bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced magnetic moment with cobalt dopant in SnS2 semiconductor
Authors: Bouzid Houcine , Rodan Steven , Singh Kirandeep , Jin Youngjo , Jiang Jinbao , Yoon Duhee , Song Hyun Yong , Lee Young Hee
Published: May 2021

We report the strong ferromagnetic order in van der Waals (vdW) layered SnS2 induced by cobalt substitution. The single-crystal Co-doped SnS2 grown by a self-flux method reveals a relatively high Curie temperature (TC) of ∼131 K with an in-plane magnetic easy axis and a large saturation magnetization of ∼0.65 emu g−1 for the 2 at. % Co concentration, which is two orders of magnitude larger than the previously reported value for transition-metal-doped SnS2. The average magnetic moment per Co atom, as high as 1.08 µB, is consistent with the calculated value based on density functional theory, i.e., 1 µB, indicating a negligible antiferromagnetic coupling between Co atoms. Magnetoresistance shows a change in sign from positive to negative, which further confirms the ferromagnetic order in Co-doped SnS2. Our s-p hybridized vdW layered SnS2 serves as a host semiconductor material to search for a suitable magnetic dopant with a high magnetic moment and room temperature TC for next-generation spintronics.
Spectral control of deterministically fabricated quantum dot waveguide systems using the quantum confined Stark effect
Authors: Schnauber Peter , Große Jan , Kaganskiy Arsenty , Ott Maximilian , Anikin Pavel , Schmidt Ronny , Rodt Sven , Reitzenstein Stephan
Published: May 2021

Quantum photonic circuits with integrated on-demand quantum emitters can act as building blocks for photonic gates and processors with enhanced quantum functionality. To scale up such quantum devices to larger and more powerful systems, eventually reaching the quantum advantage, the scalable integration of many emitters with identical emission wavelengths is of utmost importance. Here, we report on the deterministic integration of self-assembled quantum dots (QDs) in waveguide structures by means of in situ electron beam lithography (EBL). Applying external bias voltages to the p-i-n-doped and electrically contacted quantum circuits allows for spectral fine-tuning of the QDs via the quantum confined Stark effect. We achieve a tuning range of (0.40 ± 0.16) nm, which together with a spectral pre-selection accuracy of (0.2 ± 1.6) nm in the in situ EBL process is on average large enough to tune individual QDs into resonance. Thus, deterministic QD integration with spectral pre-selection in conjunction with Stark tuning of the QD emission wavelength is an attractive combination that has high potential to enable the scalable fabrication of integrated quantum photonic circuits in the future.
The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation
Authors: Kenison Jessica E. , Wang Zhongyan , Yang Kangkang , Snyder Megan , Quintana Francisco J. , Sherr David H.
Published: May 2021

Significance

Immune checkpoint inhibitors have emerged as critical therapeutics for several cancer types, including head and neck squamous cell carcinoma. However, enthusiasm remains constrained by the fact that only a minority of patients benefit. Therefore, there is a need to identify new immunotherapy targets. Here, we provide evidence supporting our hypothesis that the aryl hydrocarbon receptor (AhR) influences multiple immune checkpoints in a model of oral squamous cell carcinoma (OSCC). Remarkably, transplant of AhR-deleted OSCC cells generates completely protective tumor immunity characterized by a decrease in multiple immune checkpoints (PD-L1, CD39, CTLA4, PD1, and Lag3) on malignant and/or immune cells. These results have important implications for understanding the biology of cancer immunosuppression and for targeting the AhR for cancer immunotherapy.
No evidence for widespread island extinctions after Pleistocene hominin arrival
Authors: Louys Julien , Braje Todd J. , Chang Chun-Hsiang , Cosgrove Richard , Fitzpatrick Scott M. , Fujita Masaki , Hawkins Stuart , Ingicco Thomas , Kawamura Ai , MacPhee Ross D. E. , McDowell Matthew C. , Meijer Hanneke J. M. , Piper Philip J. , Roberts Patrick , Simmons Alan H. , van den Bergh Gerrit , van der Geer Alexandra , Kealy Shimona , O’Connor Sue
Published: May 2021

Significance

We provide global assessment of the possible link between Pleistocene hominin arrival and island extinction. The existing records on islands around the world do not support a significant and detrimental impact on island biotas following island colonization prior to the Holocene. This suggests that models using island extinctions as evidence in support of anthropogenic megafaunal overhunting, or as extensions of continental-level extinctions, need to be reconsidered.
Hindbrain neuropore tissue geometry determines asymmetric cell-mediated closure dynamics in mouse embryos
Authors: Maniou Eirini , Staddon Michael F. , Marshall Abigail R. , Greene Nicholas D. E. , Copp Andrew J. , Banerjee Shiladitya , Galea Gabriel L.
Published: May 2021

Significance

Failure to biomechanically close the embryonic neural tube in the developing brain causes fatal anencephaly. Despite their clinical importance, which cellular force-generating mechanisms close the neural tube remains poorly understood. This interdisciplinary study combines morphometric analysis, mouse embryo live imaging, and in silico modeling to formally identify cellular behaviors which complete midbrain/hindbrain closure. Two cellular force-generating behaviors not previously appreciated to act in this context are identified: contractility of supracellular actomyosin purse strings around the gap and directional movement of cells toward the gap. Both these mechanisms are required to describe gap closure, and their resulting dynamics are substantially impacted by morphogenetically imposed tissue geometry. This work provides a broadly applicable biophysical framework underlying fatal failures of midbrain/hindbrain closure.
The voltage sensor is responsible for ΔpH dependence in H
v
1 channels
Authors: Carmona Emerson M. , Fernandez Miguel , Alvear-Arias Juan J. , Neely Alan , Larsson H. Peter , Alvarez Osvaldo , Garate Jose Antonio , Latorre Ramon , Gonzalez Carlos
Published: May 2021

