Effect of sleep on overnight CSF amyloid-β kinetics.

Effect of sleep on overnight CSF amyloid-β kinetics.

Ann Neurol. 2017 Dec 08;:

Authors: Lucey BP, Hicks TJ, McLeland JS, Toedebusch CD, Boyd J, Elbert DL, Patterson BW, Baty J, Morris JC, Ovod V, Mawuenyega KG, Bateman RJ

Abstract
Sleep disturbances are associated with future risk of Alzheimer's disease. Disrupted sleep increases soluble amyloid-β, suggesting a mechanism for sleep disturbances to increase Alzheimer's disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid-β kinetics. We found that sleep deprivation increased overnight amyloid-β-38, amyloid-β-40, and amyloid-β-42 levels by 25-30% via increased overnight amyloid-β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer's disease risk via increased amyloid-β production. This article is protected by copyright. All rights reserved.

PMID: 29220873 [PubMed - as supplied by publisher]

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A descriptive analysis of sleep and wakefulness states during maternal behaviors in postpartum rats.

A descriptive analysis of sleep and wakefulness states during maternal behaviors in postpartum rats.

Arch Ital Biol. 2017 Sep 01;155(3):99-109

Authors: Benedetto L, Rivas M, Pereira M, Ferreira A, Torterolo P

Abstract
Mother rats spend most of their time nursing their litter during the early stages of the postpartum period, only occasionally leaving the nest. The suckling stimulus from the pups elicits the adoption of nursing postures, during which milk ejection occurs, an event associated with the occurrence of non-REM (NREM) sleep in the rat. Despite this evidence, the characteristics of sleep during different nursing postures along the postpartum period remain unknown. The present study aims to describe the sleep pattern of mother rats while nursing, hovering over their pups and when being away from the pups. For this purpose, lactating females were implanted with electrodes for chronic polysomnographic recording. Simultaneous recordings of sleep-wakefulness cycle and maternal behaviors were performed in both the light and dark phases of the first and second postpartum weeks. Results indicate that while mothers were most of the time awake when hovering over pups and when staying away from pups, they mainly remained in NREM sleep when adopting low kyphosis posture, the most common nursing posture. The sleep-wake pattern during most maternal behaviors was quite stable between the light and dark phases of the first and second postpartum weeks. In addition, the sleep fragmentation was higher during the nursing bouts compared to that observed when mother rats slept without the pups, but sleep depth did not differ between these behaviors. Our results provide an original description of how mother rats synchronize their own sleep-wakefulness cycle with the maternal care of the pups during the postpartum period.

PMID: 29220862 [PubMed - in process]

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Intermittent Reprogramming: A Breath of Fresh Air for Lung Regeneration.

Intermittent Reprogramming: A Breath of Fresh Air for Lung Regeneration.

Cell Stem Cell. 2017 Dec 07;21(6):712-714

Authors: Firth AL

Abstract
Recently in Stem Cell Reports, Guo et al. (2017) adopted an intermittent reprogramming strategy to generate "induced Progenitor-Like (iPL)" cells, which can maintain lineage commitment while undergoing controlled expansion. The iPLCs were successfully engrafted into a damaged airway, highlighting this significant advancement for regenerative medicine strategies in the lung.

PMID: 29220663 [PubMed - in process]

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Neuropsychological Functioning in Older Adults with Mild Cognitive Impairment and Insomnia Randomized to CBT-I or Control Group.

Neuropsychological Functioning in Older Adults with Mild Cognitive Impairment and Insomnia Randomized to CBT-I or Control Group.

Clin Gerontol. 2017 Oct 24;:1-9

Authors: Cassidy-Eagle E, Siebern A, Unti L, Glassman J, O'Hara R

Abstract
OBJECTIVES: Improving the sleep of older adults with mild cognitive impairment (MCI) represents a first step in discovering whether interventions directed at modifying this risk factor also have the potential to alter the cognitive decline trajectory.
METHODS: A six-session, adapted version of a cognitive behavioral therapy for insomnia (CBT-I) was administered to older adults (N = 28; 14 per group) with MCI across two residential facilities. Participants were randomly assigned to either the sleep intervention or an active control group and completed a neuropsychological battery at three time points (e.g., baseline-T1, post-intervention-T2, 4 month follow-up-T3).
RESULTS: Results showed a significant improvement in sleep and a change (p < .05) on a key measure of executive functioning sub task of inhibition (Condition 3 of D-KEF Color-Word Interference Test), a positive trend on the inhibition-switching task (p < .10; Condition 4 of D-KEF Color-Word Interference Test), an no change in a measure of verbal memory (HVLT-R Delayed Recall) compared with the active control group.
CONCLUSIONS: CBT-I is a nonpharmacological intervention that has the potential to cognitively benefit individuals with MCI suffering from comorbid insomnia.
CLINICAL IMPLICATIONS: Results suggest that a non-pharmacological intervention to improve sleep in older adults with MCI also improve cognitive functioning. Further exploration of the mechanisms underlying these improvements is warranted.

