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The principal controller neurons of the thermoregulatory center in the preoptic area (POA) have yet to be determined. In the present study using rats, we discovered that prostaglandin EP3 receptor-expressing POA neurons (POAEP3R neurons) are a pivotal bidirectional controller in the central thermoregulatory circuit mechanism. POAEP3R neurons were activated in response to elevated ambient temperature, but inhibited by prostaglandin E2, a pyrogenic mediator. In newly generated Ptger3 (EP3R)-tTA transgenic rats, chemogenetic stimulation of POAEP3R neurons at room temperature reduced body temperature by eliciting skin vasodilation (enhancing heat dissipation), whereas inhibition of them elicited hyperthermia involving brown adipose tissue thermogenesis and tachycardia, mimicking fever. Furthermore, we revealed that POAEP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic inhibitory signaling. Although many POAEP3R neuronal cell bodies expressed a glutamatergic mRNA marker, paradoxically, most of their axons in the DMH contained GABAergic synaptic proteins. Interestingly, such GABAergic terminals of POAEP3R→DMH axons were increased by chronic heat exposure of rats, indicating a synaptic alteration to enhance heat tolerance. Consistent with the anatomical observation, slice patch-clamp recordings from DMH neurons combined with optogenetic stimulation of POAEP3R→DMH axon terminals showed that these terminals predominantly form GABAergic synapses onto DMH neurons. These findings demonstrate that tonic GABAergic inhibitory signaling from POAEP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever. NEXT Program from JSPS (LS070 to K.N.); MEXT KAKENHI (JP21K06767, JP17K08568, JP26860159, JP23790271 to Y.N.; JP22K06844 to A.F.; JP22K06470, JP19K06954, JP16K19006 to N.K.; JP21H02592 to H.H.; JP20H03418, JP16H06276 (AdAMS), JP16H05128, JP15H05932, JP26118508, JP26713009, JP22689007 to K.N.); PRESTO (JPMJPR13M9 to K.N.), FOREST (JPMJFR204D to H.H.), Moonshot R&D (JPMJMS2024 to H.H.; JPMJMS2023 to K.N.) of JST; AMED (JP21wm0525002 to N.K.; JP21dm0207112 to H.H.; JP21gm5010002 to K.N.); Hori Sciences and Arts Foundation (to Y.N.); Kato Memorial Bioscience Foundation, Foundation of Kinoshita Memorial Enterprise (to N.K.); Takeda Science Foundation (to T.Y. and K.N.); Nakajima Foundation, Uehara Memorial Foundation, Ono Medical Research Foundation, Brain Science Foundation, Kowa Life Science Foundation (to K.N.). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The bidirectional controller of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here, we identify prostaglandin EP3 receptor–expressing POA neurons (POA EP3R neurons) as a pivotal bidirectional controller in the central thermoregulatory mechanism. POA EP3R neurons are activated in response to elevated ambient temperature but inhibited by prostaglandin E 2 , a pyrogenic mediator. Chemogenetic stimulation of POA EP3R neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POA EP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic (ceaseless) inhibitory signaling. Although many POA EP3R neuronal cell bodies express a glutamatergic messenger RNA marker, their axons in the DMH predominantly release γ-aminobutyric acid (GABA), and their GABAergic terminals are increased by chronic heat exposure. These findings demonstrate that tonic GABAergic inhibitory signaling from POA EP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.

Introduction: Although laparoscopic cotton swabs have been used in procedures such as blunt tissue dissection and elevation of organs, fluid maceration is widely known to reduce their original performance. Thus, we developed an anti-maceration laparoscopic surgical cotton swab that is expected to solve this problem by coating the cotton swab with water-resistant resin. This study aimed to determine whether anti-maceration cotton swabs perform better than conventional products. Material and methods: Fine surface shape analysis of cotton swabs was performed using microfocus X-ray computed tomography, and changes due to fluid absorption of the anti-maceration cotton swabs and pre-existing products were quantitatively compared. As indices, the degree of expansion by maceration and SMD (surface roughness index of the fiber industry showing the size of irregularities on the surface) were evaluated. Results: The degree of expansion was lower in anti-maceration swabs than in conventional products. Maceration reduced SMD in existing products, whereas the SMD in anti-maceration cotton swabs did not change. Conclusions: Anti-maceration cotton swabs have a superior performance over conventional products.