Significance

Acid extrusion in various types of cells and the reactive oxygen species production by the NADPH oxidase in phagocytes and microglia are mediated by the voltage-gated proton channel (H
v
1). One of the biophysical properties essential for the H
v
1 function is its ΔpH-dependent gating. Here, we measured the H
v
1 gating currents’ pH dependence in the monomeric nonconducting D160N
Ciona intestinalis
H
v
1 mutant. We demonstrated that H
v
1 ΔpH-dependent gating is a consequence of voltage sensor modulation by direct gating currents recordings. Around 60% of the energy stored in the ΔpH is coupled to the H
v
1 voltage sensor activation. Therefore, the proton chemical energy is transduced to the voltage sensor activation in H
v
1 to produce ΔpH-dependent gating.
Comment on ‘The 5d → 6p EUV photoabsorption spectra of Pb II and Bi III: evidence of excited states’
Authors: Ryabtsev A N
Published: May 2021

It is shown that the photoabsorption spectra of Pb II and Bi III reported by Lu et al (2020 J. Phys. B: At. Mol. Opt. Phys. 53 115001) can be almost fully explained by photoabsorption from the levels of the ground state configuration with little reference to the photoabsorption from the levels of the excited configurations.
Examining Traditional and Novel Validity Indicators from the Medical Symptom Validity Test Across Levels of Verbal and Visual Memory Impairment
Authors: Cerny Brian M , Resch Zachary J , Rhoads Tasha , Jennette Kyle J , Singh Palak G , Ovsiew Gabriel P , Soble Jason R
Published: May 2021

Objective

This cross-sectional study examined accuracy of traditional Medical Symptom Validity Test (MSVT) validity indicators, including immediate recognition (IR), delayed recognition (DR), and consistency (CNS), as well as a novel indicator derived from the mean performance on IR, DR, and CNS across verbal, visual, and combined learning and memory impairment bands.

Method

A sample of 180 adult outpatients was divided into valid (n = 150) and invalid (n = 30) groups based on results of four independent criterion performance validity tests. Verbal and visual learning and recall were classified as indicative of no impairment, mild impairment, or severe impairment based on performance on the Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test-Revised, respectively.

Results

In general, individual MSVT subtests were able to accurately classify performance as valid or invalid, even in the context of severe learning and memory deficits. However, as verbal and visual memory impairment increased, optimal MSVT cut-scores diverged from manual-specified cutoffs such that DR and CNS required cut-scores to be lowered to maintain adequate specificity. By contrast, the newly proposed scoring algorithm generally showed more robust psychometric properties across the memory impairment bands.

Conclusions

The mean performance index, a novel scoring algorithm using the mean of the three primary MSVT subtests, may be a more robust validity indicator than the individual MSVT subtests in the context of bona fide memory impairment.
Bayesian information sharing enhances detection of regulatory associations in rare cell types
Authors: Wu Alexander P , Peng Jian , Berger Bonnie , Cho Hyunghoon
Published: May 2021

Motivation

Recent advances in single-cell RNA-sequencing (scRNA-seq) technologies promise to enable the study of gene regulatory associations at unprecedented resolution in diverse cellular contexts. However, identifying unique regulatory associations observed only in specific cell types or conditions remains a key challenge; this is particularly so for rare transcriptional states whose sample sizes are too small for existing gene regulatory network inference methods to be effective.

Results

We present ShareNet, a Bayesian framework for boosting the accuracy of cell type-specific gene regulatory networks by propagating information across related cell types via an information sharing structure that is adaptively optimized for a given single-cell dataset. The techniques we introduce can be used with a range of general network inference algorithms to enhance the output for each cell type. We demonstrate the enhanced accuracy of our approach on three benchmark scRNA-seq datasets. We find that our inferred cell type-specific networks also uncover key changes in gene associations that underpin the complex rewiring of regulatory networks across cell types, tissues and dynamic biological processes. Our work presents a path toward extracting deeper insights about cell type-specific gene regulation in the rapidly growing compendium of scRNA-seq datasets.

Supplementary information

Supplementary data are available at Bioinformatics online.

Availability and implementation

The code for ShareNet is available at http://sharenet.csail.mit.edu and https://github.com/alexw16/sharenet.
CLEP: a hybrid data- and knowledge-driven framework for generating patient representations
Authors: Bharadhwaj Vinay Srinivas , Ali Mehdi , Birkenbihl Colin , Mubeen Sarah , Lehmann Jens , Hofmann-Apitius Martin , Hoyt Charles Tapley , Domingo-Fernández Daniel
Published: May 2021

As machine learning and artificial intelligence increasingly attain a larger number of applications in the biomedical domain, at their core, their utility depends on the data used to train them. Due to the complexity and high dimensionality of biomedical data, there is a need for approaches that combine prior knowledge around known biological interactions with patient data. Here, we present CLinical Embedding of Patients (CLEP), a novel approach that generates new patient representations by leveraging both prior knowledge and patient-level data. First, given a patient-level dataset and a knowledge graph containing relations across features that can be mapped to the dataset, CLEP incorporates patients into the knowledge graph as new nodes connected to their most characteristic features. Next, CLEP employs knowledge graph embedding models to generate new patient representations that can ultimately be used for a variety of downstream tasks, ranging from clustering to classification. We demonstrate how using new patient representations generated by CLEP significantly improves performance in classifying between patients and healthy controls for a variety of machine learning models, as compared to the use of the original transcriptomics data. Furthermore, we also show how incorporating patients into a knowledge graph can foster the interpretation and identification of biological features characteristic of a specific disease or patient subgroup. Finally, we released CLEP as an open source Python package together with examples and documentation.