PMID: 29220627 [PubMed - as supplied by publisher]

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Isl1β over-expression with key β cell transcription factors enhances glucose-responsive hepatic insulin production and secretion.

Isl1β over-expression with key β cell transcription factors enhances glucose-responsive hepatic insulin production and secretion.

Endocrinology. 2017 Dec 06;:

Authors: Jung Y, Zhou R, Kato T, Usui JK, Muratani M, Oishi H, Heck MMS, Takahashi S

Abstract
Adenoviral gene transfer of key β cell developmental regulators including Pdx1, Neurod1 and Mafa (PDA) has been reported to generate insulin-producing cells in liver. However, PDA insulin secretion is transient and glucose unresponsive. Here, we report that an additional β cell developmental regulator, insulin gene enhancer binding protein splicing variant (Isl1β), improved insulin production and glucose-responsive secretion in PDA mouse. Microarray gene expression analysis suggested that adenoviral PDA transfer required an additional element for mature β cell generation, such as Isl1 and Elf3 in liver. In vitro promoter analysis indicated that splicing variant Isl1, Isl1β, is an important factor for transcriptional activity of insulin gene. In vivo bioluminescence monitoring using insulin promoter-luciferase transgenic (MIP-Luc-VU) mice verified that adenoviral PDA-Isl1β transfer produced highly intense luminescence from the liver which peaked at day 7 and persisted for more than 10 days. Using insulin promoter-GFP transgenic (MIP-GFP) mice, we further confirmed that Isl1β supplementation to PDA augmented insulin-producing cells in liver, insulin production and secretion, and β cell related genes. Finally, PDA-Isl1β combination ameliorated hyperglycemia in diabetic mice for 28 days and enhanced glucose tolerance and responsiveness. Thus, our results suggest that Isl1β is a key additional transcriptional factor for advancing the generation of insulin producing cells in liver in combination with PDA.

PMID: 29220426 [PubMed - as supplied by publisher]

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Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases.

Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases.

PLoS One. 2017;12(12):e0187305

Authors: Luo G, Lin L, Jacob L, Bonvalet M, Ambati A, Plazzi G, Pizza F, Leib R, Adams CM, Partinen M, Mignot EJ

Abstract
BACKGROUND: A recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies.
METHODS: MS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA).
RESULTS: NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found positive for anti-HCRTR2 autoantibodies using two strategies or the third one, respectively. None of the post Pandemrix® narcolepsy cases (0 of 40 sera) was found positive with all three strategies.
CONCLUSION: Anti-HCRTR2 autoantibody is not a significant biological feature of narcolepsy or of post Pandemrix® autoimmune responses.

PMID: 29220370 [PubMed - in process]

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Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells.

Dendritic cell nuclear protein-1 regulates melatonin biosynthesis by binding to BMAL1 and inhibiting the transcription of N-acetyltransferase in C6 cells.

Acta Pharmacol Sin. 2017 Dec 07;:

Authors: Chen D, Li YP, Yu YX, Zhou T, Liu C, Fei EK, Gao F, Mu CC, Ren HG, Wang GH

Abstract
Dendritic cell nuclear protein-1 (DCNP1) is a protein associated with major depression. In the brains of depression patients, DCNP1 is up-regulated. However, how DCNP1 participates in the pathogenesis of major depression remains unknown. In this study, we first transfected HEK293 cells with EGFP-DCNP1 and demonstrated that the full-length DCNP1 protein was localized in the nucleus, and RRK (the residues 117-119) composed its nuclear localization signal (NLS). An RRK-deletion form of DCNP1 (DCNP1ΔRRK) and truncated form (DCNP11-116), each lacking the RRK residues, did not show the specific nuclear localization like full-length DCNP1 in the cells. A rat glioma cell line C6 can synthesize melatonin, a hormone that plays important roles in both sleep and depression. We then revealed that transfection of C6 cells with full-length DCNP1 but not DCNP1ΔRRK or DCNP11-116 significantly decreased the levels of melatonin. Furthermore, overexpression of full-length DCNP1, but not DCNP1ΔRRK or DCNP11-116, in C6 cells significantly decreased both the mRNA and protein levels of N-acetyltransferase (NAT), a key enzyme in melatonin synthesis. Full-length DCNP1 but not DCNP1ΔRRK or DCNP11-116 was detected to interact with the Nat promoter and inhibited its activity through its E-box motif. Furthermore, full-length DCNP1 but not the mutants interacted with and repressed the transcriptional activity of BMAL1, a transcription factor that transactivates Nat through the E-box motif. In conclusion, we have shown that RRK (the residues 117-119) are the NLS responsible for DCNP1 nuclear localization. Nuclear DCNP1 represses NAT expression and melatonin biosynthesis by interacting with BMAL1 and repressing its transcriptional activity. Our study reveals a connection between the major depression candidate protein DCNP1, circadian system and melatonin biosynthesis, which may contribute to the pathogenesis of depression.

PMID: 29219947 [PubMed - as supplied by publisher]

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