Neuroendocrinology and neurobiology of sebaceous glands Clayton, Richard W.; Langan, Ewan A.; Ansell, David M. ...
Biological reviews of the Cambridge Philosophical Society,
June 2020, Volume:
95, Issue:
3
Journal Article
Peer reviewed
ABSTRACT
The nervous system communicates with peripheral tissues through nerve fibres and the systemic release of hypothalamic and pituitary neurohormones. Communication between the nervous system ...and the largest human organ, skin, has traditionally received little attention. In particular, the neuro‐regulation of sebaceous glands (SGs), a major skin appendage, is rarely considered. Yet, it is clear that the SG is under stringent pituitary control, and forms a fascinating, clinically relevant peripheral target organ in which to study the neuroendocrine and neural regulation of epithelia. Sebum, the major secretory product of the SG, is composed of a complex mixture of lipids resulting from the holocrine secretion of specialised epithelial cells (sebocytes). It is indicative of a role of the neuroendocrine system in SG function that excess circulating levels of growth hormone, thyroxine or prolactin result in increased sebum production (seborrhoea). Conversely, growth hormone deficiency, hypothyroidism, and adrenal insufficiency result in reduced sebum production and dry skin. Furthermore, the androgen sensitivity of SGs appears to be under neuroendocrine control, as hypophysectomy (removal of the pituitary) renders SGs largely insensitive to stimulation by testosterone, which is crucial for maintaining SG homeostasis. However, several neurohormones, such as adrenocorticotropic hormone and α‐melanocyte‐stimulating hormone, can stimulate sebum production independently of either the testes or the adrenal glands, further underscoring the importance of neuroendocrine control in SG biology. Moreover, sebocytes synthesise several neurohormones and express their receptors, suggestive of the presence of neuro‐autocrine mechanisms of sebocyte modulation. Aside from the neuroendocrine system, it is conceivable that secretion of neuropeptides and neurotransmitters from cutaneous nerve endings may also act on sebocytes or their progenitors, given that the skin is richly innervated. However, to date, the neural controls of SG development and function remain poorly investigated and incompletely understood. Botulinum toxin‐mediated or facial paresis‐associated reduction of human sebum secretion suggests that cutaneous nerve‐derived substances modulate lipid and inflammatory cytokine synthesis by sebocytes, possibly implicating the nervous system in acne pathogenesis. Additionally, evidence suggests that cutaneous denervation in mice alters the expression of key regulators of SG homeostasis. In this review, we examine the current evidence regarding neuroendocrine and neurobiological regulation of human SG function in physiology and pathology. We further call attention to this line of research as an instructive model for probing and therapeutically manipulating the mechanistic links between the nervous system and mammalian skin.
We report an improved measurement of the free neutron lifetime τn using the UCN τ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38 × 106 surviving ultracold ...neutrons (UCNs) after storing in UCN τ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τn from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τn measurements and by performing a global likelihood fit to all data while self-consistently incorporating the β -decay lifetime. Both techniques achieve consistent results and find a value τn = 877.75 ± 0.2 8stat + 0.22/−0.16syst s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.
Fornal and Grinstein recently proposed that the discrepancy between two different methods of neutron lifetime measurements, the beam and bottle methods, can be explained by a previously unobserved ...dark matter decay mode, n→X+γ. We perform a search for this decay mode over the allowed range of energies of the monoenergetic γ ray for X to be dark matter. A Compton-suppressed high-purity germanium detector is used to identify γ rays from neutron decay in a nickel-phosphorous-coated stainless-steel bottle. A combination of Monte Carlo and radioactive source calibrations is used to determine the absolute efficiency for detecting γ rays arising from the dark matter decay mode. We exclude the possibility of a sufficiently strong branch to explain the lifetime discrepancy with 97% confidence.
