Hypocretin/orexin neurons are distributed restrictively in the hypothalamus, a brain region known to orchestrate diverse functions including sleep, reward processing, food intake, thermogenesis, and ...mood. Since the hypocretins/orexins were discovered more than two decades ago, extensive studies have accumulated concrete evidence showing the pivotal role of hypocretin/orexin in diverse neural modulation. New method of viral-mediated tracing system offers the possibility to map the monosynaptic inputs and detailed anatomical connectivity of Hcrt neurons. With the development of powerful research techniques including optogenetics, fiber-photometry, cell-type/pathway specific manipulation and neuronal activity monitoring, as well as single-cell RNA sequencing, the details of how hypocretinergic system execute functional modulation of various behaviors are coming to light. In this review, we focus on the function of neural pathways from hypocretin neurons to target brain regions. Anatomical and functional inputs to hypocretin neurons are also discussed. We further briefly summarize the development of pharmaceutical compounds targeting hypocretin signaling.
This article is part of the special issue on Neuropeptides.
•Hypocretin system plays a key role in sleep initiation and maintenance through modulation of multiple downstream arousal-promoting brain nuclei.•Hypocretin system modulates reward-processing and addiction through brain nuclei those are highly relevant to arousal modulation.•Development of hypocretin receptor antagonists (for insomnia and hyperarousal states) and agonists (for narcolepsy/cataplexy) provides new tools for sleep pharmacology.
Mesoporous silica nanoparticles (MSNs), one of the important porous materials, have garnered interest owing to their highly attractive physicochemical features and advantageous morphological ...attributes. They are of particular importance for use in diverse fields including, but not limited to, adsorption, catalysis, and medicine. Despite their intrinsic stable siliceous frameworks, excellent mechanical strength, and optimal morphological attributes, pristine MSNs suffer from poor drug loading efficiency, as well as compatibility and degradability issues for therapeutic, diagnostic, and tissue engineering purposes. Collectively, the desirable and beneficial properties of MSNs have been harnessed by modifying the surface of the siliceous frameworks through incorporating supramolecular assemblies and various metal species, and through incorporating supramolecular assemblies and various metal species and their conjugates. Substantial advancements of these innovative colloidal inorganic nanocontainers drive researchers in promoting them toward innovative applications like stimuli (light/ultrasound/magnetic)‐responsive delivery‐associated therapies with exceptional performance in vivo. Here, a brief overview of the fabrication of siliceous frameworks, along with discussions on the significant advances in engineering of MSNs, is provided. The scope of the advancement in terms of structural and physicochemical attributes and their effects on biomedical applications with a particular focus on recent studies is emphasized. Finally, interesting perspectives are recapitulated, along with the scope toward clinical translation.
Mesoporous silica nanoparticles (MSNs) have garnered enormous interest owing to their highly advantageous physicochemical and morphological attributes. Collectively, progression has been made by modifying the surface of the siliceous frameworks through incorporating diverse supramolecular assemblies. An overview of the fabrication of MSNs and discussions on significant advances in engineering of MSNs, along with their scope toward clinical translation, is provided.
Abstract
Photothermal conversion, heat localization and water supply are the keys to achieving efficient solar‐driven interfacial evaporation. However, effective coupling between the three aspects at ...the air/liquid interface remains challenging. Herein, Au@Ag‐Pd trimetallic nanostructure/polystyrene (PS) microsphere Janus structures are designed as the solar absorber and thermal insulator. The Janus structures deposited on a water supply layer act as a 2D interfacial solar evaporator. The PS microsphere localizes heat at micrometer scale and enhances plasmonic absorption of the Au@Ag‐Pd nanocrystals supported on the microsphere. Meanwhile, the Janus structures divide the surface of water supply layer into multiple regions with sub‐micrometer depths, lowering the evaporation enthalpy. Owing to the synergic effects of these components, the evaporator realizes a solar‐to‐vapor conversion efficiency of 99.1% and an evaporation rate of 3.04 kg m
−2
h
−1
in pure water under 1 sun illumination. The efficient solar‐driven evaporation can last for over 40 h. Furthermore, the solar evaporator shows high‐performance seawater desalination with salt removal ratios of near 100%. This study brings new insights for controlling evaporation thermodynamics and kinetics. The Janus nano‐micro structure design can be extended to other systems for various solar‐thermal applications.
Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we ...identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.
Systemic manifestation of preeclampsia (PE) is associated with circulating factors, including inflammatory cytokines and damage-associated molecular patterns (DAMPs), or alarmins. However, it is ...unclear whether the placenta directly contributes to the increased levels of these inflammatory triggers. Here, we demonstrate that pyroptosis, a unique inflammatory cell death pathway, occurs in the placenta predominantly from early onset PE, as evidenced by elevated levels of active caspase-1 and its substrate or cleaved products, gasdermin D (GSDMD), IL-1β, and IL-18. Using cellular models mimicking pathophysiological conditions (e.g., autophagy deficiency, hypoxia, and endoplasmic reticulum (ER) stress), we observed that pyroptosis could be induced in autophagy-deficient human trophoblasts treated with sera from PE patients as well as in primary human trophoblasts exposed to hypoxia. Exposure to hypoxia elicits excessive unfolded protein response (UPR) and ER stress and activation of the NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome in primary human trophoblasts. Thioredoxin-interacting protein (TXNIP), a marker for hyperactivated UPR and a crucial signaling molecule linked to NLRP3 inflammasome activation, is significantly increased in hypoxia-treated trophoblasts. No evidence was observed for necroptosis-associated events. Importantly, these molecular events in hypoxia-treated human trophoblasts are significantly observed in placental tissue from women with early onset PE. Taken together, we propose that placental pyroptosis is a key event that induces the release of factors into maternal circulation that possibly contribute to severe sterile inflammation and early onset PE pathology.
The long noncoding RNA NEAT1 (nuclear enriched abundant transcript 1) nucleates the formation of paraspeckles, which constitute a type of nuclear body with multiple roles in gene expression. Here we ...identify NEAT1 regulators using an endogenous NEAT1 promoter-driven enhanced green fluorescent protein reporter in human cells coupled with genome-wide RNAi screens. The screens unexpectedly yield gene candidates involved in mitochondrial functions as essential regulators of NEAT1 expression and paraspeckle formation. Depletion of mitochondrial proteins and treatment of mitochondrial stressors both lead to aberrant NEAT1 expression via ATF2 as well as altered morphology and numbers of paraspeckles. These changes result in enhanced retention of mRNAs of nuclear-encoded mitochondrial proteins (mito-mRNAs) in paraspeckles. Correspondingly, NEAT1 depletion has profound effects on mitochondrial dynamics and function by altering the sequestration of mito-mRNAs in paraspeckles. Overall, our data provide a rich resource for understanding NEAT1 and paraspeckle regulation, and reveal a cross-regulation between paraspeckles and mitochondria.
With advantageous features such as minimizing the cost, time, and sample size requirements, organ-on-a-chip (OOC) systems have garnered enormous interest from researchers for their ability for ...real-time monitoring of physical parameters by mimicking the in vivo microenvironment and the precise responses of xenobiotics, i.e., drug efficacy and toxicity over conventional two-dimensional (2D) and three-dimensional (3D) cell cultures, as well as animal models. Recent advancements of OOC systems have evidenced the fabrication of 'multi-organ-on-chip' (MOC) models, which connect separated organ chambers together to resemble an ideal pharmacokinetic and pharmacodynamic (PK-PD) model for monitoring the complex interactions between multiple organs and the resultant dynamic responses of multiple organs to pharmaceutical compounds. Numerous varieties of MOC systems have been proposed, mainly focusing on the construction of these multi-organ models, while there are only few studies on how to realize continual, automated, and stable testing, which still remains a significant challenge in the development process of MOCs. Herein, this review emphasizes the recent advancements in realizing long-term testing of MOCs to promote their capability for real-time monitoring of multi-organ interactions and chronic cellular reactions more accurately and steadily over the available chip models. Efforts in this field are still ongoing for better performance in the assessment of preclinical attributes for a new chemical entity. Further, we give a brief overview on the various biomedical applications of long-term testing in MOCs, including several proposed applications and their potential utilization in the future. Finally, we summarize with perspectives.
