Gut-to-brain regulation of Drosophila aging through neuropeptide F, insulin and juvenile hormone.

Dietary restriction slows aging in many animals, while in some cases the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here we measure how Drosophila neuropeptide F (NPF) is secreted into adult circulation by enteroendocrine cells and find that specific enteroendocrine cells differentially respond to dietary sugar and yeast. Lifespan is increased when gut NPF is genetically depleted, and this manipulation is sufficient to blunt the longevity benefit conferred by dietary restriction. Depletion of NPF receptors at insulin producing neurons of the brain also increases lifespan, consistent with observations where loss of gut NPF decreases neuronal insulin secretion. The longevity conferred by repressing gut NPF and brain NPF receptors is reversed by treating adults with a juvenile hormone (JH) analog. JH is produced by the adult corpora allata, and inhibition of the insulin receptor at this tissue decreases JH titer and extends lifespan, while this longevity is restored to wild type by treating adults with a JH analog. Overall, enteroendocrine cells of the gut modulate Drosophila aging through interorgan communication mediated by a gut-brain-corpora allata axis, and insulin produced in the brain impacts lifespan through its control of JH titer. These data suggest that we should consider how human incretins and their analogs, which are used to treat obesity and diabetes, may impact aging.

Allatostatin A Signalling: Progress and New Challenges From a Paradigmatic Pleiotropic Invertebrate Neuropeptide Family.

Neuropeptides have gained broad attraction in insect neuroscience and physiology, as new genetic tools are increasingly uncovering their wide-ranging pleiotropic functions with high cellular resolution. Allatostatin A (AstA) peptides constitute one of the best studied insect neuropeptide families. In insects and other panarthropods, AstA peptides qualify as brain-gut peptides and have regained attention with the discovery of their role in regulating feeding, growth, activity/sleep and learning. AstA receptor homologs are found throughout the protostomia and group with vertebrate somatostatin/galanin/kisspeptin receptors. In this review, we summarise the current knowledge on the evolution and the pleiotropic and cell-specific non-allatostatic functions of AstA. We speculate about the core functions of AstA signalling, and derive open questions and challengesfor future research on AstA and invertebrate neuropeptides in general.

Case Report: Familial Pseudohyperkalemia Due to Red Blood Cell Membrane Leak in a Chinese Patient.

Hyperkalemia is a critical condition requiring careful evaluation and timely intervention. Many conditions could manifest as pseudohyperkalemia and it's important to differentiate them as inappropriate potassium-lowering therapy might lead to detrimental outcomes. A 56-year-old female was admitted for hyperkalemia (5.62-8.55 mmol/L). She had no symptoms or signs of hyperkalemia. A comprehensive work-up of hyperkalemia retrieved no valuable findings. Her blood samples underwent incubation tests at different temperatures and revealed temperature-dependent potassium leaks from red blood cells. Based on all test results, a diagnosis of hyperkalemia caused by red blood cell membrane defects was suspected. Whole-genome sequencing revealed a heterozygous c.1123C>T (p. R375W) mutation in the ABCB6 gene and confirmed the diagnosis of familial pseudohyperkalemia (FP). FP is an inherited benign condition in which red blood cells have increased cold-induced permeability to potassium. The patient was discharged with no additional treatment and she was suggested avoiding blood donation.

An Hypothesis: Disproportion Between Cardiac Troponin and B-Type Natriuretic Peptide Levels-A High Risk and Poor Prognostic Biomarker in Patients With Fulminant Myocarditis?

In our clinical practice, we recently found some patients with severe fulminant myocarditis (FM) who showed persistently elevated cardiac troponin (cTn) levels and "seemingly normal" B-type natriuretic peptide (BNP) level, and who subsequently progressed to poor outcomes. Indeed, this sounds contrary to conventional wisdom, but it is not an accidental phenomenon. Fulminant myocarditis is a rapidly progressive disease associated with high mortality. Recent studies have shown that patients with FM are significantly more likely to require heart transplantation than those without FM. Prompt diagnosis of FM and the institution of advanced cardiac life support will save more lives. Cardiac troponin and BNP are widely used diagnostic markers. Cardiac troponin is a specific marker of cardiac injury and its level correlates with the severity of cardiac injury. However, plasma BNP has a dual identity; it is not only a marker of cardiac pressure/volume overload, but it is also a cardioprotective factor that provides effective neurohormonal compensation to maintain homeostasis. Similar to fulminant hepatitis (characterised by diffuse inflammation and massive parenchymal cell necrosis) sometimes showing disproportion between transaminase level and bilirubin level, the disproportion between cTn and BNP levels in FM seems to be consistent with its severe histopathological changes, including diffuse infiltration of the myocardium by inflammatory cells, as well as severe cardiomyocyte injury and necrosis. Moreover, in previous studies, a lower BNP level was found to be an adverse prognostic marker in end-stage heart failure. All these findings indicate that in patients with FM with a persistently high cTn level and ominous clinical presentation, a "seemingly normal" BNP level is not a friendly signal. We hypothesise that the combination of a persistently elevated cTn level and low BNP level in patients with FM indicates worse myocardial injury and poor prognosis.

