Search

G-protein-coupled receptors (GPCRs) are important drug targets with diverse therapeutic applications. However, there are still more than a hundred orphan GPCRs, whose protein functions and biochemical features remain unidentified. Gpr176 encodes a class-A orphan GPCR that has a role in circadian clock regulation in mouse hypothalamus and is also implicated in human breast cancer transcriptional response. Here we show that Gpr176 is N-glycosylated. Peptide-N-glycosidase treatment of mouse hypothalamus extracts revealed that endogenous Gpr176 undergoes N-glycosylation. Using a heterologous expression system, we show that N-glycosylation occurs at four conserved asparagine residues in the N-terminal region of Gpr176. Deficient N-glycosylation due to mutation of these residues reduced the protein expression of Gpr176. At the molecular function level, Gpr176 has constitutive, agonist-independent activity that leads to reduced cAMP synthesis. Although deficient N-glycosylation did not compromise this intrinsic activity, the resultant reduction in protein expression was accompanied by attenuation of cAMP-repressive activity in the cells. We also demonstrate that human GPR176 is N-glycosylated. Importantly, missense variations in the conserved N-glycosylation sites of human GPR176 (rs1473415441; rs761894953) affected N-glycosylation and thereby attenuated protein expression and cAMP-repressive activity in the cells. We show that N-glycosylation is a prerequisite for the efficient protein expression of functional Gpr176/GPR176.

Chronic jet lag, a model of shiftwork, increases mortality in aged mice. One potential reason for this association is that the chronic desynchronization between the internal clock phase and the environmental light/dark (LD) cycle might increase the mortality rate. However, this hypothesis has not been examined because of the lack of an appropriate animal model to prove this speculation. Here, we found that rapidly entrainable vasopressin receptor V1a–/–V1b–/– mice showed lower mortality under a chronic jet lag condition. Moreover, we found that pharmacological inactivation of V1a and V1b signaling decreased mortality even in aged wild-type mice, thus providing a potential pharmaceutical intervention for shiftwork-related health problems., 慢性時差環境下での老齢マウスの生存率改善に成功 --シフトワーカーの病態への創薬に期待--. 京都大学プレスリリース. 2018-07-20.

Background There has been little research on reminiscence cues and their effectiveness. The purpose of the present study was to measure the effects of reminiscence practice using olfactory stimuli on the mental health and cognitive functions of community-dwelling elderly individuals. Methods Written consent was obtained from 72 eligible community-dwelling elderly individuals. They were non-randomly divided into an intervention group and a control group. In the intervention group (n = 35), reminiscence practice was carried out bi-weekly using olfactory stimulation as the cue for eight sessions. In the control group (n = 37), reminiscence practice was carried out without olfactory stimulation. The Geriatric Depression Scale-15 and the Five-cog Test were used as the methods of assessment at baseline and again after completion of the intervention. Participants in the final analysis were 27 individuals in the intervention group and 33 individuals in the control group. Results At baseline, a significant difference was seen between the groups depending on the existence of a spouse. Repeated measures analysis of covariance with the existence of a spouse as a covariate showed a significant difference between the two groups in changes in Geriatric Depression Scale-15 scores (P = 0.038). Furthermore, analysis of the participants sorted into a depression symptoms group and a non-depression symptoms group showed a significant group main effect (P = 0.033) and interaction (P = 0.049) in the depression symptoms group. Conclusion The results suggest that reminiscence intervention using olfactory stimulation may maintain the mental health of community-dwelling elderly individuals.

Daily body temperature rhythm (BTR) is essential for maintaining homeostasis. BTR is regulated separately from locomotor activity rhythms, but its molecular basis is largely unknown. While mammals internally regulate BTR, ectotherms, including Drosophila, exhibit temperature preference rhythm (TPR) behavior to regulate BTR. Here, we demonstrate that the diuretic hormone 31 receptor (DH31R) mediates TPR during the active phase in Drosophila. DH31R is expressed in clock cells, and its ligand, DH31, acts on clock cells to regulate TPR during the active phase. Surprisingly, the mouse homolog of DH31R, calcitonin receptor (Calcr), is expressed in the suprachiasmatic nucleus (SCN) and mediates body temperature fluctuations during the active phase in mice. Importantly, DH31R and Calcr are not required for coordinating locomotor activity rhythms. Our results represent the first molecular evidence that BTR is regulated distinctly from locomotor activity rhythms and show that DH31R/Calcr is an ancient specific mediator of BTR during the active phase in organisms ranging from ectotherms to endotherms.

Micturition behavior follows regular day/night fluctuations, and unwanted increase in micturition could occur during night in jet lag condition. To clarify the effect of jet lag on micturition behavior, we simultaneously detected circadian micturition patterns and locomotor activity rhythms of mice under experimental jet lag conditions, by applying the improved automated Voided Stain on Paper (aVSOP) method. When wild-type (WT) mice were phase-advanced for 8 hours, day-night variation of micturition was disrupted suddenly, and this irregular daily micturition continued until 8 days, although their activity rhythms entrained gradually day by day until 8 days. We also examined how jet lag induced changes of micturition in Per-null mice lacking Per1, Per2 and Per3 genes, whose endogenous clock is completely disrupted. We found both micturition and locomotor activity of Per-null mice promptly entrained to the new LD cycle. These findings suggest that the irregular micturition during jet lag is caused along with the gradual shift of the endogenous clock, and paradoxically, jet lag-associated abnormality was absent when endogenous circadian oscillations were genetically disrupted.

Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time when traveling across multiple time zones. Light is known as a strong timing cue of the circadian clock. We here examined the effect of daily light on the process of jet lag by detecting c-Fos expression in the master clock neurons in the suprachiasmatic nucleus (SCN) under 8-hr phase-advanced jet lag condition. In WT mice, c-Fos-immunoreactivity was found at 1–2 hours on the first day after light/dark (LD) phase-advance. This induction was also observed on the second and third days, although their levels were diminished day by day. In contrast, c-Fos induction in the SCN of V1a–/–V1b–/– mice, which show virtually no jet lag symptoms even after 8-hr phase-advance, was only detected on the first day. These results indicate that external light has affected SCN neuronal activity for 3 days after LD phase-advance in WT mice suggesting the continuous progress of activity change of SCN neurons under jet lag conditions. Noteworthy, limited c-Fos induction in V1a–/–V1b–/– SCN is also consistent with the rapid reentrainment of the SCN clock in mutant mice after 8-hr LD phase-advance.

Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway., Circadian clock regulates hepatic gene expression and functions. Here Chao et al. show that alteration of circadian clock genes by Period deletion induces polyploidy in hepatocytes due to impaired regulation of Erk signaling by mitogen-activated protein kinase phosphatase 1.

To identify a specific sensorimotor impairment feature of autism spectrum disorder (ASD), we focused on temporal processing with millisecond accuracy. A synchronized finger-tapping task was used to characterize temporal processing in individuals with ASD as compared to typically developing (TD) individuals. We found that individuals with ASD showed more variability in temporal processing parameters than TD individuals. In addition, temporal processing instability was related to altered motor performance. Further, receiver operating characteristic (ROC) curve analyses indicated that altered temporal processing can be useful for distinguishing between individuals with and without ASD. These results suggest that instability of temporal processing with millisecond accuracy is a fundamental feature of sensorimotor impairments in ASD.

G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.

The Gm7325 gene, bioinformatically identified in the mouse genome, encodes a small protein but has not been characterized until recently. Our gene expression analysis revealed that Gm7325 transcription is remarkably upregulated in injured skeletal muscle tissues. Activated satellite cells and immature myotubes were densely decorated with positive signals for Gm7325 mRNA in in situ hybridization analysis, while no obvious signals were observed in quiescent satellite cells and mature myofibers. In the 5'-flanking regions of mouse Gm7325 and its human homologue, conserved E-box motifs for helix-loop-helix transcription factors are repeatedly arranged around the putative promoter regions. Reporter gene assays suggested that MyoD, a master transcription factor for myogenesis, binds to the conserved E-box motifs to activate Gm7325 expression. Therefore, Gm7325, as a novel MyoD-target gene, is specifically induced in activated satellite cells, and may have an important role in skeletal myogenesis.

Cancer therapy-induced cognitive impairment adversely affects the quality of life of patients with cancer but cannot be detected by neuropsychological tests.This study aimed to validate a Japanese version of the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) version 3, which is a self-report measure of the cognitive concerns of patients with cancer.The FACT-Cog was translated into Japanese and pilot tested with five patients with breast cancer and five patients with hematologic malignancy. Study participants were recruited in Hiroshima University Hospital and Kagawa Breast Clinic in Hiroshima, Japan. Patients with breast cancer (N = 236) responded to the resultant assessment and Functional Assessment of Cancer Therapy-General version 4. The internal consistency and concurrent and construct validity of the FACT-Cog were examined.The Cronbach's alphas of the four FACT-Cog subscales, namely, CogPCI, CogOth, CogPCA, and CogQOL, were 0.95, 0.73, 0.93, and 0.88, respectively. The item-to-domain correlations ranged from 0.211 to 0.920. Most of the FACT-Cog subscales were significantly correlated with other subscale and total scores (r = 0.133-0.425). Structural equation modeling was barely acceptable (χ2 = 1361.8, df = 489, P 0.001; goodness of fit index = 0.731, adjusted goodness of fit index = 0.691, comparative fit index = 0.848, root-mean-square error of approximation = 0.087).The Japanese version of the FACT-Cog is a valid and reliable self-report measure of the cognitive function of patients with breast cancer. Its utility to clinicians and researchers in measuring the cognitive concerns of patients with cancer in Japan will serve as a further test of its validity.

Non-coding cis-regulatory elements are essential determinants of development, but their exact impacts on behavior and physiology in adults remain elusive. Cis-element-based transcriptional regulation is believed to be crucial for generating circadian rhythms in behavior and physiology. However, genetic evidence supporting this model is based on mutations in the protein-coding sequences of clock genes. Here, we report generation of mutant mice carrying a mutation only at the E′-box cis-element in the promoter region of the core clock gene Per2. The Per2 E′-box mutation abolishes sustainable molecular clock oscillations and renders circadian locomotor activity and body temperature rhythms unstable. Without the E′-box, Per2 messenger RNA and protein expression remain at mid-to-high levels. Our work delineates the Per2 E′-box as a critical nodal element for keeping sustainable cell-autonomous circadian oscillation and reveals the extent of the impact of the non-coding cis-element in daily maintenance of animal locomotor activity and body temperature rhythmicity., The circadian transcription factors BMAL1:CLOCK bind to E/E′-boxes in gene regulatory elements of their targets and facilitate rhythmic expression. Here, the authors mutate the Per2 promoter E’′-box in mice and observe that cell- and tissue-autonomous oscillations are dampened and that animals are less susceptible to jet lag.