Availability and implementation

CLEP is available to the bioinformatics community as an open source Python package at https://github.com/hybrid-kg/clep under the Apache 2.0 License.

Supplementary information

Supplementary data are available at Bioinformatics online.
Early parietofrontal network upregulation relates to future persistent deficits after severe stroke—a prospective cohort study
Authors: Backhaus Winifried , Braaß Hanna , Higgen Focko L , Gerloff Christian , Schulz Robert
Published: May 2021

Recent brain imaging has evidenced that parietofrontal networks show alterations after stroke which also relate to motor recovery processes. There is converging evidence for an upregulation of parietofrontal coupling between parietal brain regions and frontal motor cortices. The majority of studies though have included only moderately to mildly affected patients, particularly in the subacute or chronic stage. Whether these network alterations will also be present in severely affected patients and early after stroke and whether such information can improve correlative models to infer motor recovery remains unclear. In this prospective cohort study, 19 severely affected first-ever stroke patients (mean age 74 years, 12 females) were analysed which underwent resting-state functional MRI and clinical testing during the initial week after the event. Clinical evaluation of neurological and motor impairment as well as global disability was repeated after three and six months. Nineteen healthy participants of similar age and gender were also recruited. MRI data were used to calculate functional connectivity values between the ipsilesional primary motor cortex, the ventral premotor cortex, the supplementary motor area and the anterior and caudal intraparietal sulcus of the ipsilesional hemisphere. Linear regression models were estimated to compare parietofrontal functional connectivity between stroke patients and healthy controls and to relate them to motor recovery. The main finding was a significant increase in ipsilesional parietofrontal coupling between anterior intraparietal sulcus and the primary motor cortex in severely affected stroke patients (P < 0.003). This upregulation significantly contributed to correlative models explaining variability in subsequent neurological and global disability as quantified by National Institute of Health Stroke Scale and modified Rankin Scale, respectively. Patients with increased parietofrontal coupling in the acute stage showed higher levels of persistent deficits in the late subacute stage of recovery (P < 0.05). This study provides novel insights that parietofrontal networks of the ipsilesional hemisphere undergo neuroplastic alteration already very early after severe motor stroke. The association between early parietofrontal upregulation and future levels of persistent functional deficits and dependence from help in daily living might be useful in models to enhance clinical neurorehabilitative decision making.
Hemostatic materials in wound care
Authors: Yu Peiyu , Zhong Wen
Published: May 2021

Blood plays an essential role in the human body. Hemorrhage is a critical cause of both military and civilian casualties. The human body has its own hemostatic mechanism that involves complex processes and has limited capacity. However, in emergency situations such as battlefields and hospitals, when the hemostatic mechanism of the human body itself cannot stop bleeding effectively, hemostatic materials are needed for saving lives. In this review, the hemostatic mechanisms and performance of the most commonly used hemostatic materials, (including fibrin, collagen, zeolite, gelatin, alginate, chitosan, cellulose and cyanoacrylate) and the commercial wound dressings based on these materials, will be discussed. These materials may have limitations, such as poor tissue adhesion, risk of infection and exothermic reactions, that may lessen their hemostatic efficacy and cause secondary injuries. High-performance hemostatic materials, therefore, have been designed and developed to improve hemostatic efficiency in clinical use. In this review, hemostatic materials with advanced performances, such as antibacterial capacity, superhydrophobicity/superhydrophilicity, superelasticity, high porosity and/or biomimicry, will be introduced. Future prospects of hemostatic materials will also be discussed in this review.
Successful coil embolization of a large right coronary artery-coronary sinus fistula causing a significant left-to-right shunt: a case report
Authors: El Nihum Lamees I , Thakkar Akanksha N , Chinnadurai Ponraj , Lin C Huie
Published: May 2021

Background

This case reviews a challenging but successful transcatheter coil embolization of a large congenital coronary artery fistula (CAF) causing a significant left-to-right shunt.

Case summary

A 51-year-old female with no significant prior history presented with symptoms of dyspnoea and chest discomfort. Extensive evaluation revealed a large CAF between a tortuous right coronary artery (RCA) and the coronary sinus (CS) composed of three aneurysmal pseudochambers. Closure of the RCA-CS fistula was attempted through coil deployment into the fistula neck. However, due to the brisk flow through the fistula, both coils embolized into the fistula sac. An alternative location was subsequently identified on three-dimensional rendering of a computed tomography angiography scan, which revealed a sharp bend in the RCA prior to the fistula neck and distal to the posterior descending artery (PDA) takeoff. Repeat attempt at embolization was accomplished using a telescoping system to reach and occlude the targeted bend. The coil mass remained stable and angiography demonstrated reduced flow through the fistula and preserved patency of the PDA. The decreased residual flow through the fistula secondary to the initial embolization attempt likely aided the successful deployment of coils in the second and final attempt. At 1 year, the patient was doing well with resolution of her symptoms and no clinical symptoms of coronary ischaemia.

