Heinrich Caro, Director of the German chemical company Badische Anilin‐ und Soda‐Fabrik. Ehrlich introduced the term ‘eosinophil’ to describe cells with granules (which he called alpha‐granules) having an affinity for eosin and other acid dyes. He also observed black‐staining, indulinophilic, beta‐granules in bone marrow‐derived eosinophils, which were probably immature crystalloid granules in eosinophil myelocytes. Ehrlich described the features of the alpha‐granule and the cell's distribution in various species and tissues. He speculated correctly that the alpha‐granule contents were secretory products and described several causes of eosinophilia including asthma, various skin diseases, helminths and reactions to medications. However, the cell was almost certainly observed by others before Ehrlich. In 1846 Thomas Wharton Jones (1808–1891) described ‘granule blood cells’ in the lamprey, frog, fowl, horse, elephant and man. He ‘borrowed’ the term granule cell from Julius Vogel (1814–1880) who had observed similar cells in inflammatory exudates. Vogel in turn was aware of the work of the Gottlieb (Théophile) Gluge (1812–1898) who used the term ‘compound inflammatory globules’ to describe cells in pus and serum. Almost 20 years before Ehrlich developed his staining methods, Max Johann Sigismund Schultze (1825–1874) performed functional experiments on coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Although these early investigators recognised distinct granular cells Ehrlich's use of stains was a landmark contribution, which heralded modern studies on eosinophils and other blood leucocytes.
Type 1 pili are the archetypal representative of a widespread class of adhesive multisubunit fibres in Gram-negative bacteria. During pilus assembly, subunits dock as chaperone-bound complexes to an ...usher, which catalyses their polymerization and mediates pilus translocation across the outer membrane. Here we report the crystal structure of the full-length FimD usher bound to the FimC-FimH chaperone-adhesin complex and that of the unbound form of the FimD translocation domain. The FimD-FimC-FimH structure shows FimH inserted inside the FimD 24-stranded β-barrel translocation channel. FimC-FimH is held in place through interactions with the two carboxy-terminal periplasmic domains of FimD, a binding mode confirmed in solution by electron paramagnetic resonance spectroscopy. To accommodate FimH, the usher plug domain is displaced from the barrel lumen to the periplasm, concomitant with a marked conformational change in the β-barrel. The amino-terminal domain of FimD is observed in an ideal position to catalyse incorporation of a newly recruited chaperone-subunit complex. The FimD-FimC-FimH structure provides unique insights into the pilus subunit incorporation cycle, and captures the first view of a protein transporter in the act of secreting its cognate substrate.
Background Evidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake ...before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure. Methods A prospective cohort in Leeds, UK, of 1303 pregnant women aged 18–45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status. Results Nearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05). Conclusions We found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnancy.
Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation.
We aimed to ...investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers.
A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism.
Markers of increased NAD+ synthesis—nicotinic acid adenine dinucleotide and methyl nicotinamide—were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.
NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed. This trial was registered at clinicaltrials.gov as NCT02835664
The Hippo pathway is a central regulator of tissue development and homeostasis, and has been reported to have a role during vascular development. Here we develop a bioluminescence-based biosensor ...that monitors the activity of the Hippo core component LATS kinase. Using this biosensor and a library of small molecule kinase inhibitors, we perform a screen for kinases modulating LATS activity and identify VEGFR as an upstream regulator of the Hippo pathway. We find that VEGFR activation by VEGF triggers PI3K/MAPK signaling, which subsequently inhibits LATS and activates the Hippo effectors YAP and TAZ. We further show that the Hippo pathway is a critical mediator of VEGF-induced angiogenesis and tumor vasculogenic mimicry. Thus, our work offers a biosensor tool for the study of the Hippo pathway and suggests a role for Hippo signaling in regulating blood vessel formation in physiological and pathological settings.
Summary
Background
The mechanism of wealing in chronic spontaneous urticaria (CSU) is largely unknown. We previously demonstrated increased expression of T‐helper 2 interleukin (IL)‐4 and IL‐5 ...cytokines in skin biopsies from CSU. This suggested that Th2‐initiating cytokines IL‐33, IL‐25 and thymic stromal lymphopoietin (TSLP), released through innate immune mechanisms, may play a role in pathogenesis.