Oxytocin alters autonomic functions besides social behaviors. However, the central neuronal links between hypothalamic oxytocinergic neurons and the autonomic nervous system remain unclear. Here we show that oxytocinergic neurons in the rat paraventricular hypothalamic nucleus (PVH), a pivotal site for energy homeostasis, innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR) to stimulate brown adipose tissue (BAT) thermogenesis and cardiovascular functions. Oxytocin receptor stimulation in the rMR evokes BAT thermogenesis and tachycardia. In vivo optogenetic stimulation of the PVH→rMR long-range oxytocinergic pathway, using a virus-mediated system for amplified gene expression in oxytocinergic neurons, not only elicits BAT thermogenic and cardiac responses but also potentiates sympathetic responses evoked by glutamatergic transmission in the rMR. The PVH→rMR oxytocinergic pathway connects the hypothalamic circuit for energy homeostasis to thermogenic and cardiac sympathetic outflow, and, therefore, its defects may cause obesity and impaired thermoregulation, as seen in Prader-Willi syndrome.

The transient receptor potential vanilloid type 1 (TRPV1), a thermosensitive cation channel, is known to trigger pain in the peripheral nerves. In addition to its peripheral function, its involvement in brain functions has also been suggested. Resiniferatoxin (RTX), an ultrapotent TRPV1 agonist, has been known to induce long-term desensitization of TRPV1, and this desensitization has been an alternative approach for investigating the physiological relevance of TRPV1-expressing cells. Here we describe a protocol for intracerebroventricular (i.c.v.) treatment with RTX in mice. Procedures are described for testing nociception to peripheral TRPV1 stimulation (RTX test) and mechanical stimulation (tail pressure test) then follow. Although the nociceptive responses of mice that had been administered RTX i.c.v. were comparable to those of the control groups, RTX-i.c.v.-administered mice were insensitive to the analgesic effect of acetaminophen, suggesting that i.c.v. RTX treatment can induce supraspinal-selective TRPV1 desensitization. This mouse model can be used as a convenient experimental system for studying the role of TRPV1 in brain/supraspinal function. These techniques can also be applied to studies of the central actions of other drugs.

Down syndrome is a complex genetic disorder caused by the presence of three copies of the chromosome 21 in humans. The most common models, carrying extra-copies of overlapping fragments of mouse chromosome 16 that is syntenic to human chromosome 21, are Ts2Cje, Ts1Cje and Ts1Rhr mice. In electrophysiological analyses using hippocampal slices, we found that the later phase of the depolarization during tetanic stimulation, which was regulated by GABAB receptors, was significantly smaller in Ts1Cje and Ts2Cje mice than that in WT controls but not in Ts1Rhr mice. Furthermore, isolated GABAB receptor-mediated inhibitory synaptic responses were larger in Ts1Cje mice. To our knowledge, this is the first report that directly shows the enhancement of GABAB receptor-mediated synaptic currents in Ts1Cje mice. These results suggest that GABAB receptor-mediated synaptic inhibition was enhanced in Ts1Cje and Ts2Cje mice but not in Ts1Rhr mice. The Cbr1 gene, which is present in three copies in Ts1Cje and Ts2Cje but not in Ts1Rhr, encodes carbonyl reductase that may facilitate GABAB-receptor activity through a reduction of prostaglandin E2 (PGE2). Interestingly, we found that a reduction of PGE2 and an memory impairment in Ts1Cje mice were alleviated when only Cbr1 was set back to two copies (Ts1Cje;Cbr1+/+/−). However, the GABAB receptor-dependent enhancement of synaptic inhibition in Ts1Cje was unaltered in Ts1Cje;Cbr1+/+/− mice. These results indicate that Cbr1 is one of the genes responsible for DS cognitive impairments and the gene(s) other than Cbr1, which is included in Ts1Cje but not in Ts1Rhr, is responsible for the GABAB receptor-dependent over-inhibition.

The anti-influenza virus drug oseltamivir has been reported to have several pharmacological actions including blocking of nicotinic acetylcholine receptor channels and activation of the dopaminergic system. These pharmacological actions highly overlap those of amantadine, another anti-influenza virus drug authorized in Japan, and ester-type local anesthetics. Moreover, oseltamivir and amantadine can clinically induce similar adverse neuropsychiatric reactions. In the present study, from the database of the Pharmaceuticals and Medical Devices Agency (PMDA), we surveyed 2576 drugs for which neuropsychiatric side effects similar to those of oseltamivir, amantadine and local anesthetics (abnormal behavior, confusion, consciousness disturbance, convulsion, delirium, delusion, hallucination, myoclonus, tremor) are listed as "clinically significant adverse reactions", and found 327 that had at least one of these adverse reactions. Other neuraminidase inhibitors (laninamivir, peramivir and zanamivir) did not elicit such adverse reactions. By discussing the pharmacological effects of drugs that elicit these adverse reactions, we propose that the similarity of adverse neuropsychiatric reactions between oseltamivir and amantadine is possibly attributable to their common pharmacological effects.

