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Anatomical variations often occur in the anterior communicating artery (AComA) complex, and a careful preoperative evaluation is required before repair of this lesion. We report a case of a fenestrated AComA complex mimicking an unruptured cerebral aneurysm. A 49-year-old woman was referred to our hospital under suspicion of unruptured aneurysms of the AComA and the left middle cerebral artery on magnetic resonance angiography (MRA). Additional three-dimensional computed tomographic angiography (CTA) showed the lesion arising from the AComA complex with a maximum diameter of 4.2 mm. Intraoperative findings showed that the putative aneurysm was actually a fenestrated AComA complex as the blood vessels that formed the AComA complex were dilated and meandering. After the operation, MRA and CTA three-dimensional images were reviewed again but we could still not diagnose the lesion as a fenestrated AComA complex rather than an aneurysm. However, in the MRA source image, a secant line in the lesion was the only finding suggestive of a fenestration. The AComA complex is often associated with various vascular malformations, and it is essential to consider this association in the preoperative evaluation. The interpretation of source images may be helpful for accurate diagnosis and surgical planning.

Heading/flowering at the appropriate time in each cultivation region can greatly contribute to stabilizing and maximizing yield. Genotype combinations of Vrn-1 and Ppd-1, the major genes determining heading time, can explain the variation in heading time. However, the genes that can explain the remaining variations in heading time are still unknown. In this study, we aimed to identify the genes conferring early heading using doubled haploid lines derived from Japanese wheat varieties. Quantitative trait loci (QTL) analysis revealed a significant QTL on the long arm of chromosome 1B in multiple growing seasons. Genome sequencing using Illumina short reads and Pacbio HiFi reads revealed a large deletion of a ~500 kb region containing TaELF-B3, an orthologue of Arabidopsis clock gene EARLY FLOWERING 3 (ELF3). Plants with the deleted allele of TaELF-B3 (ΔTaELF-B3allele) headed earlier only under short-day vernalization conditions. Higher expression levels of clock- and clock-output genes, such as Ppd-1 and TaGI, were observed in plants with the ΔTaELF-B3 allele. These results suggest that the deletion of TaELF-B3 causes early heading. Of the TaELF-3 homoeoalleles conferring early heading, the ΔTaELF-B3 allele showed the greatest effect on the early heading phenotype in Japan. The higher allele frequency of the ΔTaELF-B3 allele in western Japan suggests that the ΔTaELF-B3 allele was preferred during recent breeding to adapt to the environment. TaELF-3 homoeolog will help to expand the cultivated area by fine-tuning the optimal timing of heading in each environment.

Behavioral thermoregulation is a thermoregulatory mechanism using behavioral measures, such as avoidance from cold and hot temperature, but its central circuit mechanism is largely unknown. We have previously reported that the lateral parabrachial nucleus (LPB) mediates thermosensory afferent signaling required for thermoregulatory behavior. In this study, we explored thermosensory neural pathways ascending from the LPB that mediate thermoregulatory behavior in rats.Because the LPB contains neurons sending cold- and warm-sensory signals to the thermoregulatory center, preoptic area (POA), we examined whether the LPB→POA projecting neurons are involved in behavioral thermoregulation. Retro- and anterograde adeno-associated viruses (AAV) were used to selectively express the tetanus toxin light chain (TeTxLC) in LPB→POA projecting neurons to suppress their transmission. The rats were then subjected to the two-plate thermal preference test for behavioral analysis, in which one of the plates was set at 28ºC, the thermoneutral temperature for laboratory rats, and the other was set at 39ºC (hot) or 15ºC (cold) under 25ºC room temperature. Suppressing LPB→POA projecting neurons eliminated heat avoidance, but not cold avoidance. Next, we selectively transduced LPB→POA neurons with hM4Dinrxn, an inhibitory designer receptor exclusively activated by designer drugs (DREADD). Suppression of neurotransmission at LPB→POA axon endings with microinjection of DREADD agonist 21 (C21) inhibited heat avoidance, but suppression of their axon collaterals in the dorsomedial hypothalamus did not affect thermoregulatory behavior. These results indicate that the LPB→MnPO pathway evokes heat avoidance.We explored other LPB-mediated ascending pathways for cold avoidance behavior. Our retrograde neural tracing with cholera toxin subunit (CTb) combined with immunohistochemistry for Fos, a marker for neuronal activation, revealed that a group of LPB→central amygdala (CeA) projecting neurons were activated by cold exposure. TeTxLC-mediated selective suppression of LPB→CeA transmission inhibited both cold and heat avoidance. However, optogenetic inhibition of axon endings of LPB→CeA projecting neurons through iChloC, a photosensitive chloride ion channel, eliminated cold avoidance, but not heat avoidance. Optogenetic inhibition of their axon collaterals in the ventromedial hypothalamic nucleus affected neither cold nor heat avoidance. These results indicate that the LPB→CeA pathway evokes cold avoidance. Our findings show the separate circuit structures for cold- and heat-avoidance behaviors, Moonshot R&D (JPMJMS2023 to K.N.) of the Japan Science and Technology Agency; Grants-in-Aid for Scientific Research (JP22K06470 to N.K.; JP20H03418 and JP15H05932 to K.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Agency for Medical Research and Development (JP21wm0525002 to N.K.); Takeda Science Foundation (to T.Y) 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 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.

Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with autonomous thermoregulatory responses. In contrast to the progress in understanding the central mechanisms of autonomous thermoregulation, those of behavioral thermoregulation remain poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates cutaneous thermosensory afferent signaling for thermoregulation. To understand the thermosensory neural network for behavioral thermoregulation, in the present study, we investigated the roles of ascending thermosensory pathways from the LPB in avoidance behavior from innocuous heat and cold in rats. Neuronal tracing revealed two segregated groups of LPB neurons projecting to the median preoptic nucleus (MnPO), a thermoregulatory center (LPB→MnPO neurons), and those projecting to the central amygdaloid nucleus (CeA), a limbic emotion center (LPB→CeA neurons). While LPB→MnPO neurons include separate subgroups activated by heat or cold exposure of rats, LPB→CeA neurons were only activated by cold exposure. By selectively inhibiting LPB→MnPO or LPB→CeA neurons using tetanus toxin light chain or chemogenetic or optogenetic techniques, we found that LPB→MnPO transmission mediates heat avoidance, whereas LPB→CeA transmission contributes to cold avoidance.In vivoelectrophysiological experiments showed that skin cooling-evoked thermogenesis in brown adipose tissue requires not only LPB→MnPO neurons but also LPB→CeA neurons, providing a novel insight into the central mechanism of autonomous thermoregulation. Our findings reveal an important framework of central thermosensory afferent pathways to coordinate behavioral and autonomous thermoregulation and to generate the emotions of thermal comfort and discomfort that drive thermoregulatory behavior.

Stable organic luminescent radicals have attracted much attention, but their stability under light irradiation is not yet satisfactory. New luminescent radicals (TTMs) based on terminal benzene ring modified carbazole donors were synthesized and evaluated. Their photostability (half-life under continuous laser irradiation) has improved by 1 order of magnitude compared to simple carbazole donors. This is a new molecular design strategy to improve the photostability of luminescent radicals without reducing other photophysical properties.

Repeat-associated non-AUG (RAN) translation of mRNAs/transcripts responsible for polyglutamine (polyQ) diseases may generate peptides containing different mono amino acid tracts such as polyserine (polyS) and polyleucine (polyL). The propagation of aggregated polyQ from one cell to another is also an intriguing feature of polyQ proteins. However, whether the RAN translation-related polyS and polyL have the ability to propagate remains unclear, and if they do, whether the exogenous polyS and polyL exert toxicity on the recipient cells is also not known yet. In the present study, we found that aggregated polyS and polyL peptides spontaneously enter neuron-like cells and astrocytes in vitro. Aggregated polyS led to the degeneration of the differentiated neuron-like cultured cells. Likewise, the two types of aggregates taken up by astrocytes induced aberrant differentiation and cell death in vitro. Furthermore, injection of each of the two types of aggregates into the ventricles of adult mice resulted in their behavioral changes. The polyS-injected mice showed extensive vacuolar degeneration in the brain. Thus, the RAN translation-related proteins containing polyS and polyL have the potential to propagate and the proteins generated by all polyQ diseases might exert universal toxicity in the recipient cells.

