Electrical impedance myography detects progressive pathological alterations in the hindlimb muscle of the PMP22-C3 mice, an animal model of CMT1A.

Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited peripheral dysmyelinating neuropathy. Although lower limb muscle weakness is the most important factor affecting the quality of life of patients with CMT1A, existing clinical measures for its evaluation have limitations, including low sensitivity in detecting disease progression. Electrical impedance myography (EIM) is a newer tool that enables noninvasive evaluation of muscle state by measuring muscle composition, and potentially supports the evaluation of neuromuscular disease progression and treatment effects.

Electrical impedance myography detects dystrophin-related muscle changes in mdx mice.

Background: The lack of functional dystrophin protein in Duchenne muscular dystrophy (DMD) causes chronic skeletal muscle inflammation and degeneration. Therefore, the restoration of functional dystrophin levels is a fundamental approach for DMD therapy. Electrical impedance myography (EIM) is an emerging tool that provides noninvasive monitoring of muscle conditions and has been suggested as a treatment response biomarker in diverse indications.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.

Urine titin as a novel biomarker for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy that is caused by lack of dystrophin, a critical structural protein in skeletal muscle. DMD treatments, and quantitative biomarkers to assess the efficacy of potential treatments, are urgently needed. Previous evidence has shown that titin, a muscle cell protein, is increased in the urine of patients with DMD, suggesting its usefulness as a DMD biomarker.

Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist.

To develop potent and orally bioavailable melatonin receptor (MT and MT) agonists, a novel series of 5-6-5 tricyclic derivatives was designed, synthesized, and evaluated. The synthesized indeno[5,4-][1,3]oxazole, cyclopenta[]pyrazolo[1,5-]pyridine, indeno[5,4-][1,3]thiazole, and cyclopenta[]indazole derivatives showed potent binding affinities for MT/MT receptors. Further optimization of these derivatives based on their metabolic stability in human hepatic microsomes revealed that ()- (()--[2-(2-methyl-7,8-dihydro-6-indeno[5,4-][1,3]oxazol-8-yl)ethyl]acetamide) was a potent MT and MT ligand (MT, = 0.

TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models.

Changes in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling are implicated in older people with dementia. Drugs that modulate the cAMP/cGMP levels in the brain might therefore provide new therapeutic options for the treatment of cognitive impairment in aging and elderly with dementia. Phosphodiesterase 2A (PDE2A), which is highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyze cAMP and cGMP.

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders.

It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats.

Autophosphorylation of Specific Threonine and Tyrosine Residues in Arabidopsis CERK1 is Essential for the Activation of Chitin-Induced Immune Signaling.

Pattern recognition receptors on the plant cell surface mediate the recognition of microbe/damage-associated molecular patterns (MAMPs/DAMPs) and activate downstream immune signaling. Autophosphorylation of signaling receptor-like kinases is a critical event for the activation of downstream responses but the function of each phosphorylation site in the regulation of immune signaling is not well understood. In this study, 41 Ser/Thr/Tyr and 15 Ser/Thr residues were identified as in vitro and in vivo autophosphorylation sites of Arabidopsis CERK1, which is essential for chitin signaling.

Regulatory mechanism of the gastric hyperemic response following barrier disruption: roles of cyclooxygenase-1, the prostaglandin E2/EP1 receptor and sensory neurons.

We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice.

Selective regulation of the chitin-induced defense response by the Arabidopsis receptor-like cytoplasmic kinase PBL27.

Recognition of microbe-associated molecular patterns (MAMPs) initiates pattern-triggered immunity in host plants. Pattern recognition receptors (PRRs) and receptor-like cytoplasmic kinases (RLCKs) are the major components required for sensing and transduction of these molecular patterns. However, the regulation of RLCKs by PRRs and their specificity remain obscure.

Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists.

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.

Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.

Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.

[IgG4-related Mikulicz's disease: a report of 3 cases].

Introduction: We report three cases of hyper-IgG4 disease with synchronous or asynchronous lymphocytic infiltration onset, IgG4 positive plasma cell infiltration, and fibril formation in multiple exocrine glands and extranodal organs. IgG4-related sialadenitis attracting recent attention has yet to be clarified as a clinical entity.

Case Report: Case 1, a 61-year-old man, had a submandibular gland sample showing IgG4-positive plasma cell infiltration.

