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Abstract Developing a safe and potent repellent of mosquitoes applicable to human skins is an effective measure against the spread of mosquito-borne diseases. Recently, we have identified that hydrophobic solutions such as low viscosity polydimethylsiloxane (L-PDMS) spread on a human skin prevent mosquitoes from staying on and biting it. This is likely due to the ability of L-PDMS in wetting mosquito legs and exerting a capillary force from which the mosquitoes attempt to escape. Here we show three additional functions of L-PDMS that can contribute to repel Aedes albopictus, by combining physicochemical analysis and behavioral assays in both an arm cage and a virtual flight arena. First, L-PDMS, when mixed with topical repellents and applied on a human skin, enhances the effect of topical repellents in reducing mosquito bites by efficiently transferring them to mosquito legs upon contact. Second, L-PDMS applied to mosquito tarsi compromises visual object tracking during flight, exerting an influence outlasting the contact. Finally, L-PDMS applied to mosquito tarsi acts as an aversive reinforcer in associative learning, making mosquitoes avoid the conditioned odor. These results uncover a multifaceted potential of L-PDMS in altering a sequence of mosquito behaviors from biting a human skin, visual object tracking following takeoff, to the response to an odor linked with L-PDMS.

Abstract Optogenetics enables precise regulation of intracellular signaling in target cells. However, the application of optogenetics to induce the differentiation of precursor cells and generate mature cells with specific functions has not yet been fully explored. Here, we focused on osteoclasts, which play an important role in bone remodeling, to develop a novel optogenetics tool, Opto-RANK, which can manipulate intracellular signals involved in osteoclast differentiation and maturation using blue light. We engineered Opto-RANK variants, Opto-RANKc and Opto-RANKm, and generated stable cell lines through retroviral transduction. Differentiation was induced by blue light, and various assays were conducted for functional analysis. Osteoclast precursor cells expressing Opto-RANK differentiated into multinucleated giant cells on light exposure and displayed upregulation of genes normally induced in differentiated osteoclasts. Furthermore, the differentiated cells exhibited bone-resorbing activities, with the possibility of spatial control of the resorption by targeted light illumination. These results suggested that Opto-RANK cells differentiated by light possess the features of osteoclasts, both morphological and functional. Thus, Opto-RANK should be useful for detailed spatiotemporal analysis of intracellular signaling during osteoclast differentiation and the development of new therapies for various bone diseases.

Abstract The mechanisms of impaired glucose-induced insulin secretion from the pancreatic β-cells in obesity have not yet been completely elucidated. Here, we aimed to assess the effects of adipocyte-derived factors on the functioning of pancreatic β-cells. We prepared a conditioned medium using 3T3-L1 cell culture supernatant collected at day eight (D8CM) and then exposed the rat pancreatic β-cell line, INS-1D. We found that D8CM suppressed insulin secretion in INS-1D cells due to reduced intracellular calcium levels. This was mediated by the induction of a negative regulator of insulin secretion—NECAB1. LC–MS/MS analysis results revealed that D8CM possessed steroid hormones (cortisol, corticosterone, and cortisone). INS-1D cell exposure to cortisol or corticosterone increased Necab1 mRNA expression and significantly reduced insulin secretion. The increased expression of Necab1 and reduced insulin secretion effects from exposure to these hormones were completely abolished by inhibition of the glucocorticoid receptor (GR). NECAB1 expression was also increased in the pancreatic islets of db/db mice. We demonstrated that the upregulation of NECAB1 was dependent on GR activation, and that binding of the GR to the upstream regions of Necab1 was essential for this effect. NECAB1 may play a novel role in the adipoinsular axis and could be potentially involved in the pathophysiology of obesity-related diabetes mellitus.