Introduction In cerebral blood flow (CBF) quantification with pseudo-continuous arterial spin labeling (pCASL) MRI, arterial blood T1 (T1a) is usually fixed to a typical value (e.g., 1650 ms). However, individual T1a depends strongly on hematocrit (Hct) level. To investigate the utility of Hct-based T1a as an alternative to the fixed T1a method, we performed a comparative study with 15O-water positron emission tomography (PET). Methods For patients with unilateral occlusion or stenosis of major arteries, hemispheric CBF on the healthy side was measured using pCASL and 15O-water PET. The pCASL CBFs were calculated with both (a) fixed T1a (1650 ms) and (b) individual T1a estimated from blood-sampled Hct (Hct-based T1a). Correlation coefficients of Hct–CBF were calculated and compared between pCASL and PET. Results In pCASL, CBF with fixed T1a showed a strong negative correlation with Hct (r = −0.568), which was reduced with individual Hct-based T1a (r = −0.341 to −0.190), consistent with the Hct–CBF relation measured with PET (r = −0.349). Discussion and conclusion We demonstrated that Hct-based T1a resulted in smaller inter-individual variations in pCASL CBF and an inverse Hct–CBF relationship more similar to that of PET. Care must be taken in the interpretation of pCASL CBF imaging in relation to Hct level even in subjects without anemia. Further comparative studies are needed to investigate whether advanced techniques improve pCASL CBF quantification at the individual level.

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.

Lymphoepithelial carcinoma (LEC) of the submandibular gland is a very rare neoplasm that constitutes only 0.4 % of the salivary gland neoplasms, mainly involving the parotid glands, and is well known to have a racial prevalence in Southwest Asia, southern China, Africa, and the Arctic Circle. This report describes the case of a 49-year-old Japanese woman who was diagnosed with an LEC of the right submandibular gland. The patient presented with a painless, gradually enlarging mass in the right submandibular gland for 2 years. Computed tomography scanning showed a 20 × 16 mm, slightly enhanced solid mass in the right submandibular gland; magnetic resonance imaging revealed an isointense and hyperintense mass in T1- and T2-weighted images. Fine-needle aspiration cytology revealed a few small salivary gland cells and acidophilic cells against a background of lymphocytes, suggesting Warthin tumor or chronic sialadenitis. The right submandibular gland was resected, and intraoperative frozen section analysis suggested a diagnosis of LEC of the submandibular gland. Histopathological findings from the resected submandibular gland were consistent with a diagnosis of LEC, and a definitive pathologic staging of T3N0M0. Postoperative adjuvant radiation therapy was administered, and the patient was disease free at the 4-year follow-up.

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here we demonstrated that dorsomedial hypothalamus-specific PR-domain containing protein 13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during sleep deprivation (SD). These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep alterations, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated sleep fragmentation and excessive sleepiness during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

Tuberculosis has been attracting attention as a re-emerging infection in recent years. Extrapulmonary tuberculosis in the head and neck region usually takes the form of tuberculous cervical lymphadenitis, and salivary gland tuberculosis is rare. Parotid gland tuberculosis is frequently difficult to differentiate from malignant tumors, and definitive diagnosis is often based on postoperative pathology. We report a case in which we reached a definitive diagnosis by appropriate and careful investigation and immediately initiated antimycobacterial therapy while avoiding surgery. The gentleman in his 70s presented with swelling below the left ear. The only local signs were mild tenderness and swelling, with no reddening of the skin or facial paralysis. Results from fine needle aspiration cytology were suggestive of acid-fast bacterial infection. Following puncture, reddening of the skin and necrosis appeared, and a local biopsy was performed. Pathology demonstrated the presence of Langerhans multinucleated giant cells and epithelioid granuloma. As polymerase chain reaction testing of a sample submitted at the same time was positive for Mycobacterium tuberculosis DNA, parotid gland tuberculosis was diagnosed. Outpatient combination therapy was initiated with isoniazid, ethambutol, and rifampicin, to which the infection was sensitive. Since completion of this oral treatment, the patient has shown an uneventful course, with no parotid gland swelling, cervical lymph node swelling, or signs of recurrence. Parotid gland tuberculosis must always be borne in mind as a differential diagnosis for parotid gland tumors.