The methyl cycle is a universally conserved metabolic pathway operating in prokaryotes and eukaryotes. In this pathway, the amino acid methionine is used to synthesize S-adenosylmethionine, the methyl donor co-substrate in the methylation of nucleic acids, histone and non-histone proteins and many other molecules within the cell. The methylation of nucleic acids and proteins is the foundation of epigenetic and epitranscriptomic regulations of gene expression, but whether the methyl cycle centrally regulates gene expression and function by controlling the availability of methyl moieties is poorly understood.From cyanobacteria to humans, a circadian clock that involves an exquisitely regulated transcription-translation-feedback loop driving oscillations in gene expression and orchestrating physiology and behavior has been described. We reported previously that inhibition of the methyl cycle in mammalian cells caused the lengthening of the period of these oscillations, suggesting the methyl cycle may indeed act as a central regulator of gene expression, at least in mammals. Here, we investigated whether the methyl cycle, given its universal presence among living beings, regulates the circadian clock in species across the phylogenetic tree of life.We reveal a remarkable evolutionary conservation of the link between the methyl cycle and the circadian clock. Moreover, we show that the methyl cycle also regulates the somite segmentation clock, another transcription-translation negative feedback loop-based timing mechanism that orchestrate embryonic development in vertebrates, highlighting the methyl cycle as a master regulator of biological clocks.SIGNIFICANCE STATEMENTHere we reveal that the methyl cycle, a universal metabolic pathway leading to the synthesis of S-adenosylmethionine, the methyl donor co-substrate in virtually all transmethylation reactions within the cell, is a conserved regulator of biological clocks. These discoveries highlight the methyl cycle as a metabolic hub that regulates gene expression via the availability of methyl moieties for the methylation of nucleic acids, proteins and many other molecules with the cell.

We aimed to determine whether voice rehabilitation after radiotherapy improves the quality of life (QOL), voice function, and self-rated voice function in patients with laryngeal cancer. We searched CENTRAL, MEDLINE, EMBASE, PEDro, and World Health Organization International Clinical Trials Registry Platform for randomized controlled trials published between inception and October 2018. The primary outcome was QOL, adverse events and mortality. Secondary outcomes included voice function and self-rated voice function. The quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation approach. Three trials (enrolling 122 patients) compared voice rehabilitation to usual care or no intervention after radiotherapy. Voice rehabilitation did not significantly improve any QOL scores. Data on adverse events and mortality were not available in any of the trials. Voice rehabilitation did not improve any voice function scores, such as jitter (mean difference: – 0.48 [– 1.27 to 0.32]), shimmer (mean difference: – 0.04 [– 0.27 to 0.19]), maximum phonation time (mean difference: 1.54 [– 1.13 to 4.22]), and the grade, roughness, breathiness, asthenia, and strain scale (mean difference: – 0.39 [– 2.59 to 1.80]). Voice rehabilitation also did not improve the voice handicap index, which was used as a self-rated voice function score (mean difference: 5.54 [– 2.07 to 13.16]). The certainty of the evidence was graded as low for primary and secondary outcomes. Voice rehabilitation for patients with laryngeal cancer after radiotherapy might not improve QOL, voice function, and self-rated voice function. Pre-specified voice rehabilitation programs may not be necessary for all patients with laryngeal cancer after radiotherapy.

Background Like most women, female nurses in the workforce experience life events such as marriage, childbirth, and child-rearing, and carry out numerous personal roles. This may result in an increase in various demands for nurses, and coping with these roles may promote work engagement. However, few studies have focused on work engagement or spillover effects, including those in the family domain, in female nurses with multiple roles. In the present study, we aimed to examine work engagement in female nurses and investigate its relationship with factors such as the presence or absence of multiple personal roles. Methods The subjects of this study were 1225 female nurses working at three general hospitals, each with at least 200 hospital beds in Fukuoka Prefecture, Japan. The cross-sectional design of the study used anonymous self-administered questionnaires. Responses were received from 650 nurses (response rate 53.1%), of which 612 were valid (valid response rate 50.0%). Multiple regression analysis was performed on the 612 responses regarding associations between work engagement and the presence or absence of multiple roles (role as a wife or mother), spillover effects, coping characteristics, job demands, and job resources. Results In general, the work engagement of female nurses was low, as is the case with other female workers in Japan, but work engagement was higher among female nurses with multiple roles than among those without. The regression analysis showed that factors associated with better work engagement in female nurses were family-to-work positive spillover, job resources, coping strategies including “changing a point of view,” “active solution for problems,” “avoidance and suppression,” and the presence of multiple roles. Conclusions The results indicate that in addition to resources in the work domain, a family-to-work positive spillover effect, which is a variable in the non-work domain, may also promote energetic work among female nurses. Therefore, it is necessary for nurses to receive support at work and use effective coping strategies.