Discussion

We suggest that an initial unsuccessful attempt at transcatheter embolization of a CAF should not preclude subsequent attempts for closure when there exists an appropriate indication.
Toward a Stable Global Noctuidae (Lepidoptera) Taxonomy
Authors: Keegan Kevin L , Rota Jadranka , Zahiri Reza , Zilli Alberto , Wahlberg Niklas , Schmidt B Christian , Lafontaine J Donald , Goldstein Paul Z , Wagner David L
Published: May 2021

Noctuidae are one of the world’s most diverse, ecologically successful, and economically important animal lineages with over 12,000 species in ~1,150 genera. We inferred a phylogeny using eight protein-coding genes for the global fauna, greatly expanding upon previous attempts to stabilize Noctuidae higher classification by sampling 341 genera (nearly half represented by their type species) representing 70/76 widely recognized family-group taxa: 20/21 subfamilies, 32/35 tribes, and 18/20 subtribes. We evaluated 17 subfamily-level taxa in detail, discussing adult and larval morphology, life histories, and taxonomic implications of our results. We significantly alter concepts of Acontiinae, Condicinae, Eustrotiinae, Metoponiinae, and Stiriinae. Our results supported recognition of two new subfamilies: Cobubathinae Wagner & Keegan, 2021 subf. nov. and Cropiinae Keegan & Wagner, 2021 subf. nov. Other nomenclatural changes we made are as follows. We moved: ‘Acontia’ viridifera (Hampson, 1910), ‘Azenia’ virida Barnes and McDunnough, 1916, Aleptinoides, Austrazenia, Chalcoecia, Megalodes, and Trogotorna to Chamaecleini in Acontiinae; Apaustis to, and reinstated Emmelia as a valid genus in Acontiinae; Allophyes and Meganephria to Cuculliinae; ‘Plagiomimicus’ navia (Harvey, 1875), Airamia, Alvaradoia, Hypoperigea, Neotarache, and Mesotrosta to Condicinae; Axenus, Azenia, Metaponpneumata, Sexserrata, and Tristyla to Metoponiinae; ‘Paramiana’ canoa (Barnes, 1907) to Noctuinae; Aucha, Cobubatha, and Tripudia to Cobubathinae; Anycteola and Supralathosea to Oncocnemidinae; Cropia to Cropiinae; Desmoloma to Dyopsinae; Eviridemas and Gloanna to Bryophilinae; Fota and Stilbia to Stiriinae; and Copibryophila, Homolagoa, and Tyta to Noctuidae incertae sedis. We conclude with discussion of instances where current understanding of noctuid biogeography and life histories were changed by our results.
Breast Imaging Radiologists’ Role in Value Pathways
Authors: Golding Lauren P , Nicola Gregory N
Published: May 2021

The Merit-Based Incentive Payment System (MIPS) has fallen short of its intended goal to substantially transform the delivery of healthcare by tying clinician payments to quality and cost reduction. Policy makers made changes to the program over its first five years in efforts to address concerns about complexity and lack of meaningful impact on outcomes for our patients. One of these changes, the creation of MIPS Value Pathways (MVPs), aims to streamline reporting of increasingly aligned measures and serve as a stepping-stone for the transition to alternative payment models. As MIPS continues to evolve, these value pathways will provide new opportunities for breast imaging radiologists to participate in value-based care.
Is transverse screw fixation really necessary in PAO?—A comparative in vivo study
Authors: Leopold Vincent J , Conrad Juana , Hipfl Christian , Müllner Maximilian , Khakzad Thilo , Perka Carsten , Hardt Sebastian
Published: May 2021

The optimal fixation technique in periacetabular osteotomy (PAO) remains controversial. This study aims to assess the in vivo stability of fixation in PAO with and without the use of a transverse screw. We performed a retrospective study to analyse consecutive patients who underwent PAO between January 2015 and June 2017. Eighty four patients (93 hips) of which 79% were female were included. In 54 cases, no transverse screw was used (group 1) compared with 39 with transverse screw (group 2). Mean age was 26.5 (15–44) in group 1 and 28.4 (16–45) in group 2. Radiological parameters relevant for DDH including lateral center edge angle of Wiberg (LCEA), Tönnis angle (TA) and femoral head extrusion index (FHEI) were measured preoperatively, post-operatively and at 3-months follow-up. All patients were mobilized with the same mobilization regimen. Post-operative LCEA, TA and FHEI were improved significantly in both groups for all parameters (P ≤ 0.0001). Mean initial correction for LCEA (P = 0.753), TA (P = 0.083) and FHEI (P = 0.616) showed no significant difference between the groups. Final correction at follow-up of the respective parameters was also not significantly different between both groups for LCEA (P = 0.447), TA (P = 0.100) and FHEI (P = 0.270). There was no significant difference between initial and final correction for the respective parameters. Accordingly, only minimal loss of correction was measured, showing no difference between the two groups for LCEA (P = 0.227), TA (P = 0.153) and FHEI (P = 0.324). Transverse screw fixation is not associated with increased fragment stability in PAO. This can be taken into account by surgeons when deciding on the fixation technique of the acetabular fragment in PAO.
Transcription factor allosteric regulation through substrate coordination to zinc
Authors: Almeida Beatriz C , Kaczmarek Jennifer A , Figueiredo Pedro R , Prather Kristala L J , Carvalho Alexandra T P
Published: May 2021