Abstract Mosquitoes carry lethal pathogens for humans and hundreds of thousands of people are killed by mosquito-borne diseases every year. Therefore, controlling mosquitoes is essential to protect the lives of people around the world. Insecticides are highly effective in controlling mosquitoes and have been used extensively worldwide. However, they have potentially harmful effects on biodiversity and environment, and some mosquitoes are resistant to insecticide ingredients and survive upon their application. Therefore, there is a demand for a method to control mosquitoes without using conventional insecticide ingredients. Here, we used Aedes albopictus to test whether solutions with low surface tension, particularly surfactant solutions can alter mosquito behavior by spreading over the hydrophobic cuticle of mosquitoes. We found that solutions with low surface tension indeed attached to mosquitoes flying or resting on the wall, and made them fall. In addition, solutions with yet lower surface tension covered the mosquito surface more quickly and widely, knocking down or killing mosquitoes. These results suggest that surfactants such as sodium dioctyl sulfosuccinate can be used to alter mosquito behavior without relying on conventional insecticides.

Abstract Sjögren's syndrome (SS) is an autoimmune disease characterized by dry mouth. The cause of SS is unknown, and its diverse symptoms make diagnosis difficult. The Saxon test, an intraoral examination, is used as the primary diagnostic method for SS, however, the risk of salivary infection is problematic. Therefore, we investigate the possibility of diagnosing SS by non-contact and imaging observation of the tongue surface. In this study, we obtained tongue photographs of 60 patients at the Tsurumi University School of Dentistry outpatient clinic to clarify the relationship between the features of the tongue and SS. We divided the tongue into four regions, and the color of each region was transformed into CIE1976L*a*b* space and statistically analyzed. To clarify experimentally the possibility of SS diagnosis using tongue color, we employed three machine-learning models: logistic regression, support vector machine, and random forest. In addition, we constructed diagnostic prediction models based on the Bagging and Stacking methods combined with three machine-learning models for comparative evaluation. This analysis used dimensionality compression by principal component analysis to eliminate redundancy in tongue color information. We found a significant difference between the a* value of the rear part of the tongue and the b* value of the middle part of the tongue in SS and non-SS patients. In addition to the principal component scores of tongue color, the support vector machine was trained using age, and achieved high accuracy (71.3%) and specificity (78.1%). The results indicate that the prediction of SS diagnosis by tongue color reaches a level comparable to machine learning models trained using the Saxon test. This is the first study using machine learning to predict SS diagnosis by non-contact tongue observation. Our proposed method can potentially support early SS detection simply and conveniently, eliminating the risk of infection at diagnosis, and it should be validated and optimized in clinical practice.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes are interacting comorbidities of obesity, and increased hepatic de novo lipogenesis (DNL), driven by hyperinsulinemia and carbohydrate overload, contributes to their pathogenesis. Fatty acid synthase (FASN), a key enzyme of hepatic DNL, is upregulated in association with insulin resistance. However, the therapeutic potential of targeting FASN in hepatocytes for obesity-associated metabolic diseases is unknown. Here, we show that hepatic FASN deficiency differentially affects NAFLD and diabetes depending on the etiology of obesity. Hepatocyte-specific ablation of FASN ameliorated NAFLD and diabetes in melanocortin 4 receptor–deficient mice but not in mice with diet-induced obesity. In leptin-deficient mice, FASN ablation alleviated hepatic steatosis and improved glucose tolerance but exacerbated fed hyperglycemia and liver dysfunction. The beneficial effects of hepatic FASN deficiency on NAFLD and glucose metabolism were associated with suppression of DNL and attenuation of gluconeogenesis and fatty acid oxidation, respectively. The exacerbation of fed hyperglycemia by FASN ablation in leptin-deficient mice appeared attributable to impairment of hepatic glucose uptake triggered by glycogen accumulation and citrate-mediated inhibition of glycolysis. Further investigation of the therapeutic potential of hepatic FASN inhibition for NAFLD and diabetes in humans should thus consider the etiology of obesity.