Background It has become necessary to develop mental health management methods that do not require specialized skills or tools to implement. With this in mind, we performed a subjective and objective investigation of the stress-reducing effect of hearing laughter. Methods Ninety healthy students were randomly assigned to a laughter (n = 45) or rest (n = 45) group. Both groups were then administered the Uchida-Kraepelin test for 15 min, which served as a stress-loading method. The laughter group listened to a specially prepared CD for five minutes, while the rest group rested for five minutes. The participants’ subjective stress level was assessed using a visual analogue scale and their physiological status was assessed by measuring blood pressure and monitoring heart rate variability. Results The visual analogue scale score for subjective stress was found to decrease significantly in both the laughter and rest groups after the intervention. However, a two-way repeated-measures analysis of variance revealed significant interaction and main effects for the change in heart rate and the natural logarithm of the high-frequency component of heart rate variability (lnHF). A post-hoc analysis using Dunnett’s test showed that hearing laughter caused the lnHF to significantly increase compared to that recorded during the Uchida-Kraepelin test and the rest period. Conclusions These results suggest that hearing laughter might produce a relaxing effect by increasing parasympathetic nervous activity. This would make it an easily accessible method for improving the recovery process of the autonomic nervous system after a stress-loading task that does not require specialized skills or tools. Trial registration UMIN000016422. Retrospectively registered on 2 February 2015. Electronic supplementary material The online version of this article (10.1186/s13030-018-0141-0) contains supplementary material, which is available to authorized users.

Background Objective evaluation is important to achieve an effective intervention. However, there are limited assessment tools to easily apply to autism spectrum disorder (ASD) individuals with various severities in the clinical setting. This study aimed to characterize the timing control ability of ASD individuals and clarify the relationship between timing control ability and ASD severity level in order to establish an assessment tool for ASD function. Method We developed a simple touchscreen-based task for evaluate motor timing control ability and used two types of sensorimotor timing controls (i.e., simple timing and delayed timing tasks) in ASD (n = 77) and typically developing (TD) individuals (n = 87). Results Each participant with ASD completed the simple timing task. Regarding the delayed timing task, two participants in the ASD group were excluded as they faced difficulties when conducting the task according to the instruction. Accuracy of motor-timing control was significantly lower in participants with ASD than in those with TD for each timing task. The mean timing error in the adaptive timing control were correlated with clinically evaluated ASD severity and participant age in the ASD group. Furthermore, receiver operating characteristic curve analysis indicated that altered motor timing control is useful for distinguishing individuals with and without ASD (area under the curve = .845). Conclusions We showed that our assessment tool accurately assessed timing control ability of individuals with ASD, regardless of the varying ranges of symptomatic severities, and served as a useful tool for capturing the overall severity of such a heterogeneous disorder, which may lead to more effective therapies for ASD.

Falls are adverse events affecting psychiatric inpatients that can lead to external injuries, fractures, and death. However, none have attempted to examine fall-related factors, particularly focused on balance, specifically among inpatients with schizophrenia. The present preliminary study aimed to assess the association between falls and balance in patients with schizophrenia. The authors performed baseline assessments of background factors, postural sway, and maximum step length in 120 patients with schizophrenia hospitalized in the psychiatric ward. A prospective 3-month follow-up was conducted, and participants were divided into a fall or non-fall group according to their history of falls during the follow-up. Variance among individual variables was compared between the fall group and non-fall group using the t-test, Mann–Whitney U test, and chi-square test. A total of 16 participants experienced falls in the 3-month follow-up period (13.3%). Comparative factor analysis revealed significant differences between the fall and non-fall groups in terms of the presence or absence of falls within 3 months before follow-up (p = 0.002) and Romberg quotients for sway length (p = 0.02). These findings suggest that fall history could be considered a predictor of future falls, which could help with fall prevention, and that assessment of visual contribution to postural control using the Romberg quotient could play an important role in fall prevention.

In the original publication of the article, the reference 14 was published incorrectly. The correct reference is given below.

Objective: This study investigates the presence or absence of reminiscence experiences in older adults when using aromas. Focusing on 40 scents familiar to Japanese people, our objective was to determine points of caution for aroma selection and use in reminiscence therapy. Materials and Methods: The participants were 118 community-dwelling older adults aged 65 years and older. They were asked about the experience of recalling the past in response to stimuli of 40 aromas on the Japanese version of the University of Pennsylvania Smell Identification Test (UPSIT-J). In addition, an olfactory visual analog scale (VAS) was used to evaluate olfactory function. Furthermore, a questionnaire-based survey was administered instead of asking participants to actually smell the odorants in the UPSIT-J. Results: At least 70% of the participants experienced recalling the past triggered by 16 aromas including sandalwood and yuzu fruit. Furthermore, 15 of the scents demonstrated a significant association with age, gender, and olfactory function. Conclusion: These results suggest the importance of considering method, age, and gender when selecting olfactory stimuli. In addition, frequently recalled aromas might evoke reminiscence in older adults.