The development of new synthetic biology circuits for biotechnology and medicine requires deeper mechanistic insight into allosteric transcription factors (aTFs). Here we studied the aTF UxuR, a homodimer of two domains connected by a highly flexible linker region. To explore how ligand binding to UxuR affects protein dynamics we performed molecular dynamics simulations in the free protein, the aTF bound to the inducer D-fructuronate or the structural isomer D-glucuronate. We then validated our results by constructing a sensor plasmid for D-fructuronate in Escherichia coli and performed site-directed mutagenesis. Our results show that zinc coordination is necessary for UxuR function since mutation to alanines prevents expression de-repression by D-fructuronate. Analyzing the different complexes, we found that the disordered linker regions allow the N-terminal domains to display fast and large movements. When the inducer is bound, UxuR can sample an open conformation with a more pronounced negative charge at the surface of the N-terminal DNA binding domains. In opposition, in the free and D-glucuronate bond forms the protein samples closed conformations, with a more positive character at the surface of the DNA binding regions. These molecular insights provide a new basis to harness these systems for biological systems engineering.
Tidally perturbed oblique pulsations in the hierarchical triple system V1031 Orionis
Authors: Lee Jae Woo
Published: May 2021

We present Transiting Exoplanet Survey Satellite (TESS) photometry of the triple star system V1031 Ori (AB)C, which exhibits short-period oscillations superimposed on an eclipsing light curve.The high-quality data were analyzed in detail and combined with the published spectroscopic measurements to obtain the fundamental stellar parameters of the program target. The masses and radii of the eclipsing pair (AB) were determined to about $0.5\%$ and $0.7\%$ precision, respectively. We found 23 significant frequencies in two ranges of <2 d−1 and 10.9–12.7 d−1 from the eclipse-subtracted residuals. Among them, 16 in the gravity (g)-mode region may be aliases and artefacts due to imperfect removal of the systematic trends and the binary effects from the TESS data. Seven frequencies in the pressure (p)-mode region were separated by the orbital frequency and split by an average offset of 0.042 ± 0.003 d−1 from their adjacent harmonics. Further, the pulsation amplitudes are clearly modulated with the binary star orbit. The results indicate that the p-mode frequencies are tidally perturbed pulsations from the secondary component and the pulsation axis could be aligned with the tidal axis.
002 Daridorexant, a dual orexin receptor antagonist, improves age-related insomnia in rats
Authors: Roch Catherine , Fischer Cédric , Jenck Francois , Steiner Michel
Published: May 2021

Introduction

Sleep disturbances develop with age, and prevalence of insomnia is higher in the elderly. Daridorexant is a new medication in development for the treatment of insomnia. Our aim was to investigate whether an insomnia-like phenotype develops in old rats, and then to assess the effect of repeated administration of daridorexant in these animals.

Methods

We recorded the electroencephalogram and electromyogram of freely moving male Wistar rats implanted with telemetry transmitters. Time spent sleeping during the inactive phase was measured at the ages of 4 (n=50), 6 (n=55), 8 (n=37), 12 (n=44), 18 (n=22) and 24 (n=9) months. The age at which the rats’ time spent sleeping started to be significantly reduced compared to that of 4-month-old rats was when the insomnia-like phenotype would start to occur. The impact of 100 mg/kg daridorexant, given orally at the beginning of the inactive phase, was evaluated in 16-month-old rats (n=8). Rats were consecutively treated daily for 6 days with vehicle (baseline period), for 3 weeks with daridorexant, and again for 1 week with vehicle (wash-out period).

Results

The total time spent sleeping during the 12-h inactive period decreased from 51.3±1.1% (mean ± SEM) at 4-months old to 39.3±4.4% at 24-months, with a significant decrease starting from 8-months (p<0.05). Whereas the time spent in rapid-eye-movement (REM) sleep (~10%) was not affected by age (p=0.64), the time spent in non-REM sleep decreased from 41.7±0.8% at 4 months to 28.7±3.2% at 24 months (p<0.001). In 16-month-old rats daridorexant increased the time spent in non-REM sleep over the first 6-h following administration (p<0.001). The time spent in REM sleep was unaffected (p=0.47). The average time spent in non-REM sleep over those 6h was 37.2±2.5% at baseline, and 43.8±2.4%, 44.6±2.7% and 44.5±3.0% in the 1st (p<0.05 vs baseline), 2nd (p<0.001) and 3rd (p<0.01) week of treatment, respectively. During the wash-out period, the non-REM sleep time returned to baseline levels (35.6±2.7%; p=0.06).

Conclusion

In rats, an insomnia-like phenotype, characterized by reduced non-REM sleep time, develops with age. Daridorexant improves this phenotype and its effect is maintained upon repeated administration over three weeks.

Support (if any)

Funded by Idorsia Pharmaceuticals Ltd
003 Treatment of Sleep Disordered Breathing with Leptin Loaded Exosomes
Authors: Freire Carla , Pho Huy , Ramsey Jacob , Streeter Stone , Kojima Ryo , Berger Slava , Fleury-Curado Thomaz , Sokolsky Marina , Batrakova Elena , Kabanov Alexander , Polotsky Vsevolod
Published: May 2021

Introduction

Obstructive sleep apnea (OSA) is characterized by recurrent periods of upper airway obstruction. The prevalence of OSA exceeds 50% in obese individuals and in 10–20% of obese patients OSA coexists with obesity hypoventilation syndrome (OHS) defined as daytime hypercapnia and hypoventilation during sleep attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Leptin is a potent respiratory stimulant and a potential therapeutic candidate. However, diet-induced obesity (DIO) results in reduced permeability of the blood-brain barrier (BBB) for leptin. Previous studies have shown that the BBB can be penetrated by exosomes, natural nanoparticles that can be used as drug delivery vehicles. In this study, we aimed to determine if exosomes overcome the BBB and treat OSA and OHS in DIO mice.