Background The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity. Methods We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI. Results We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: −0.52 kg/m2 [−0.86, −0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group. Conclusion BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.

BackgroundThe number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity.MethodsWe searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI.ResultsWe included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: -0.52 kg/m2 [-0.86, -0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group.ConclusionBTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.

Although intestinal obstruction is a relatively common condition to be seen in daily clinical practice, cases with no history of laparotomy can often create difficulties in determining its diagnosis and surgical indication. This is a case report of a recurrent intestinal obstruction, with no surgical history, treated successfully using laparoscopy for both diagnosis and surgical operation.The patient, 62-year-old male, was hospitalized about a year ago due to abdominal pain and diarrhea likely caused by acute enteritis. As the inflammation had reduced and X-Ray image no longer indicated any gas patterns in the small intestine, he was later discharged from the hospital. However, the symptoms recurred after seven months which included abdominal pain, diarrhea as well as bloating. The patient was then introduced to our hospital through a local clinic for further diagnosis.The results resembled patient's previous hospitalization observing a formation of niveau, or mirror-image, in the upper abdomen as well as a sentinel loop with some swelling on computed tomography (CT) image. With conservative treatment, the patient showed rather a quick recovery soon after his admission. The inflammation and the intestinal obstruction had reduced. However, as recurrence had appeared in a similar area as his previous experience, the patient underwent diagnostic laparoscopy for further inspection of its underlying cause.Adhesion of the ileum and the sigmoid colon was observed. After diagnosis, laparoscopic adhesiolysis was performed in order to divide the adhesion and to remove the inflated part of the small intestine. The postoperative course was positive and the patient was discharged from the hospital 13 days after the surgery. There has been no report of recurrence thereafter.Technological development of CT scanners in recent years has enabled new levels of information. However, cases with no surgical history and fluctuating symptoms, such as the patient mentioned in this paper, requires direct observation of the tract. Doing so also helps determine the possibility of an internal hernia. Furthermore, laparoscopy enables a smooth shift from diagnosis to treatment, with the assistance of laparoscope, which avoids unnecessary invasion and requires only small incisions; serving it as a very effective approach to certain cases of intestinal obstruction.

Abstract Background Insomnia has a high prevalence in modern society. Various tools have been developed to assess insomnia. We performed a direct comparison between the Insomnia Severity Index (ISI) and the Athens Insomnia Scale (AIS) in a Japanese population. Methods A cross-sectional questionnaire-based study was conducted in September 2017 as part of the Night in Japan Home Sleep Monitoring Study. In addition to insomnia, assessed using the AIS and ISI, depression, sleepiness, quality of life, and work performance were assessed using the Patient Health Questionnaire (PHQ)-9, a Japanese version of the Epworth Sleepiness Scale, the Short Form-8 Health Survey Questionnaire (SF-8), and the World Health Organization Health and Work Performance Questionnaire, respectively. Receiver operating characteristic (ROC) curves were constructed to compare the outcomes of the AIS and the ISI. Results A total of 1685 (81.9%) of all eligible employees were enrolled. The total scores of the AIS and ISI had a Pearson correlation coefficient (r) of 0.80 (p