The

Background Poststroke gait disorders negatively impact activities of daily living. Rehabilitation for stroke patients is aimed at improving their walking ability, balance, and quality of life. Robot-assisted gait training (RAGT) is associated with an increased number of task-specific exercises, which may benefit poststroke motor learning. We investigated the effects of RAGT using Stride Management Assist (SMA, which increases walk ratio by inducing hip-joint flexion and extension) in subacute stroke patients with hemiplegia. Methods We conducted a single center, open-label randomized controlled trial in hemiplegia patients who experienced a first ever stroke and were admitted to the convalescent rehabilitation ward. A total of 41 were divided into the control (20 patients) and experimental group (21 patients). A 10-day, conventional gait training program was carried out for the control group; and RAGT with SMA was used for the experimental group. The maximum walking speed and other gait parameters were compared preintervention and postintervention. The intergroup differences in the improvement ratio were compared using an intention-to-treat analysis. Results Ten-day intervention was completed by 36 patients. There was no difference between the 2 groups regarding gait parameters at intervention initiation. The improvement ratio of the maximum walking speed was significantly higher for the experimental group. Significant improvements were observed postintervention for maximum walking speed, paralysis-side step length, symmetry, and cadence in the experimental group. No adverse events attributable to the SMA were observed. Conclusions Ten days of RAGT with the SMA was effective for improving gait disorders of subacute stroke patients.

Background Patients receiving chemotherapy experience anorexia and food aversion in their daily lives, and one of the causes is the smell of food. However, it is not clear why the aversion to these smells occurs. This study aimed to determine the emotional responses of patients when they sniff representative food odors during chemotherapy and to investigate factors influencing smell-induced food aversion. Methods The subjects were 26 patients with lung cancer undergoing chemotherapy with carboplatin. A visual analog scale (VAS) was used to evaluate whether they felt unpleasantness, with a focus on nizakana (simmered fish) and citrus fruits odors. This evaluation was performed both before and 2 days after the patients were administered carboplatin. Results The results revealed that the VAS scores of emotional responses due to the sniffing of each food sample did not differ significantly (P = 0.942) before and during chemotherapy. However, the smell of nizakana with added ammonia altered VAS scores of the emotional responses significantly during chemotherapy (P = 0.015). Moreover, patients with lung cancer who had a heightened level of odor awareness in their daily lives felt more unpleasantness by sniffing nizakana with added ammonia (correlation coefficient [rs] = -0.437, P = 0.026). However, patients with a lower odor awareness level felt no unpleasantness. Conclusions The present findings suggest that patients with food aversion during chemotherapy are those with heightened odor awareness level; furthermore, this happens when they sense smells characteristic of substances harmful to the body.

Background/Aims: We investigated the efficacy of a combined exercise and cognitive training system that we devised for improvement of attention and concentration, cognition, and activities of daily living in older adults with dementia. Methods: A total of 100 dementia patients were randomly assigned to an intervention group or a control group. The intervention group was subjected to a combined exercise and cognitive training for 6 consecutive weeks. Evaluations were performed using the Trail Making Test-Part A, the Mini-Mental State Examination, and an N-type activities of daily living evaluation scale for the elderly. Results: A comparison of the changes in scores on the evaluation scales between the intervention group and the control group showed significant interactions for all scores. Conclusions: The combined system is effective in increasing attention and concentration and improving cognitive function and activities of daily living in dementia patients.

Micturition behavior follows regular day/night fluctuations, and unwanted increase in micturition could occur during night in jet lag condition. To clarify the effect of jet lag on micturition behavior, we simultaneously detected circadian micturition patterns and locomotor activity rhythms of mice under experimental jet lag conditions, by applying the improved automated Voided Stain on Paper (aVSOP) method. When wild-type (WT) mice were phase-advanced for 8 hours, day-night variation of micturition was disrupted suddenly, and this irregular daily micturition continued until 8 days, although their activity rhythms entrained gradually day by day until 8 days. We also examined how jet lag induced changes of micturition in Per-null mice lacking Per1, Per2 and Per3 genes, whose endogenous clock is completely disrupted. We found both micturition and locomotor activity of Per-null mice promptly entrained to the new LD cycle. These findings suggest that the irregular micturition during jet lag is caused along with the gradual shift of the endogenous clock, and paradoxically, jet lag-associated abnormality was absent when endogenous circadian oscillations were genetically disrupted.

We present a case of heterotopic cervical pregnancy where intrauterine gestation was preserved successfully. A 40‐year‐old Japanese woman presented with heterotopic cervical pregnancy after intracytoplasmic sperm injection with elongated spermatid. An ultrasound examination showed heterotopic cervical pregnancy. Intrauterine gestation was preserved successfully with the use of local vasopressin injection, followed by curettage of cervical implantation and local methotrexate injection. The cervical pregnancy resolved, and a healthy full‐term infant was delivered. When early diagnosis of a heterotropic cervical pregnancy is made, selective reduction of a cervical implantation might allow preservation of the intrauterine gestation, without hysterectomy. (Reprod Med Biol 2005; 4: 221–223)