Water plays a crucial role in the formation and destruction of biomolecular structures. The mechanism for destroying biomolecular structures was thought to be an active breaking of hydrogen bonds by water molecules. However, using nonequilibrium molecular dynamics simulations, in which an amyloid-β amyloid fibril was destroyed via infrared free-electron laser (IR-FEL) irradiation, we discovered a new mechanism, in which water molecules disrupt protein aggregates. The intermolecular hydrogen bonds formed by C═O and N-H in the fibril are broken at each pulse of laser irradiation. These bonds spontaneously re-form after the irradiation in many cases. However, when a water molecule happens to enter the gap between C═O and N-H, it inhibits the re-formation of the hydrogen bonds. Such sites become defects in the regularly aligned hydrogen bonds, from which all hydrogen bonds in the intermolecular β-sheet are broken as the fraying spreads. This role of water molecules is entirely different from other known mechanisms. This new mechanism can explain the recent experiments showing that the amyloid fibrils are not destroyed by laser irradiation under dry conditions. Additionally, we found that helix structures form more after the amyloid disruption; this is because the resonance frequency is different in a helix structure. Our findings provide a theoretical basis for the application of IR-FEL to the future treatment of amyloidosis.

Exercise including locomotion requires appropriate autonomic cardiovascular adjustments to meet the metabolic demands of contracting muscles, yet the functional brain architecture underlying these adjustments remains unknown. Here, we demonstrate brainstem circuitry that plays an essential role in relaying volitional motor signals, i.e., central command, to drive locomotor activities and sympathetic cardiovascular responses. Mesencephalic locomotor neurons in rats transmit central command-driven excitatory signals onto the rostral ventrolateral medulla at least partially via glutamatergic processes, to activate both somatomotor and sympathetic nervous systems. Optogenetic excitation of this monosynaptic pathway elicits locomotor and cardiovascular responses as seen during running exercise, whereas pathway inhibition suppresses the locomotor activities and blood pressure elevation during voluntary running without affecting basal cardiovascular homeostasis. These results demonstrate an important subcortical pathway that transmits central command signals, providing a key insight into the central circuit mechanism required for the physiological conditioning essential to maximize exercise performance.

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Spontaneous radiographic disappearance of cerebral aneurysms is often observed under special conditions such as giant aneurysms. However, spontaneous disappearance of an unruptured and nongiant intracranial saccular aneurysms is rare. We describe two cases of this rare vascular phenomenon. The first patient is a 64-year-old female diagnosed with a small unruptured aneurysm arising from the distal anterior cerebral artery. Spontaneous disappearance of the aneurysm on magnetic resonance angiography (MRA) was observed 5 years after the initial diagnosis. Continuous imaging surveillance also revealed spontaneous reappearance of the aneurysm 2 years later. The second patient is a 57-year-old female harboring a small unruptured saccular aneurysm arising from the M1–M2 bifurcation of the middle cerebral artery. The aneurysm showed spontaneous disappearance on MRA 13 years after the initial diagnosis. These cases provide a new insight into this natural dynamic process even in cases of a small unruptured intracranial saccular aneurysm.