Abstract
Mosquito bites transmit a number of pathogens via salivary droplets deposited during blood-feeding, resulting in potentially fatal diseases. Little is known about the genomic content of ...these nanodroplets, including the transmission dynamics of live pathogens. Here we introduce Vectorchip, a low-cost, scalable microfluidic platform enabling high-throughput molecular interrogation of individual mosquito bites. We introduce an ultra-thin PDMS membrane which acts as a biting interface to arrays of micro-wells. Freely-behaving mosquitoes deposit saliva droplets by biting into these micro-wells. By modulating membrane thickness, we observe species-dependent differences in mosquito biting capacity, utilizable for selective sample collection. We demonstrate RT-PCR and focus-forming assays on-chip to detect mosquito DNA, Zika virus RNA, as well as quantify infectious Mayaro virus particles transmitted from single mosquito bites. The Vectorchip presents a promising approach for single-bite-resolution laboratory and field characterization of vector-pathogen communities, and could serve as a powerful early warning sentinel for mosquito-borne diseases.
The ultracold neutron (UCN) source at Los Alamos National Laboratory (LANL), which uses solid deuterium as the UCN converter and is driven by accelerator spallation neutrons, has been successfully ...operated for over 10 years, providing UCN to various experiments, as the first production UCN source based on the superthermal process. It has recently undergone a major upgrade. This paper describes the design and performance of the upgraded LANL UCN source. Measurements of the cold neutron spectrum and UCN density are presented and compared to Monte Carlo predictions. The source is shown to perform as modeled. The UCN density measured at the exit of the biological shield was 184(32) UCN/cm3, a fourfold increase from the highest previously reported. The polarized UCN density stored in an external chamber was measured to be 39(7) UCN/cm3, which is sufficient to perform an experiment to search for the nonzero neutron electric dipole moment with a one-standard-deviation sensitivity of σ(dn)=3×10-27ecm.
We review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell–derived cardiomyocytes (PSC-CMs) as a ...leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation.
We conducted an unstructured literature review of PubMed-listed articles, selecting the most comprehensive and relevant research articles, review articles, clinical trials, and basic or translation articles in the field of cardiac cell therapy. Articles were identified using the search terms adult stem cells, pluripotent stem cells, cardiac stem cell, and cardiac regeneration or from references of relevant articles, Articles were prioritized and selected based on their impact, originality, or potential clinical applicability.
Since its inception, the ASC therapy field has been troubled by conflicting preclinical data, academic controversies, and inconsistent trial designs. These issues have damaged perceptions of cardiac cell therapy among investors, the academic community, health care professionals, and, importantly, patients. In hindsight, the key issue underpinning these problems was the inability of these cell types to differentiate directly into genuine cardiomyocytes, rendering them unable to replace damaged myocardium. Despite this, beneficial effects through indirect paracrine or immunomodulatory effects remain possible and continue to be investigated. However, in preclinical models, PSC-CMs have robustly remuscularized infarcted myocardium with functional, force-generating cardiomyocytes. Hence, PSC-CMs have now emerged as a leading candidate for cardiac regeneration, and unpublished reports of first-in-human delivery of these cells have recently surfaced. However, the cardiac cell therapy field's history should serve as a cautionary tale, and we identify several translational hurdles that still remain. Preclinical solutions to issues such as arrhythmogenicity, immunogenicity, and poor engraftment rates are needed, and next-generation clinical trials must draw on robust knowledge of mechanistic principles of the therapy.
The clinical transplantation of functional stem cell–derived heart tissue with seamless integration into native myocardium is a lofty goal. However, considerable advances have been made during the past 2 decades. Currently, PSC-CMs appear to be the best prospect to reach this goal, but several hurdles remain. The history of adult stem cell trials has taught us that shortcuts cannot be taken without dire consequences, and it is essential that progress not be hurried and that a worldwide, cross-disciplinary approach be used to ensure safe and effective clinical translation.
•Machine learning models for scintillator performance require self-consistent data.•High-throughput screening needs a universal preparation technique.•Multi-component aluminate garnets were ...synthesized by quenching of the melt.•Structural and luminescence properties of powder samples were evaluated.•A simplified model was developed for interpretation of radioluminescence intensity.