ObjectiveRecently, rehabilitation therapists have become involved in cancer rehabilitation; however, no communication skills training that increases the ability to provide emotional support for cancer patients has been developed for rehabilitation therapists. In addition, no study has examined associations between rehabilitation therapists’ communication skills and their level of autistic-like traits (ALT), which are in-born characteristics including specific communication styles and difficulty communicating with patients. In this study, we aimed to investigate whether confidence in communicating with patients mitigates communication difficulties experienced by rehabilitation therapists who have high levels of ALT.MethodRehabilitation therapists who treat patients with cancer completed self-administered postal questionnaires anonymously. Scores were obtained on the Autism-Spectrum Quotient short form, confidence in communication, and communication difficulties. We used covariance structure analyses to test hypothetical models, and confirmed that confidence in communication mediates the relationship between ALT and perceived communication difficulties.ResultsParticipants included 1,343 respondents (49.6%). Autism-Spectrum Quotient scores were positively correlated with communication difficulties (r = 0.16, p < 0.001). The correlation was mitigated by confidence in communication in the fit model. However, higher confidence in creating a supportive atmosphere was associated with more difficulty in communication (r = 0.16, p < 0.001).Significance of resultsCommunication difficulty was linked to rehabilitation therapists’ ALTs. By increasing confidence in areas of communication other than creation of a supportive atmosphere, ALT-related difficulties in communication may be ameliorated. Confidence to create supportive environments correlated positively with difficulty. Communication skills training to increase confidence in communication for rehabilitation therapists should be developed with vigilance regarding ALT levels.

Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY-Y1R activation that is responsible for impaired antiviral response and promoting pro-inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY-Y1R-SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection.

It is not known whether the endogenous mammalian core clock proteins sustain measurable oscillations in cells in culture where de novo translation is pharmacologically inhibited. We studied here the mammalian core clock protein PER2, which undergoes robust circadian oscillations in both abundance and phosphorylation. With a newly developed antibody that enables tracing the endogenous PER2 protein oscillations over circadian cycles with cultured mouse embryonic fibroblast cells, we provide evidence that PER2 does not persist noticeable circadian rhythms when translation is inhibited.

The suprachiasmatic nucleus (SCN) is an extremely robust self-sustained oscillator, containing virtually the same molecular clock present in other tissues in the body but, in addition, endowed with tight intercellular coupling dependent on multiple neurotransmitter systems that allow the SCN to function as the "master clock." Several studies on the circadian SCN transcriptome have been published and compared with the transcriptome of other tissues, but the recent focus shift toward the circadian metabolome and the importance of small molecules for circadian timekeeping has so far been limited to macroscopic tissues such as the liver. Here, we report the successful use of laser capture microdissection coupled with liquid chromatography/tandem mass spectrometry for the circadian profiling of SCN amino acids. Among 18 amino acids detected, 10 (55.5%) showed significant variations, particularly marked for proline, lysine, and histidine, with higher levels during the subjective day. Moreover, we compared SCN and cortical amino acid levels between wild-type and Bmal1-deficient animals, either in the whole body or specifically in the liver. Interestingly, lack of Bmal1 in the whole body led to a significant increase in most amino acids in the SCN but not in the cerebral cortex. In contrast, deletion of Bmal1 in the liver mostly affected cortical amino acid levels during the subjective day. This study demonstrates that laser capture microdissection can be used for the isolation of microscopic brain structures for metabolomic purposes and reveals interactions between liver and SCN amino acid metabolism.

It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA (P < 0.0001), but only HSD3B1 mRNA significantly correlated with CYP11B2 (aldosterone synthase) mRNA (P < 0.0001) and plasma aldosterone concentration (PAC) of the patients (P < 0.0001). Results of immunohistochemistry subsequently revealed that HSD3B2 immunoreactivity was detected in the great majority of APA but a significant correlation was also detected between HSD3B1 and CYP11B2 (P < 0.0001). In KCNJ5 mutated APA, CYP11B2 mRNA (P < 0.0001) and HSD3B1 mRNA (P = 0.011) were significantly higher than those of wild type APA. These results suggest that HSD3B1 is involved in aldosterone production, despite its lower levels of expression compared with HSD3B2, and also possibly associated with KCNJ5 mutation in APA.

In the adrenal, the type I 3β-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully defined, particularly in terms of transcriptional regulation of steroidogenic enzyme genes. We previously showed that AngII can stimulate expression of HSD3B1. But, K(+) responsiveness of this gene has remained unexplored. Here, we report that K(+) stimulation lacks the ability to induce HSD3B1 expression in human adrenocortical H295R cells. Both AngII and K(+) were able to enhance transcription of the aldosterone synthase gene (CYP11B2). Promoter analysis revealed that although both AngII and K(+) activate transcription from the Ca(2+)/cAMP-responsive element (CRE) located in the CYP11B2 promoter, the orphan nuclear receptor NGFIB-responsive element (NBRE) located in the HSD3B1 promoter fails to respond to K(+), being only able to enhance transcription after AngII treatment. We found that induction of de novo protein synthesis of NGFIB occurs only after AngII treatment. This sharply contrasts with the phosphorylation that occurs in response to both AngII and K(+) on the CREB/ATF family transcription factor ATF2. Chromatin immunoprecipitation assay confirmed that the NGFIB protein occupies the HSD3B1 promoter only after AngII, while ATF2 binds to the CYP11B2 promoter in response to both AngII and K(+). These data provide evidence that downstream signals from AngII and K(+) can be uncoupled in the regulation of HSD3B1 in the human adrenocortical H295R cells.