Effect of Frequency of Platelet Apheresis on Coagulation Function in Donors: A Prospective Cohort Study.

The maximum number of plateletpheresis donation was permitted up to 24 times every year for each donor in China. This study was investigated the effect of donation frequency on coagulation function of the plateletpheresis donors. A total of 96 plateletpheresis regular donors (splitted into A, B, C groups with 32 donors each group. A was 6-11 times donations, B with 12-17 times and C with 18-24 times) and 32 first time plateletpheresis donors (D group) were analyzed. The coagulation reaction time (R), blood clot formation time (K), α-Angle, normal maximum amplitude (MA) were tested using thromboelastography instrument. Platelet (PLT) count was measured using a hematology analyzer. The ratio of the male to female were 23:9, 24:8, 27:5 and 24:8, the mean age were 40.7 ± 7.6, 39.8 ± 8.3, 40.2 ± 7.9 and 37.0 ± 9.3, and the platelet collection amount were 1.55 ± 0.37 U, 1.58 ± 0.38 U, 1.61 ± 0.33 U and 1.46 ± 0.31 U in the A, B, C, D groups respectively. There were significant difference in the values of the R, K, α-Angle, MA and PLT count between before and after plateletpheresis donation in each group (p < 0.05). However, the values of R, K, α-Angle, MA and PLT count in the before donation were not difference among the A, B, C, D groups (p > 0.05). Similar results were found in the after plateletpheresis donation. The number of the PLT was significantly correlated with the values of the R, K, α-Angle and MA (p < 0.05). However, the frequency of plateletpheresis were not significantly correlated with R, k, α and MA parameters (p > 0.05) using Spearman correlation analysis. The regular donation of apheresis platelets and the frequency of annual blood donation had no adverse effect upon coagulation function of the donors in China.

Characterization of three new HLA Class I Alleles in Chinese individuals, HLA-B*46:68,-B*46:71,-B*46:72.

Three new HLA class I alleles were described in the Chinese population. HLA-B*46:68,-B*46:71,-B*46:72 alleles differ from HLA-B*46:01:01 by a single nucleotide substitution at position 485C>T, 484A>G, 299T>A respectively.

Metabolic Labeling to Quantify Drosophila Neuropeptides and Peptide Hormones.

Neuropeptides and peptide hormones are involved in the regulation of most if not all body functions, ranging from physiology to neuronal processing and the control of behavior. To assess their functions, it is often vital to determine when and in which quantities they are produced, stored, and released. The latter is especially difficult to assess in small insects, such as the genetically amenable fruit fly Drosophila melanogaster, and cannot be achieved merely by quantifying mRNA transcripts. We have adapted and optimized methods to quantify neuropeptides and peptide hormones by metabolic labeling followed by LC-MS. In this chapter, we describe the labeling protocols used in our laboratory and discuss problems and pitfalls that we encountered.

Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila.

Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals.

Correction: Allatostatin A Signalling in Drosophila Regulates Feeding and Sleep and Is Modulated by PDF.

[This corrects the article DOI: 10.1371/journal.pgen.1006346.].

Allatostatin A Signalling in Drosophila Regulates Feeding and Sleep and Is Modulated by PDF.

Feeding and sleep are fundamental behaviours with significant interconnections and cross-modulations. The circadian system and peptidergic signals are important components of this modulation, but still little is known about the mechanisms and networks by which they interact to regulate feeding and sleep. We show that specific thermogenetic activation of peptidergic Allatostatin A (AstA)-expressing PLP neurons and enteroendocrine cells reduces feeding and promotes sleep in the fruit fly Drosophila. The effects of AstA cell activation are mediated by AstA peptides with receptors homolog to galanin receptors subserving similar and apparently conserved functions in vertebrates. We further identify the PLP neurons as a downstream target of the neuropeptide pigment-dispersing factor (PDF), an output factor of the circadian clock. PLP neurons are contacted by PDF-expressing clock neurons, and express a functional PDF receptor demonstrated by cAMP imaging. Silencing of AstA signalling and continuous input to AstA cells by tethered PDF changes the sleep/activity ratio in opposite directions but does not affect rhythmicity. Taken together, our results suggest that pleiotropic AstA signalling by a distinct neuronal and enteroendocrine AstA cell subset adapts the fly to a digestive energy-saving state which can be modulated by PDF.