Methods

o examine the ability of exosomes to cross the BBB, male, lean (n=5) and DIO (n=5) C57BL/6J mice were injected with fluorescent exosomes or saline into the lateral tail vein. After 4h fluorescent exosomes biodistribution was evaluated by an in vitro imaging system (IVIS). Saline injected mice images were used for background adjustment. A separate subgroup of male, DIO (n=10) and lean (n=10) mice were headmounted with EEG and nuchal EMG leads. Sleep studies were performed in a plethysmography chamber and mice received saline, empty exosomes, free leptin, or leptin-loaded exosomes in a crossover manner.

Results

Exosomes were successfully delivered to the brain and the transport across the BBB was more efficient in DIO mice with 2-times greater relative fluorescence units measured in DIO when compared to lean mice (p<0.005). In DIO mice, exosomal leptin induced dramatic 1.7-2.2-fold increases in minute ventilation and 1.5-2.0-fold increases in maximal inspiratory flow during both flow-limited (upper airway/sleep apnea) and non-flow limited breathing (control of breathing) (p<0.05). In contrast, free leptin had no effect. Lean mice did not present significant sleep disordered breathing and no differences were observed between groups.

Conclusion

We demonstrated that exosomes overcome the BBB and that leptin-loaded exosomes treat OSA and OHS in DIO mice.

Support (if any)

R01HL 128970, R01HL 138932, R61 HL156240, U18 DA052301, FAPESP 2018/08758-3
007 NLRP3 inflammasomes contribute to dysregulated sleep and electroencephalogram delta power after mild and moderate TBI in mice
Authors: Zielinski Mark , Gibbons Allison , Lakis Gabrielle , Kaplan Gary
Published: May 2021

Introduction

Most traumatic brain injuries (TBI) are mild to moderate and can cause persistent dysregulated sleep, although the mechanisms are not well understood. Interleukin-1 beta (IL-1β) is a pro-inflammatory molecule that is activated in the cortex after waking activity and pathogenic challenge and alters non-rapid eye movement (NREM) sleep and electroencephalogram (EEG) delta power. Nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasomes sense changes in their local environment to stimulate caspase-1 to activate IL-1β into its mature form. We previously found that NLRP3 inflammasomes are increased in the cortex after acute sleep loss and contribute to increased NREM sleep and EEG delta power after sleep loss and toxin challenge. We aimed to determine if NLRP3 inflammasomes contribute to the persistent dysregulated sleep caused by TBI.

Methods

Using 2-3-month-old mice lacking NLRP3 and C57BL/6J wild-type control mice, we assessed sleep states and sleep state episode durations and frequencies prior to TBI, and 24 h, 2-weeks, and 2 months after mild or moderate TBI using polysomnography. TBI occurred in the frontal cortex from a controlled cortical impact device. Additional mice received identical treatments serving as a TBI procedural control but received a craniectomy without the TBI.

Results

Similar sleep findings were observed between the craniectomy control group and baseline measures. However, when compared to baseline values, mice lacking NLRP3 had attenuations in the significant increased amounts of NREM sleep and EEG delta power occurring 24 h after TBI and the significant reductions in NREM sleep and EEG delta power seen 2 months after TBI that were observed in wild-type mice. These effects were similar in moderate and mild TBI groups. Mice lacking NLRP3 were not found to exhibit the fragmented sleep after mild or moderate TBI that was found to persist from 24 h to 2 months post-TBI in the wild-type mice. These effects were evident by significant increased frequencies of waking episodes induced by the TBIs.

Conclusion

Our findings suggest that NLRP3 inflammasomes contribute to dysregulated sleep occurring acutely or more persistently after TBI.

Support (if any)

Career Development Award IBX002823 (MZ) and Merit Review Award I01RX001144 (GK) from the United States Department of Veterans Affairs
009 Self-Reported Sleep Efficiency and Duration are Associated with Systemic Bioenergetic Function in Community-Dwelling Adults
Authors: Lehrer H Matthew , Chu Lauren , Hall Martica , Murdock Kyle
Published: May 2021

Introduction

Sleep is important for aging, health, and disease, but its cellular role in these outcomes is poorly understood. Basic research suggests that disturbed and insufficient sleep impair mitochondrial bioenergetics, which is involved in numerous aging-related chronic conditions. However, the relationship between sleep and bioenergetics has not been examined in humans. We examined associations of self-reported sleep with systemic bioenergetic function in peripheral blood mononuclear cells (PBMCs) of community-dwelling adults.

Methods

N = 43 adults (79% female) ages 48–70 (M = 61.63, SD = 5.99) completed the Pittsburgh Sleep Quality Index (PSQI) from which key components of sleep (satisfaction, alertness, timing, efficiency, and duration) were calculated. Participants provided blood samples from which PBMCs were isolated and measured for bioenergetics using extracellular flux analysis. Associations of sleep components with bioenergetic parameters, including the Bioenergetic Health Index (BHI), were examined.