Day-night changes in the storage capacity of the urinary bladder are indispensable for sound sleep. Connexin 43 (Cx43), a major gap junction protein, forms hemichannels as a pathway of ATP in other cell types, and the urinary bladder utilizes ATP as a mechanotransduction signals to modulate its capacity. Here, we demonstrate that the circadian clock of the urothelium regulates diurnal ATP release through Cx43 hemichannels. Cx43 was expressed in human and mouse urothelium, and clock genes oscillated in the mouse urothelium accompanied by daily cycles in the expression of Cx43 and extracellular ATP release into the bladder lumen. Equivalent chronological changes in Cx43 and ATP were observed in immortalized human urothelial cells, but these diurnal changes were lost in both arrhythmic Bmal1-knockout mice and in BMAL1-knockdown urothelial cells. ATP release was increased by Cx43 overexpression and was decreased in Cx43 knockdown or in the presence of a selective Cx43 hemichannel blocker, which indicated that Cx43 hemichannels are considered part of the components regulating ATP release in the urothelium. Thus, a functional circadian rhythm exists in the urothelium, and coordinates Cx43 expression and function as hemichannels that provide a direct pathway of ATP release for mechanotransduction and signalling in the urothelium.

Bmal1 (encoded by Arntl gene) is a core circadian clock gene that regulates various genes involved in circadian rhythm. Although Bmal1 is expressed rhythmically in macrophages, the role of Bmal1 in the regulation of their cellular function remains insufficiently understood. Here, we report that Bmal1 regulates time-dependent inflammatory responses following Toll-like receptor 4 (TLR4) activation by modulating enhancer activity. Global transcriptome analysis indicated that deletion of Arntl perturbed the time-dependent inflammatory responses elicited by TLR4 activation by Kdo2-lipid A (KLA). Although the recruitment of NF-κB p65 was unaffected, the acetylation status of lysine 27 of histone 3, which correlates positively with enhancer activity, was globally increased at PU.1-containing enhancers in Arntl−/− macrophages as compared to wild-type cells. Expression of Nr1d1 and Nr1d2, encoding RevErb transcription factors, which repress enhancer RNA expression, was significantly decreased in Arntl−/− macrophages. Moreover, the level of H3K27 acetylation was increased by Arntl deletion at RevErb-dependent eRNA-expressing enhancers. These results suggest that Bmal1 controls KLA-responsive enhancers, in part by regulating RevErb-directed eRNA transcription. Taken together, the results of this study show that the clock transcription factor network containing Bmal1 controls the inflammatory responses of macrophages by regulating the epigenetic states of enhancers.

The Gm7325 gene, bioinformatically identified in the mouse genome, encodes a small protein but has not been characterized until recently. Our gene expression analysis revealed that Gm7325 transcription is remarkably upregulated in injured skeletal muscle tissues. Activated satellite cells and immature myotubes were densely decorated with positive signals for Gm7325 mRNA in in situ hybridization analysis, while no obvious signals were observed in quiescent satellite cells and mature myofibers. In the 5'-flanking regions of mouse Gm7325 and its human homologue, conserved E-box motifs for helix-loop-helix transcription factors are repeatedly arranged around the putative promoter regions. Reporter gene assays suggested that MyoD, a master transcription factor for myogenesis, binds to the conserved E-box motifs to activate Gm7325 expression. Therefore, Gm7325, as a novel MyoD-target gene, is specifically induced in activated satellite cells, and may have an important role in skeletal myogenesis.

There has been little research on reminiscence cues and their effectiveness. The purpose of the present study was to measure the effects of reminiscence practice using olfactory stimuli on the mental health and cognitive functions of community-dwelling elderly individuals.Written consent was obtained from 72 eligible community-dwelling elderly individuals. They were non-randomly divided into an intervention group and a control group. In the intervention group (n = 35), reminiscence practice was carried out bi-weekly using olfactory stimulation as the cue for eight sessions. In the control group (n = 37), reminiscence practice was carried out without olfactory stimulation. The Geriatric Depression Scale-15 and the Five-cog Test were used as the methods of assessment at baseline and again after completion of the intervention. Participants in the final analysis were 27 individuals in the intervention group and 33 individuals in the control group.At baseline, a significant difference was seen between the groups depending on the existence of a spouse. Repeated measures analysis of covariance with the existence of a spouse as a covariate showed a significant difference between the two groups in changes in Geriatric Depression Scale-15 scores (P = 0.038). Furthermore, analysis of the participants sorted into a depression symptoms group and a non-depression symptoms group showed a significant group main effect (P = 0.033) and interaction (P = 0.049) in the depression symptoms group.The results suggest that reminiscence intervention using olfactory stimulation may maintain the mental health of community-dwelling elderly individuals.

Among nonphotic stimulants, a classic cholinergic agonist, carbachol, is known to have a strong and unique phase-resetting effect on the circadian clock: Intracerebroventricular carbachol treatment causes phase delays during the subjective early night and phase advances in the subjective late night, but the effects of this drug on the suprachiasmatic nucleus (SCN) in vivo and in vitro are still controversial. In the present study, we succeeded in reproducing the biphasic phase-shifting effect of carbachol on clock gene expression in organotypic SCN slices prepared from mice carrying a Per1-promoter fused luciferase gene ( Per1-luc). Since this biphasic effect of carbachol in Per1-luc SCN was prevented by atropine but not by mecamylamine, we concluded that these phase shifts were muscarinic receptor–dependent. Next, we analyzed the expression of muscarinic receptors in the SCN by in situ hybridization and found that M3 and M4 subtypes were expressed in SCN cells. These signals appeared neonatally and reached adult levels at postnatal day 10. Together, these findings suggest that carbachol has a phase-dependent phase-shifting effect on the SCN clock through muscarinic receptor subtypes expressed in the SCN.