High lithium ion conducting Li 2 S-P 2 S 5 -Li 3 N glasses and glass–ceramics were prepared using mechanical milling. Glasses of (75–1.5 x )Li 2 S·25P 2 S 5 · x Li 3 N (mol%) were obtained in the composition range of 0 ≤ x ≤ 20. The glass conductivity increased with an increase in the Li 3 N content. Glass with 20 mol% of Li 3 N showed the highest conductivity of 5.8 × 10 − 4 S cm − 1 at room temperature. For glass–ceramics, the conductivity also increased with an increase in the Li 3 N content up to 20 mol%. A new crystal phase was precipitated in the glass–ceramics. The glass–ceramic with 10 mol% of Li 3 N showed the highest conductivity of 1.4 × 10 − 3 S cm − 1 at room temperature. Moreover, the glass–ceramic had a wide electrochemical window and high chemical stability to moisture. An all-solid-state In/LiCoO 2 cell using the glass-ceramic electrolyte operated as a rechargeable battery. The addition of nitrogen to the Li 2 S-P 2 S 5 system improved electrolyte properties.

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D2-selective antagonist L-741,626, but not by D1/D5-selective and D3-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D2 receptors.

Oseltamivir, an anti-influenza virus drug, induces marked hypothermia in normal mice. We have proposed that the hypothermic effect arises from inhibition of the nicotinic acetylcholine receptor function of sympathetic ganglion neurons which innervate the brown adipose tissue (a heat generator). It has been reported that local anesthetics inhibit nicotinic acetylcholine receptor function by acting on its ionic channels, and that bupropion, a nicotinic antagonist, induces hypothermia. In this study, we compared the effects of oseltamivir, procaine and bupropion on body temperature, cardiovascular function and neuromuscular transmission. Intraperitoneal administration of oseltamivir (100mg/kg), procaine (86.6mg/kg) and bupropion (86.7mg/kg) lowered the core body temperature of normal mice. At lower doses (10-30mg/kg oseltamivir, 8.7-26mg/kg procaine and bupropion), when administered subcutaneously, the three drugs antagonized the hypothermia induced by intraperitoneal injection of nicotine (1mg/kg). In anesthetized rats, intravenous oseltamivir (30-100mg/kg), procaine (10mg/kg) and bupropion (10mg/kg) induced hypotension and bradycardia. Oseltamivir alone (100mg/kg) did not inhibit neuromuscular twitch contraction of rats, but at 3-30mg/kg it augmented the muscle-relaxing effect of d-tubocurarine. Similar effects were observed when lower doses of procaine (10-30mg/kg) and bupropion (3-10mg/kg) were administered, suggesting that systemic administration of oseltamivir inhibits muscular nicotinic acetylcholine receptors. These results support the idea that the hypothermic effect of oseltamivir is due to its effects on sympathetic ganglia which innervate the brown adipose tissue, and suggest that oseltamivir may exert non-selective ion channel blocking effects like those of ester-type local anesthetics.

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D

The transient receptor potential vanilloid type 1 (TRPV1) is a thermosensitive cation channel that triggers heat pain in the periphery. Long-term desensitization of TRPV1, which can be induced by excess amounts of agonists, has been a method for investigating the physiological relevance of TRPV1-containing neuronal circuits, and desensitization induced by various routes of administration, including systemic, intrathecal and intraganglionic, has been demonstrated in rodents. In the present study, we examined the effect of intracerebroventricular (i.c.v.) treatment with an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), on nociception and the analgesic effect of acetaminophen, which is known to mediate the activation of central TRPV1. I.c.v. administration of RTX a week before the test did not affect the licking/biting response to intraplantar injection of RTX (RTX test), suggesting that such i.c.v. treatment spares the function of TRPV1 at the hindpaw. Mice that had been i.c.v.-administered RTX also exhibited normal nociceptive responses in the formalin test and the tail pressure test, but acetaminophen failed to induce analgesia in those mice in any of the tests. These results suggest that i.c.v. administration of RTX leads to brain-selective TRPV1 desensitization in mice.