Results

In bivariate analyses, lower sleep efficiency was associated with lower maximal respiration, spare capacity, and BHI (ps < 0.05). Longer sleep duration was associated with lower BHI (p < 0.01) and later sleep timing was associated with higher basal respiration, ATP-linked respiration, maximal respiration, spare capacity, and non-mitochondrial respiration (ps < 0.05). After adjustment for age, sex, and body mass index, lower sleep efficiency (β = 0.52, p < 0.01) and longer sleep duration (β = -0.43, p < 0.01) were associated with lower BHI.

Conclusion

Self-reported indices of sleep efficiency and duration are related to systemic bioenergetic function in humans, suggesting a possible cellular pathway linking sleep to health.

Support (if any)

T32HL082610
010 Association between Objective Sleep Duration and DNA methylation in Adolescents
Authors: Larsen Michael , He Fan , Imamura Yuka , Berg Arthur , Vgontzas Alexandros , Liao Duanping , Bixler Edward , Gehrman Philip , Fernandez-Mendoza Julio
Published: May 2021

Introduction

Insufficient sleep and circadian misalignment are highly prevalent in adolescents and have been associated with physical and mental health disorders. Several genome wide association studies (GWAS) in adults have identified genes that may be involved in the regulation of sleep and circadian traits. However, little is known regarding the epigenetic basis and significance of short sleep duration in adolescence, a critical developmental period.

Methods

To investigate the association between objective sleep duration, as measured by 9-hour in-lab polysomnography (PSG), and DNA methylation in GWAS-informed sleep-related genes, data from 263 adolescents of the Penn State Child Cohort (12-23y, 55.9% male, 23.2% racial/ethnic minorities) were analyzed. Using DNA extracted from peripheral leukocytes, epigenome-wide and GWAS-informed single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions were obtained. Multivariable-adjusted linear regression models assessed the association between PSG sleep duration and site-specific methylation levels. Covariates in these models included sex, age, race/ethnicity, body mass index percentile, and psychoactive medication use (i.e., stimulants, anti-depressants, anxiolytics, sedatives, and/or anti-psychotics). P-values were adjusted using the Benjamini & Hochberg method to correct for false discovery rate and, thus, q-values are reported.

Results

PSG sleep duration was associated with differential methylation at 162 intragenic sites in the epigenome-wide analysis with a q<0.05. In GWAS-informed analysis, five genes were associated with altered DNA methylation, by which shorter PSG sleep duration was associated with hypermethylation in MAD1L1 (q=0.02), MAP2K1 (q=0.03), and RBM19 (q=0.01) and with hypomethylation in Brain Enriched Guanylate Kinase Associated (BEGAIN; q=0.0005) and SLC39A8 (q=0.02).

Conclusion

Objective sleep duration in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian traits. Importantly, our data also provides evidence for a potential epigenetic link between objective short sleep duration and genes involved in postsynaptic density (BEGAIN), circadian regulation (MAP2K1/RBM19) as well as internalizing (MAD1L1) and psychotic (SLC38A8) disorders.

Support (if any)

NIH Awards Number R01HL136587, R01MH118308, R01HL97165, R01HL63772, UL1TR000127
012 Overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day
Authors: Grimaldi Daniela , Reid Kathryn , Mason Ivy , Warlick Chloe , Malkani Roneil , Abbott Sabra , Zee Phyllis
Published: May 2021

Introduction

Prior reports indicate that exposure to light at night negatively impacts sleep quality, autonomic and metabolic function, but the interaction between these physiologically interconnected systems is not fully elucidated. We examined the acute effects of nighttime light exposure on sleep macro and microarchitecture, heart rate (HR) and response to oral glucose tolerance test (OGTT), and the relationship between these measures.

Methods

Twenty healthy adults (18 - 40 years) were randomized into Light or Dark groups and run in parallel for a three-day and two-night laboratory stay. The Light group (n=10) slept in the dark (< 3 lux) on Night 1 and slept with overhead room lights on (100 lux) on Night 2, while the Dark group (n=10) slept in the dark (< 3 lux) on both Nights 1 and 2. Overnight polysomnography (PSG) was used to assess sleep macro and microstructure (slow wave activity: SWA: 0.5–4 Hz, and slow oscillatory (SO) activity: 0.5–1 Hz), and beat-to-beat measurement of HR. A two-hour OGTT was completed each morning. The between groups change in PSG-derived measures and metabolic parameters from Night/Day 2 to Night/Day 1, was calculated.

Results

While a greater percentage of time was spent in stage 2 (p= 0.003) and a smaller percentage of time was spent in stage 3 (p= 0.04), there were no between group differences in SWA and SO activity. Time series analysis of HR changes across the night from Night 1 to Night 2 showed higher HR in the Light vs the Dark group (p< 0.001). The change from Day 1 to Day 2 of the initial insulin response (60-min. area under the curve, AUC) showed a higher insulin response in the Light vs the Dark group (p= 0.029). The change in HR was positively correlated with the change in the 60-min. AUC of insulin (R= 0.46, p= 0.049).

Conclusion

A single overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day and these responses appear to be associated, suggesting that elevated autonomic activity in response to light at night impacts next day metabolic responses.