CRISPR-Cas9 are widely used for gene targeting in mice and rats. The non-homologous end-joining (NHEJ) repair pathway, which is dominant in zygotes, efficiently induces insertion or deletion (indel) mutations as gene knockouts at targeted sites, whereas gene knock-ins (KIs) via homology-directed repair (HDR) are difficult to generate. In this study, we used a double-stranded DNA (dsDNA) donor template with Cas9 and two single guide RNAs, one designed to cut the targeted genome sequences and the other to cut both the flanked genomic region and one homology arm of the dsDNA plasmid, which resulted in 20–33% KI efficiency among G0 pups. G0 KI mice carried NHEJ-dependent indel mutations at one targeting site that was designed at the intron region, and HDR-dependent precise KIs of the various donor cassettes spanning from 1 to 5 kbp, such as EGFP, mCherry, Cre, and genes of interest, at the other exon site. These findings indicate that this combinatorial method of NHEJ and HDR mediated by the CRISPR-Cas9 system facilitates the efficient and precise KIs of plasmid DNA cassettes in mice and rats. Electronic supplementary material The online version of this article (10.1007/s00439-020-02198-4) contains supplementary material, which is available to authorized users.

BACKGROUND Aplastic or twiglike middle cerebral artery (Ap/T-MCA) is a rare anomaly characterized by a unilateral MCA occlusion with plexiform vessels that causes hemorrhagic and (less commonly) ischemic strokes. The reasons for this are rarely discussed, and thus optimal treatment for ischemic Ap/T-MCA remains controversial. Here, the authors report a case of Ap/T-MCA with transient ischemic attacks treated by bypass surgery and discuss the mechanism of ischemic development and treatment methods. OBSERVATIONS A 62-year-old hypertensive man with transient, recurrent left hemiparesis visited the authors’ hospital. Magnetic resonance angiography showed proximal occlusion of the right MCA and stenosis in the left MCA. Digital subtraction angiography revealed occlusion of the right MCA and abnormal vascular networks, leading to a diagnosis of Ap/T-MCA with contralateral MCA stenosis. Antiplatelet therapy with aspirin was insufficient, and a superficial temporal artery–MCA bypass was performed. There were no ischemic or hemorrhagic events postoperatively. LESSONS Atherosclerosis seems to have a significant impact on the development of ischemic stroke in patients with Ap/T-MCA, and the presence of coexisting atherosclerotic stenotic vascular lesions outside the Ap/T-MCA site is substantial in its development. Bypass surgery is a promising treatment option for ischemic Ap/T-MCA.

Repeat-associated non-AUG translation (RAN translation) is observed in transcripts that are causative for polyglutamine (polyQ) diseases and generates proteins with mono amino acid tracts such as polyalanine (polyA), polyleucine (polyL) and polyserine (polyS) in neurons, astrocytes and microglia. We have previously shown that microglia with aggregated polyQ led to defective differentiation and degeneration of neuron-like cells. However, it has not been determined whether only microglia containing a specific RAN product, but not other RAN products, is harmful in vitro and in vivo. Here we show that polyL-incorporating microglia specifically led to altered startle response in mice. Aggregated polyA, polyS and polyL induced aberrant differentiation of microglia-like BV2 cells. Differentiated PC12 cells treated with conditioned medium (CM) of polyS- and polyL- but not polyA-incorporating microglia-like BV2 cells showed retraction of neurites and loss of branch of neurites. Injection of the polyL-CM, but not polyA-CM and polyS-CM, into the lateral ventricle lowered startle response in mice. Consistently, polyL induced the highest expression of CD68 in BV2 cells. The lowered startle response was replicated in mice given the polyL-CM in the caudal pontine reticular nucleus (PnC), the key region of startle response. Thus, endogenous RAN proteins having polyL derived from polyQ diseases-causative genes in microglia might specifically impair startle response.