Quenching from the melt using an Optical Floating Zone furnace was investigated as a possible high-throughput preparation method in order to screen novel scintillating materials. To validate this method, polycrystalline rare-earth aluminum garnets and yttrium gallium aluminum garnets were synthesized and characterized by X-ray diffraction, photoluminescence and radioluminescence emission spectra as well as radioluminescence imaging and compared to the previously reported properties of those materials. In order to achieve rapid, but quantitative comparison of the materials, pellets fabricated from the synthesized powders were sintered; two different sintering conditions were investigated and compared. A simplistic energy deposition and light absorption model for brightness of opaque samples under X-ray irradiation was developed to estimate the relative scintillation efficiency of the materials. Based on the results, Y3Al5O12, LuY2Al5O12 and GdY2Al5O12 seem to have the highest scintillation efficiency among the prepared samples.
A stepwise logistic-regression procedure is proposed for evaluation of the relative importance of variants at different sites within a small genetic region. By fitting statistical models with main ...effects, rather than modeling the full haplotype effects, we generate tests, with few degrees of freedom, that are likely to be powerful for detecting primary etiological determinants. The approach is applicable to either case/control or nuclear-family data, with case/control data modeled via
unconditional and family data via
conditional logistic regression. Four different conditioning strategies are proposed for evaluation of effects at multiple, closely linked loci when family data are used. The first strategy results in a likelihood that is equivalent to analysis of a matched case/control study with each affected offspring matched to three pseudocontrols, whereas the second strategy is equivalent to matching each affected offspring with between one and three pseudocontrols. Both of these strategies require parental phase (i.e., those haplotypes present in the parents) to be inferable. Families in which phase cannot be determined must be discarded, which can considerably reduce the effective size of a data set, particularly when large numbers of loci that are not very polymorphic are being considered. Therefore, a third strategy is proposed in which knowledge of parental phase is not required, which allows those families with ambiguous phase to be included in the analysis. The fourth and final strategy is to use conditioning method 2 when parental phase can be inferred and to use conditioning method 3 otherwise. The methods are illustrated using nuclear-family data to evaluate the contribution of loci in the
HLA region to the development of type 1 diabetes.
The PI3K‐AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several ...segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Hypoglycaemia is common in other overgrowth syndromes but has been described only sporadically in association with PIK3CA and CCND2 variants. We report a cohort of 6 children with megalencephaly‐capillary malformation (MCAP) and megalencephaly‐polydactyly‐polymicrogyria‐hydrocephalus (MPPH) syndromes who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia.
We report a cohort of 6 children with segmental overgrowth (MCAP and MPPH) who developed clinically significant hypoglycaemia.
Summary
NHS England recently mandated that the National Early Warning Score of vital signs be used in all acute hospital trusts in the UK despite limited validation in the postoperative setting. We ...undertook a multicentre UK study of 13,631 patients discharged from intensive care after risk‐stratified cardiac surgery in four centres, all of which used VitalPACTM to electronically collect postoperative National Early Warning Score vital signs. We analysed 540,127 sets of vital signs to generate a logistic score, the discrimination of which we compared with the national additive score for the composite outcome of: in‐hospital death; cardiac arrest; or unplanned intensive care admission. There were 578 patients (4.2%) with an outcome that followed 4300 sets of observations (0.8%) in the preceding 24 h: 499 out of 578 (86%) patients had unplanned re‐admissions to intensive care. Discrimination by the logistic score was significantly better than the additive score. Respective areas (95%CI) under the receiver‐operating characteristic curve with 24‐h and 6‐h vital signs were: 0.779 (0.771–0.786) vs. 0.754 (0.746–0.761), p < 0.001; and 0.841 (0.829–0.853) vs. 0.813 (0.800–0.825), p < 0.001, respectively. Our proposed logistic Early Warning Score was better than the current National Early Warning Score at discriminating patients who had an event after cardiac surgery from those who did not.
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