Support (if any)

Center for Circadian and Sleep Medicine, UL1TR001422
013 Associations Between Rest-Activity Rhythms and Nocturnal Blood Pressure are Sex-Dependent in Apparently Healthy Emerging Adults
Authors: Hoopes Elissa , Patterson Freda , Berube Felicia , D’Agata Michele , Brewer Benjamin , Malone Susan , Farquhar William , Witman Melissa
Published: May 2021

Introduction

Misalignment between endogenous circadian rhythms and environmental signals – an emerging risk factor for cardiovascular disease (CVD) – can disrupt diurnal blood pressure (BP) rhythms, resulting in higher nocturnal BP and less-pronounced BP dipping (i.e., % decline in nighttime systolic BP [SBP] relative to daytime values). Daily patterns of rest and activity (‘rest-activity rhythms’ [RAR]) are a proxy for estimating circadian disruption in free-living settings and have been independently associated with elevated CVD risk. However, the relation between RAR and nocturnal BP is unclear. Thus, we aimed to quantify the associations between RAR and nocturnal BP characteristics in male and female emerging adults (18-25y).

Methods

Fifty healthy emerging adults (20±1y; 20M/30F) underwent 24-h ambulatory BP monitoring following 14 consecutive days of continuous wrist actigraphy. RAR variables of interdaily stability (IS; day-to-day consistency in RAR), intradaily variability (IV; within-day fragmentation of RAR), and relative amplitude (RA; difference between trough vs. peak activity) were computed. Bivariate correlations were used to quantify associations between RAR variables and nocturnal BP characteristics for all participants, and separately for males and females. Linear regression models of mean nocturnal SBP, nocturnal diastolic BP (DBP), and SBP dipping were also generated to test main and interactive effects of sex and RAR. Potential confounders (variables associated with outcomes at p<0.10) of daytime BP, race, body mass index, physical activity, sleep duration, alcohol, caffeine, and sodium intake were also included as indicated.

Results

Overall, IS and RA positively correlated with % SBP dipping (IS: r=0.33, p=0.02; RA: r=0.35, p=0.01). Among females only, correlations strengthened (IS: r=0.50, p<0.01; RA: r=0.52, p<0.01) and an inverse association between RA and mean nocturnal SBP emerged (r=-0.46, p=0.01). Conversely, among males, no significant associations were apparent. Multivariate regressions revealed a significant sex*RAR interaction, such that in females, every 1-standard deviation increase in IS and RA were associated with an average decrease in nocturnal SBP of 5.4 mmHg (95% CI: -10.0, -0.73) and 4.8 mmHg (95% CI: -9.2, -0.34), respectively.

Conclusion

Findings suggest that consistent and high-amplitude RAR associate with more favorable nocturnal BP characteristics, particularly in emerging female adults.

Support (if any)

Supported in part by NIH P20-GM113125.
021 Poor sleep quality in traumatic brain injury patients is associated with elevated inflammatory biomarkers
Authors: Pucci Josephine , Mithani Sara , Leete Jacqueline , Lai Chen , Kenney Kimbra , Gill Jessica , Werner J Kent
Published: May 2021

Introduction

Mild traumatic brain injury (mTBI) and sleep disorders are independently associated with inflammation. Following mTBI, elevated levels of cytokines, such as interleukin-6 (IL-6), 10 (IL-10) and tumor necrosis factor alpha (TNFα), have been observed. These signals are also known to modulate sleep homeostasis. IL-6, IL-10 and TNFα concentrations are typically measured in plasma, but recent work has shown that their measurement in extracellular vesicles (EVs) may hold additional value, as they are shielded from degradation and may be more biologically relevant. We hypothesized that inflammatory biomarkers in chronic mTBI patients would be elevated in poor sleepers.

Methods

In a cross-sectional cohort of warfighters (n=137 mTBI, 44 controls), the Pittsburgh Sleep Quality Index (PSQI) was compared with EV and plasma IL-6, IL-10, TNFα. Protein quantification was performed with Simoa. Two-tailed tests were used with a type I error of p<0.05. Linear models controlled for age, sex, and body mass index.

Results

In the mTBI cohort, poor sleepers (PSQI>=10, a published military cutoff) had elevated IL-6 vs. good sleepers (mean [SD] pg/mL, EV: 0.47 [0.63] vs 1.01 [1.54], p=0.04, d=0.44; plasma: 5.00 [13.31] vs 6.88 [13.51], p=0.03, d=0.14). Poor sleepers with mTBI had less EV IL-10 (1.71 [8.18] vs 0.30 [0.54], p=0.017). Comparisons of plasma IL-10 were not significant. No differences in TNFα were observed in mTBI groups. In our model, PSQI was the strongest predictor of EV IL-6 (βstd=0.27, p=0.03) in mTBI patients, whereas only BMI predicted IL-6 in controls. EV IL-6, IL-10, and TNFα correlated with PSQI (R=0.21, p=0.019; R=0.21, p=0.014; R=0.22, p=0.013, respectively), but these relationships were not found with plasma. In controls, no correlations or differences in any biomarker were observed between groups.

Conclusion

Warfighters who report poor sleep had significantly elevated inflammatory biomarkers after chronic mTBI. Cytokine levels in EVs had greater effect sizes between groups compared to plasma levels suggesting EV measurements may have improved signal. Poor sleep and its association with inflammatory cytokines after mTBI may have therapeutic implications.

Support (if any)

DoD: Contract W91YTZ-13-C-0015/ HT0014-19-C-0004 with VHA Central Office VA TBI Model Systems Program of Research/DHA Contracting Office (CO-NCR) HT0014