Simultaneous Epigenetic and Gene Expression Profiling at Single Cell Resolution Uncovers Stem-Like Treg Subsets Induced With Oligonucleotide Expansion in Humans.

Tregs play a central role in maintaining immune tolerance. Recent progress in the clinical application of Tregs underscores their potential for cell therapy. Nevertheless, a notable hurdle remains in producing functional Tregs .

Hydroxychloroquine reduces hypertension and soluble fms-like kinase-1 in a Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model.

Objective: Hydroxychloroquine, a drug used for malaria and autoimmune diseases reportedly has beneficial effects against preeclampsia in pregnant women with lupus. However, its mechanism against preeclampsia remains unclear. We investigated the effect of hydroxychloroquine on an Nω-nitro-l-arginine methyl ester-induced preeclampsia rat model.

Structural Responses Estimation of Cable-Stayed Bridge from Limited Number of Multi-Response Data.

A cable-stayed bridge is widely adopted to construct long-span bridges. The deformation of cable-stayed bridges is relatively larger than that of conventional bridges, such as beam and truss types. Therefore, studies regarding the monitoring systems for cable-stayed bridges have been conducted to evaluate the performance of bridges based on measurement data.

Living Place Matters: The Duplicity of Shared Housing in the Young Adults of South Korea.

This study focus on the phenomenon of the preference for co-living among young adults that has manifested in South Korea. The study examines life in a shared house as a living place, which is the representative form of co-living that the younger adults in South Korea have been choosing. The objective of the study is to examine shared housing as living place matters and their possibility of being a home and house for the young generation.

mGlu potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits.

Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs).

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys.

Purpose: The sensitivity and accuracy of chemical exchange saturation transfer (CEST) and nuclear Overhauser enhancement (NOE) effects for assessing injury-associated changes in cervical spinal cords were evaluated in squirrel monkeys. Multiple interacting pools of protons, including one identified by an NOE at -1.6 ppm relative to water (NOE(-1.

Bidirectional and state-dependent modulation of brain activity by transcranial focused ultrasound in non-human primates.

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions.

Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment.

Anti-CD154 blockade-based regimens remain unequaled in prolonging graft survival in various organ transplantation models. Several studies have focused on transplantation tolerance with the anti-CD154 blockade, but none of these studies has investigated the mechanisms associated with its use as the sole treatment in animal models, delaying our understanding of anti-CD154 blockade-mediated immune tolerance. The purpose of this study was to investigate the mechanism underlying the anti-CD154 monoclonal antibody (mAb) blockade in inducing immune tolerance using an intrahepatic murine allogeneic islet transplantation model.

Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging.

Spinal cord injuries (SCIs) are a leading cause of disability and can severely impact the quality of life. However, to date, the processes of spontaneous repair of damaged spinal cord remain incompletely understood, partly due to a lack of appropriate longitudinal tracking methods. Noninvasive, multiparametric magnetic resonance imaging (MRI) provides potential biomarkers for the comprehensive evaluation of spontaneous repair after SCI.

Brief exposure to obesogenic diet disrupts brain dopamine networks.

Objective: We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).

Construction of EMSC-islet co-localizing composites for xenogeneic porcine islet transplantation.

Pancreatic islet transplantation is an ultimate solution for treating patients with type 1 diabetes (T1D). The pig is an ideal donor of islets for replacing scarce human islets. Besides immunological hurdles, non-immunological hurdles including fragmentation and delayed engraftment of porcine islets need solutions to succeed in porcine islet xenotransplantation.

Cholinergic Projections to the Substantia Nigra Pars Reticulata Inhibit Dopamine Modulation of Basal Ganglia through the M Muscarinic Receptor.

Cholinergic regulation of dopaminergic inputs into the striatum is critical for normal basal ganglia (BG) function. This regulation of BG function is thought to be primarily mediated by acetylcholine released from cholinergic interneurons (ChIs) acting locally in the striatum. We now report a combination of pharmacological, electrophysiological, optogenetic, chemogenetic, and functional magnetic resonance imaging studies suggesting extra-striatal cholinergic projections from the pedunculopontine nucleus to the substantia nigra pars reticulata (SNr) act on muscarinic acetylcholine receptor subtype 4 (M) to oppose cAMP-dependent dopamine receptor subtype 1 (D) signaling in presynaptic terminals of direct pathway striatal spiny projections neurons.