SUMMARYThe circuit mechanism of the thermoregulatory center in the preoptic area (POA) is unknown. Using rats, here we show prostaglandin EP3 receptor-expressing POA neurons (POAEP3R neurons) as a pivotal bidirectional controller in the central thermoregulatory mechanism. POAEP3R neurons are activated in response to elevated ambient temperature, but inhibited by prostaglandin E2, a pyrogenic mediator. Chemogenetic stimulation of POAEP3R neurons at room temperature reduces body temperature by enhancing heat dissipation, whereas inhibition of them elicits hyperthermia involving brown fat thermogenesis, mimicking fever. POAEP3R neurons innervate sympathoexcitatory neurons in the dorsomedial hypothalamus (DMH) via tonic inhibitory signaling. Although many POAEP3R neuronal cell bodies express a glutamatergic mRNA marker, paradoxically, their axons in the DMH predominantly contain terminals with GABAergic presynaptic proteins, which are increased by chronic heat exposure. These findings indicate that tonic GABAergic inhibitory signaling from POAEP3R neurons is a fundamental determinant of body temperature for thermal homeostasis and fever.

Old animals display significant alterations in sleep–wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specificPrdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression ofPrdm13in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep–wake patterns during aging.

Amyloidosis is known to be caused by the deposition of amyloid fibrils into various biological tissues; effective treatments for the disease are little established today. An infrared free-electron laser (IR-FEL) is an accelerator-based picosecond-pulse laser having tunable infrared wavelengths. In the current study, the irradiation effect of an IR-FEL was tested on an 11-residue peptide (NFLNCYVSGFH) fibril from β2-microglobulin (β2M) with the aim of applying IR-FELs to amyloidosis therapy. Infrared microspectroscopy (IRM) and scanning electron microscopy showed that a fibril of β2M peptide was clearly dissociated by IR-FEL at 6.1 µm (amide I) accompanied by a decrease of the β-sheet and an increase of the α-helix. No dissociative process was recognized at 6.5 µm (amide II) as well as at 5.0 µm (non-specific wavelength). Equilibrium molecular dynamics simulations indicated that the α-helix can exist stably and the probability of forming interchain hydrogen bonds associated with the internal asparagine residue (N4) is notably reduced compared with other amino acids after the β-sheet is dissociated by amide I specific irradiation. This result implies that N4 plays a key role for recombination of hydrogen bonds in the dissociation of the β2M fibril. In addition, the β-sheet was disrupted at temperatures higher than 340 K while the α-helix did not appear even though the fibril was heated up to 363 K as revealed by IRM. The current study gives solid evidence for the laser-mediated conversion from β-sheet to α-helix in amyloid fibrils at the molecular level.

BACKGROUND Infected intracranial aneurysms are relatively rare but tend to occur in multiple locations. Establishing an optimal treatment strategy for multiple ruptured aneurysms is often challenging, especially when simultaneous ruptures occur in different locations. We report a case of simultaneous intracerebral and subarachnoid hemorrhages caused by the rupture of multiple infected intracranial aneurysms. OBSERVATIONS A 23-year-old male with a 2-week history of chronic fever presented with sudden onset of severe headache and visual disturbance. Computed tomography showed intracerebral hemorrhage in the right occipital lobe and subarachnoid hemorrhage in the area of the left Sylvian fissure. Further investigation documented Staphylococcus bacteremia, verrucae on the mitral valve, and aneurysms arising from the right posterior cerebral artery (PCA) and the left middle cerebral artery (MCA). A larger aneurysm arising from the PCA was successfully occluded endovascularly, but subsequent endovascular occlusion of the MCA aneurysm was unsuccessful because some important branches were observed extending from the aneurysm. The left MCA aneurysm was then obliterated by angioplastic clipping via left pterional craniotomy. The patient showed a favorable neurological recovery after treatment. LESSONS In such complex cases of infectious aneurysms, the method and timing of treatment need to be carefully determined based on the medical condition.

In addition to maintaining a constant core body temperature, the mammalian thermoregulatory system, including that in humans deviates body temperature from the normally defended range as necessary to protect the organism from various environmental stressors, such as ambient temperature (heat and cold), pathogens, natural enemies, and starvation. Recent studies have reported that neural circuits of the brain are involved in thermoregulatory responses to environmental stresses. This article summarizes the most recent findings on the central neural network associated with thermoregulatory physiological responses to environmental stresses.

In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.