Objectives
To identify Th2‐initiating cytokines in lesional and nonlesional skin from patients with CSU and to compare the results with a control group.
Methods
Paired biopsies (one from a 4–8 h spontaneous weal and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects, and studied by immunohistochemistry and confocal microscopy.
Results
There were increases in IL‐4+ and IL‐5+ cells in lesional skin vs. controls (P = 0·03 and P < 0·001, respectively) and marked elevations in the numbers of IL‐33+, IL‐25+ and TSLP+ cells in the dermis of lesional skin vs. both nonlesional skin (P = 0·002, P = 0·01 and P = 0·04, respectively) and controls (P = 0·001, P < 0·001 and P = 0·005, respectively). There was also a correlation between the numbers of IL‐33+ and IL‐25+ cells (r = 0·808, P = 0·015). IL‐33 localized to CD31+ endothelial cells, CD90+ fibroblasts, CD68+ macrophages and tryptase+ mast cells, whereas IL‐25 was expressed by epithelial cells, mast cells and major basic protein‐positive eosinophils. IL‐33 and IL‐25 were constitutively expressed in the epidermis of both controls and patients with CSU.
Conclusions
Increased expression of Th2‐initiating cytokines in lesional skin in CSU suggests that innate pathways might play a role in the mechanism of wealing. As Th2‐initiating cytokines play a role in mast cell activation, inflammation and vascular leakage in CSU, these findings may also have therapeutic implications.
What's already known about this topic?
Increased expression of T‐helper (Th)2 interleukin (IL)‐4 and IL‐5 cytokines was previously demonstrated in skin biopsies from chronic spontaneous urticaria (CSU).
What does this study add?
The Th2‐initiating cytokines (IL‐33, IL‐25 and thymic stromal lymphopoietin) are also expressed in CSU, but in lesional, not unaffected, skin.
This suggests that innate pathways may play a role in the mechanism of wealing.
IL‐33 colocalized to endothelial cells, fibroblasts, macrophages and mast cells; IL‐25 was expressed by epithelial cells, mast cells and eosinophils.
Summary
Background
In chronic spontaneous urticaria (CSU) mast cell activation together with inflammatory changes in the skin are well documented and may play an important role in mechanisms of ...tissue oedema.
Objectives
To confirm and extend these observations by measuring microvascular markers, leucocytes and mast cell numbers in lesional and uninvolved skin and to compare findings with a control group.
Methods
Paired biopsies (one from 4–8‐h spontaneous weals and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects and studied using immunohistochemistry and confocal microscopy using the lectin Ulex europaeus agglutinin 1 (UEA‐1).
Results
Lesional skin in CSU contained significantly more CD31+ endothelial cells; CD31+ blood vessels, neutrophils, eosinophils, basophils and macrophages; and CD3+ T cells than nonlesional skin. Increased vascularity was confirmed by confocal imaging using the lectin UEA‐1. Uninvolved skin from CSU contained significantly more CD31+ endothelial cells, CD31+ blood vessels and eosinophils compared with the control subjects. There was a threefold increase in mast cell numbers when CSU was compared with controls but no difference was observed between lesional and uninvolved skin.
Conclusions
Increased vascular markers together with eosinophil and neutrophil infiltration are features of lesional skin in CSU and might contribute to tissue oedema. Eosinophils and microvascular changes persist in uninvolved skin, which, together with increased mast cells, suggests that nonlesional skin is primed for further wealing.
What's already known about this topic?
Earlier studies, mainly using conventional histology, showed increases in eosinophils and neutrophils in chronic urticaria weals.
There are conflicting reports on mast cell numbers.
What does this study add?
Increases in vascularity, as well as eosinophil, neutrophil and basophil infiltration are features of lesional skin in chronic spontaneous urticaria.
Uninvolved skin may be primed as there were persisting vascular markers and eosinophils, as well as increases in mast cells.
Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral ...dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.
Pre-eclampsia is a serious clinical gestational disorder occurring in 3%-5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of ...pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls.
Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay.
Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia.
This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies.
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