PurposeThe purpose of this paper is to propose two hybrid forecasting models which integrate available ones. A hybrid contaminated normal distribution (CND) model accurately reflects the non‐normal features of monthly S&P 500 index returns, and a hybrid GARCH model captures a serial correlation with respect to volatility. The hybrid GARCH model potentially enables financial institutions to evaluate long‐term investment risks in the S&P 500 index more accurately than current models.Design/methodology/approachThe probability distribution of an expected investment outcome is generated with a Monte Carlo simulation. A taller peak and fatter tails (kurtosis), which the probability distribution of monthly S&P 500 index returns contains, is produced by integrating a CND model and a bootstrapping model. The serial correlation of volatilities is simulated by applying a GARCH model.FindingsThe hybrid CND model can simulate the non‐normality of monthly S&P 500 index returns, while avoiding the influence of discrete observations. The hybrid GARCH model, by contrast, can simulate the serial correlation of S&P 500 index volatilities, while generating fatter tails. Long‐term investment risks in the S&P 500 index are affected by the serial correlation of volatilities, not the non‐normality of returns.Research limitations/implicationsThe hybrid models are applied only to the S&P 500 index. Cross‐sectional correlations among different asset groups are not examined.Originality/valueThe proposed hybrid models are unique because they combine available ones with a decision tree algorithm. In addition, the paper clearly explains the strengths and weaknesses of existing forecasting models.

PurposeThis paper seeks to propose a hybrid performance measurement framework integrating available frameworks and mathematical models. The hybrid framework potentially allows decision makers to move from intuitive decisions to analysis‐based decisions by using a complete hierarchy of objectives, mathematical equations and a simulation of increased capabilities. To illustrate the utility of the proposed framework, this paper aims to apply the framework to a hypothetical decision‐making scenario in a computer manufacturing company.Design/methodology/approachIn the proposed framework, a developed hierarchy is verified with correlation and regression analyses. Mathematical equations relating performance indicators are defined with a multiple linear regression model. An expected final outcome and uncertainty are evaluated with a Monte Carlo simulation.FindingsAn organization can find consistent performance indicators based on correlation and regression analyses. In addition, based on a forecast final outcome, the organization can make proactive decisions about up‐front investments in its capabilities.Research limitations/implicationsA hierarchy of objectives developed in this paper is not comprehensive. A scenario used for simulating a future outcome is hypothetical.Originality/valueAlthough some studies illustrate mathematical equations relating objectives, the studies are limited to parts of a hierarchy and there are few practical directions. This paper proposes mathematical equations that represent vertical relationships among objectives in a hierarchy, while evaluating the importance of a performance measurement system in a big picture. Moreover, this paper explains a decision‐making procedure based on a forecast outcome.

Reactions of a neutral pentacoordinated monohydrosilane bearing a dative N‒Si bond with phenol and benzoic acid derivatives gave the corresponding pentacoordinated phenoxysilane and carboxysilanes, respectively. X-ray crystallographic analyses of these silanes revealed that the distance of the N‒Si dative bond is shortened and the pentacoordination character of the silicon center becomes greater with the increase in the electron-withdrawing character of the apical substituent on silicon.

A pentacoordinated hydrosilane activated by an intramolecular nitrogen-silicon dative bond was utilized as an end-capping agent for catalyst-free syntheses of [2]rotaxanes. The end-capping reaction of a pseudo[2]rotaxane bearing a salicylic acid terminus with the pentacoordinated hydrosilane readily proceeded at room temperature to produce the corresponding silyl-capped [2]rotaxane.

We reviewed CT scans in 38 cases with pathologically proved bronchioloalveolar carcinoma. CT revealed three CT patterns: solitary, pneumonic and diffuse forms. The solitary pattern (22 patients) had a high percentage of air bronchograms (95%), pleural indentation (77%) and spiculation (68%). The pneumonia-like pattern (16 lesions in 10 patients) had air bronchograms in all cases (100%), low attenuation (88%) and protrusion of interlobar fissures (63%). The diffuse form (six patients) had 2 or 3 mm diffuse small nodules scattered throughout the entire lung. CT of bronchioloalveolar carcinoma revealed many findings and was useful in recognizing the tumor distribution and extent. We conclude that CT is helpful for the diagnosis and evaluation of bronchioloalveolar carcinoma.

The title compound, C23H25NSi, has an eight-membered silicon-containing heterocyclic ring with an intramolecular N...Si close contact, the transannular distance of which is 2.6294 (18) Å. The resulting geometry about the Si atom is distorted trigonal-bypyramidal, with the N and H atoms occupying apical sites. The dihedral angle between the aromatic rings fused to the eight-membered ring is 63.27 (7)°.