The endogenous circadian clock drives oscillations that are completely synchronized with the environmental day–night rhythms with a period of approximately 24 hours. Temporal misalignment between one’s internal circadian clock and the external solar time often occurs in shift workers and long-distance travelers; such misalignments are accompanied by sleep disturbances and gastrointestinal distress. Repeated exposure to jet lag and rotating shift work increases the risk of lifestyle-related diseases, such as cardiovascular complaints and metabolic insufficiencies. However, the mechanism behind the disruption of one’s internal clock is not well understood. In this paper, we therefore present a new theoretical concept called “jet lag separatrix” to understand circadian clock disruption and slow recovery from jet lag based on the mathematical model describing the hierarchical structure of the circadian clock. To demonstrate the utility of our theoretical study, we applied it to predict that re-entrainment via a two-step jet lag in which a four-hour shift of the light-dark cycle is given in the span of two successive days requires fewer days than when given as a single eight-hour shift. We experimentally verified the feasibility of our theory in C57BL/6 strain mice, with results indicating that this pre-exposure of jet lag is indeed beneficial., 出発前日の早起きで時差ボケを軽減--シフトワーカーのからだに優しい勤務スケジュールの作成に期待--. 京都大学プレスリリース. 2017-04-28.

The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3 h, 6 h, 12 h or 24 h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3β-HSD1, CYP11A1, StAR, 17β-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3β-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3β-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.

The 3β-hydroxysteroid dehydrogenase (3β-HSD) is an enzyme crucial for steroid synthesis. Two different 3β-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG), where aldosterone is produced, raising the question of why this isozyme needs to be expressed in this cell type. Here we show that in both human and mouse, expression of the ZG isoform 3β-HSD is rapidly induced upon angiotensin II (AngII) stimulation. AngII is the key peptide hormone regulating the capacity of aldosterone synthesis. Using the human adrenocortical H295R cells as a model system, we show that the ZG isoform HSD3B1 differs from HSD3B2 in the ability to respond to AngII. Mechanistically, the induction of HSD3B1 involves de novo protein synthesis of the nuclear orphan receptors NGFIB and NURR1. The HSD3B1 promoter contains a functional NGFIB/NURR1-responsive element to which these proteins bind in response to AngII. Knockdown of these proteins and overexpression of a dominant negative NGFIB both reduce the AngII responsiveness of HSD3B1. Thus, the AngII-NGFIB/NURR1 pathway controls HSD3B1. Our work reveals HSD3B1 as a new regulatory target of AngII.

Objective:Much of the cancer rehabilitation research that has been conducted has consisted of relatively early recovery-of-function rehabilitation, and little attention has been paid to the psychosocial aspects of palliative rehabilitation. The aim of the present preliminary study was to examine the “narratives” of elderly cancer patients that emerged as a result of a life review performed in association with collage activity and to assess the effectiveness of this intervention.Method:We conducted a collage activity based on a life review in two sessions. Some 11 cancer patients who were 65 years of age or older and receiving palliative care participated. Evaluations using the Functional Assessment of Chronic Illness Therapy–Spiritual (FACIT–Sp) Scale, the Hospital Anxiety and Depression Scale (HADS), and the Self-Efficacy Scale for Terminal Cancer (SESTC) were administered before and immediately after the intervention.Results:The mean scores for the FACIT–Sp and affect regulation efficacy on the SESTC significantly increased, while the mean HADS score significantly decreased. Regarding the impressions after completion of the intervention, generally favorable evaluations were heard from families and medical staff members as well as from the subjects.Significance of results:A collage activity based on a life review may be effective for improving spiritual well-being, mitigating anxiety and depression, and improving self-efficacy. The collage itself was also useful in facilitating interactions with others, including family members, and the activity provided psychological support for families.

Objective We conducted this study with the aim of demonstrating the feasibility and efficacy of speed-feedback therapy with a bicycle ergometer on cognitive function in elderly cancer patients. Methods The subjects were patients with breast or prostate cancer who were 65 years of age or over. Among 146 patients, 78 were randomly assigned to the intervention group (n = 38) or the control group (n = 40). The intervention group received speed-feedback therapy with a bicycle ergometer once a week for four successive weeks. The control group was advised to spend the 4-week period engaged in their routine activities. Evaluations were carried out at the baseline and 4 weeks after the baseline (week 4) using the Frontal Assessment Battery, the Barthel Index, the Lawton and Brody Instrumental Activities of Daily Living, and the Functional Assessment of Cancer Therapy-General ver.4. Data were analyzed by a two-way repeated-measures analysis of variance. Results The mean score of Frontal Assessment Battery for the intervention group was higher than that for the control group at week 4. In addition to significant main effects of time and group, we also found a significant interaction between the two groups (p = 0.006). Moreover, all of the subjects in the intervention group could complete all the four sessions of therapy without any pain or distress. Conclusion These results suggest that speed-feedback therapy with a bicycle ergometer may be feasible as well as effective for improving the cognitive function in elderly cancer patients. Copyright © 2014 John Wiley & Sons, Ltd.