Assembled from Th48Ni6 nanocages, the first transition‐metal (TM)‐thorium metal–organic framework (MOF, 1) has been synthesized and structurally characterized. 1 exhibits high solvent and acid/base ...stability, and resistance to 400 kGy β irradiation. Notably, 1 captures ReO4− (an analogue of radioactive 99TcO4−, a key species in nuclear wastes) with a maximum capacity of 807 mg g−1, falling among the largest values known to date. Furthermore, 1 can enrich methylene blue (MB) and can also serve as an effective and recyclable catalyst for CO2 fixation with epoxides; there is no significant loss of catalytic activity after 10 cycles. Theoretical studies with nucleus‐independent chemical shifts and natural bond orbital analysis reveal that the Th6O8 clusters in 1 have a unique stable electronic structure with (d–p)π aromaticity, partially rationalising 1′s stability.
Resistance is useful: The stable Th48Ni6 nanocage‐based metal–organic framework (MOF) is radiation resistant, effectively and selectively captures ReO4− and catalytically converts CO2 into epoxides. The aromatic character of the Th6O8 clusters accounts for the stability of the MOF.
Assembled from Th
Ni
nanocages, the first transition-metal (TM)-thorium metal-organic framework (MOF, 1) has been synthesized and structurally characterized. 1 exhibits high solvent and acid/base ...stability, and resistance to 400 kGy β irradiation. Notably, 1 captures ReO
(an analogue of radioactive
TcO
, a key species in nuclear wastes) with a maximum capacity of 807 mg g
, falling among the largest values known to date. Furthermore, 1 can enrich methylene blue (MB) and can also serve as an effective and recyclable catalyst for CO
fixation with epoxides; there is no significant loss of catalytic activity after 10 cycles. Theoretical studies with nucleus-independent chemical shifts and natural bond orbital analysis reveal that the Th
O
clusters in 1 have a unique stable electronic structure with (d-p)π aromaticity, partially rationalising 1's stability.
Microscale cell carriers have recently garnered enormous interest in repairing tissue defects by avoiding substantial open surgeries using implants for tissue regeneration. In this study, the highly ...open porous microspheres (HOPMs) are fabricated using a microfluidic technique for harboring proliferating skeletal myoblasts and evaluating their feasibility toward cell delivery application in situ. These biocompatible HOPMs with particle sizes of 280–370 µm possess open pores of 10–80 µm and interconnected paths. Such structure of the HOPMs conveniently provide a favorable microenvironment, where the cells are closely arranged in elongated shapes with the deposited extracellular matrix, facilitating cell adhesion and proliferation, as well as augmented myogenic differentiation. Furthermore, in vivo results in mice confirm improved cell retention and vascularization, as well as partial myoblast differentiation. These modular cell‐laden microcarriers potentially allow for in situ tissue construction after minimally invasive delivery providing a convenient means for regeneration medicine.
Highly open porous microspheres (HOPMs) are conveniently designed using a microfluidic setup and evaluated for their feasibility toward minimally invasive cell delivery‐based tissue regeneration. These biocompatible HOPMs with interconnected paths facilitate a high cell proliferation rate, and partial differentiation of skeletal myoblasts. These modular cells‐laden microcarriers provide a convenient means for in situ repair of tissue defects and applications in regenerative medicine.
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