A case of nasal natural killer/T lymphoma revealed by repeated deep neck abscess.

A diagnosis of natural killer (NK)/T-cell lymphoma was clarified after repeated deep neck abscess in a 63-year-old man. The absolute number of lymphocytes was mildly decreased. Lymphopenia induced by latent malignant lymphoma in this case likely caused the immunodeficiency, which induced repeated infection in the head and neck region.

Peritonsillar abscess with parapharyngeal and retropharyngeal involvement: incidence and intraoral approach.

Conclusion: This study illustrates common sites of infection seen in peritonsillar abscesses with involvement of the pharyngeal space and retropharyngeal space. Abscesses behind and/or inferior to the tonsil were encountered more frequently than expected. In these cases, the drainage had to be placed in the inferior pole of the tonsil and these types were frequently seen in older patients.

Primary laryngeal natural killer/T-cell lymphoma--report of a rare case.

Background: Natural killer (NK)/T-cell lymphoma involving the larynx is a rare entity, and its clinical picture has not been described.

Methods And Results: A 73-year-old man had a granulomatous tumor involving the larynx. Multiple biopsies over 1 year were needed to reach an accurate diagnosis of NK/T-cell lymphoma.

Tonsillar cyst of the false vocal cord.

Objectives/hypothesis: To report, for the first time, tonsillar cyst of the false vocal cord.

Study Design: Case report.

Methods: Case presentation and literature review.

No role for prostacyclin IP receptors in duodenal HCO3- secretion induced by mucosal acidification in mice--comparison with capsaicin-induced response.

Background/aim: We investigated the role of prostacyclin (PGI2) IP receptors in the acid-induced secretion of HCO3- using IP receptor knockout [IP (-/-)] mice, in comparison with capsaicin-induced secretion.

Methods: Male C57/BL6 mice, both wild-type [WT] and [IP (-/-)], fasted for 18 h were used. Under urethane anesthesia, a proximal duodenal loop was perfused with saline, and the secretion of HCO3- was measured at pH 7.

Participation of prostaglandin E receptor EP4 subtype in duodenal bicarbonate secretion in rats.

We examined, by using a specific PGE receptor subtype EP4 agonist and antagonist, the involvement of EP4 receptors in duodenal HCO(3)(-) secretion induced by PGE(2) and mucosal acidification in rats. Mucosal acidification was achieved by exposing a duodenal loop to 10 mM HCl for 10 min, and various EP agonists were given intravenously 10 min before the acidification. Secretion of HCO(3)(-) was dose-dependently stimulated by AE1-329 (EP4 agonist), the maximal response being equivalent to that induced by sulprostone (EP1/EP3 agonist) or PGE(2).

Prostaglandin E receptor EP1 subtype but not prostacyclin IP receptor involved in mucosal blood flow response of mouse stomachs following barrier disruption.

Aim: We investigated the role of prostacyclin IP receptors in gastric mucosal protection as well as functional responses induced by taurocholate Na (TC) as a mild irritant using IP receptor knockout mice, in comparison with prostaglandin (PG) E receptor EP1 subtype knockout animals.

Methods: Male C57/BL6 mice fasted for 18 h were used under urethane anesthesia. The stomach mounted on an ex vivo chamber was perfused with 20 mM HCl, and the transmucosal potential difference (PD), luminal acid loss, and gastric blood flow (GMBF) were simultaneously measured before and after exposure of the stomach to 20 mM TC for 20 min.

Optical power limiting with photoinduced anisotropy of azobenzene films.

We study the power-limiting properties of photoanisotropic azobenzene films with low-power laser. The trans-cis photoisomerization and molecular reorientation of azobenzene molecules induced by polarized laser beams result in intensity-dependent anisotropic effects. Consequently, the transmittance of the input beam that passes through the film between two crossed polarizers becomes enhanced at low intensities and clamped at high intensities.

Facilitation by endogenous prostaglandins of capsaicin-induced gastric protection in rodents through EP2 and IP receptors.

We investigated the role that prostaglandins (PGs) and EP receptors play in facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats and mice. Male Sprague-Dawley rats and C57BL/6 mice were used after 18 h of fasting. The animals were given HCl/ethanol (60% in 150 mM HCl) p.