Resting-state functional connectivity in the rat cervical spinal cord at 9.4 T.

Purpose: Numerous studies have adopted resting-state functional MRI methods to infer functional connectivity between cortical regions, but very few have translated them to the spinal cord, despite its critical role in the central nervous system. Resting-state functional connectivity between gray matter horns of the spinal cord has previously been shown to be detectable in humans and nonhuman primates, but it has not been reported previously in rodents.

Methods: Resting-state functional MRI of the cervical spinal cord of live anesthetized rats was performed at 9.

In vivo neuroimaging and behavioral correlates in a rat model of chemotherapy-induced cognitive dysfunction.

Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [F]fluorodeoxyglucose (FDG) positron emission tomography (PET).

Cross-sensitization between xeno- and allo-antigens on subsequent allogeneic and xenogeneic pancreatic islet transplantation in a murine model.

The number of patients in need of organ transplantation is continuously on the rise. However, because of organ donor shortage, xenotransplantation has been highlighted as an alternative. Among the various porcine organs and tissues, porcine islets are considered to be the best-matching implantable candidates for clinical application based on recent progress in nonhuman primate pre-clinical studies.

Cell enrichment-free massive ex-vivo expansion of peripheral CD20⁺ B cells via CD40-CD40L signals in non-human primates.

Non-human primates (NHPs) are valuable as preclinical resources that bridge the gap between basic science and clinical application. B cells from NHPs have been utilized for the development of B-cell targeted drugs and cell-based therapeutic modalities; however, few studies on the ex-vivo expansion of monkey B cells have been reported. In this study, we developed a highly efficient ex-vivo expansion protocol for monkey B cells resulting in 99% purity without the requirement for prior cell-enrichment procedures.

A novel method for murine intrahepatic islet transplantation via cecal vein.

Islet transplantation is one of the most beneficial treatment modality to treat type 1 diabetic patients with frequent hypoglycemic unawareness. In clinical setting, human islets are infused via portal vein and are settled in the end-portal venules in the liver. However, mouse islets are transplanted into kidney subcapsule or liver through direct portal vein.

Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function.

Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration.

N-aryl piperazine metabotropic glutamate receptor 5 positive allosteric modulators possess efficacy in preclinical models of NMDA hypofunction and cognitive enhancement.

Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits.

Mosaic-like monolayer of graphene oxide sheets decorated with tetrabutylammonium ions.

We report the fabrication of mosaic-like monolayers of graphene oxide (G-O) coated with tetrabutylammonium ions (TBA) using a simple spin-coating method. The TBA-coated G-O (TG-O) sheets were prepared by "spontaneous exfoliation" of graphite oxide intercalated with tetrabutylammonium hydroxide (TBAOH) in the wet state, without the need for sonication. Mosaic-like monolayers could be formed on a variety of substrates such as Si wafer (coated with the thin native oxide), SiO2/Si wafer, graphene grown by chemical vapor deposition and then transferred on SiO2/Si wafer, Au film on Si wafer, and Cu foil.

Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models.

M(1) muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M(1) receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M(1) allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M(1) coupling to different signaling pathways including Ca(2+) and β-arrestin responses.

Muscarinic receptor pharmacology and circuitry for the modulation of cognition.

The muscarinic cholinergic system constitutes an important part of the neuronal circuitry that modulates normal cognition. Muscarinic receptor antagonists are well known to produce or exacerbate impairments in attention, learning, and memory. Conversely, both direct-acting muscarinic receptor agonists and indirect-acting muscarinic cholinergic agonists, such as acetylcholinesterase inhibitors, have shown cognition-enhancing properties, including improvements in normal cognitive function, reversal of cognitive deficits induced by muscarinic receptor antagonists, and attenuation of cognitive deficits in psychiatric and neurological disorders, such as Alzheimer's disease and schizophrenia.