Ischemic colitis, often idiopathic, is a disease of the digestive system commonly found in patients with symptoms of abdominal pain and/or melena. In most cases, however, ischemic colitis is treated with conservative treatment and only in rare cases requires surgery. This is a case report of a patient who was diagnosed with ischemic colitis and later was required surgery due to advanced cicatricial stenosis. Patient is a 75-year-old female who had been experiencing abdominal pain followed by diarrhea and melena from several days before. Making a visit to a local clinic, she was recommended and admitted to our hospital for further diagnosis as well as adequate treatment. After conducting a colonoscopy, a lesion consisting of a 5 centimeter-long submucosal bleeding around the entire circumference of the descending colon, closer to the anus, was found. Under a pre-condition of fasting, the patient was given medical treatment via central venous hyperalimentation. In a later colonoscopy, only a mild case of cicatricial stenosis was found. However, even after resuming oral intake, there were no recurrences of symptoms such as abdominal pain, melena or ileus. On the 14th day of illness, patient was discharged from the hospital. Nevertheless, after some time of ambulatory care visits, on the 54th day of illness, the patient was again hospitalized for a thorough reexamination of the narrow pass. After conducting a colonoscopy, it was found that the lesioned part had generated a more severe, stiffer cicatricial stenosis. After checking with family members about patient's progress, a decline in amount of ingestion was revealed which, as a result, necessitated surgery on the patient. Postoperative course was uneventful, and the patient was able to leave the hospital rather quickly, 12 days after the surgery. Ten to 15 % of ischemic colitis cases are regarded constrictive. Most cases are ischemic changes on the outside layer of the mucosa. However, in case of significant ischemic change, the surface layer of the mucous membrane can be replaced with a fibrous structure which results in the occurrence of delayed cicatricial stenosis. In this case, possibilities of significant ischemia at first endoscopy, as well as possibilities of delayed changes at the following endoscopy, should have been considered. Patient's refusal to undergo surgery caused a delay in finding ileus of the intestine. As far as symptoms of significant ischemia and constriction were found, swift reexamination with awareness of possibilities of surgery should have taken place.

Abstract Background This descriptive study was conducted to examine the changes in the symptom frequency in patients with rapid eye movement (REM) sleep behavior disorder (RBD) without medical intervention, in order to determine the association of RBD symptom frequency with disease duration. Methods Data were collected from 70 consecutive RBD patients who visited the Sleep Clinic in Shiga University of Medical Science. RBD symptom frequencies at the first visit to the clinic were quantified based on the reports by the patients and their family members. For quality assurance, patients living alone or those with cognitive decline were excluded. Finally, 50 patients with family-confirmed symptom history were enrolled. The symptom frequencies were converted to a unit that reflects the estimated number of nights in a year affected by RBD (NAR). Using NAR, we observed the relation between RBD symptom frequency and the disease duration. Results Of the 50 patients, 41 were male and 9 were female, consistent with the male-dominant nature of this disease. The mean age at RBD onset was 62.2 ± 9.1 years, and the mean disease duration at the time of visit was 6.0 ± 4.9 years. The median symptom frequency was 50 NAR, with a 1st quantile value of 24 NAR and a 3rd quantile value of 115 NAR. When RBD symptom frequency was plotted against disease duration, we found that the frequency was lowest in the first 2 years of RBD (median, 18; range, 2–29 NAR), and higher frequencies were found in 2-year bin groups from 2 to 8 years after RBD onset (median, 60; range, 50–150 NAR). Intriguingly, after 8 years of RBD, the frequency returned to a level comparable to that in the first 2 years of RBD (median, 50; range, 12–100 NAR). Conclusions There was no association between RBD symptom frequency and disease duration. RBD clinical symptoms could be less prominent when neural damage becomes severe. Therefore, a natural decrease in RBD symptom frequency may be indicative of progression of neurodegeneration.

We previously observed an inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, through its measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS). However, the cost of equipment for LC-MS/MS and its maintenance fee is very expensive and a cost-efficient method is required. In this study, we have developed a sensitive enzyme-linked immunosorbent assay (ELISA) system to measure 3-HPMA using a chicken antibody recognizing 3-HPMA-conjugated chicken albumin as antigen. Linearity to measure 3-HPMA was obtained from 0 to 10 μM, indicating that this ELISA system is useful for measurement of urine 3-HPMA. It was confirmed that 3-HPMA in urine of stroke patients decreased significantly compared with that of control subjects using the ELISA system. Using the ELISA kit, it became possible to evaluate the risk of brain stroke by not only plasma but also by urine. These results confirm that shortage of glutathione to detoxify acrolein is one of the major causes of stroke incidence. Our method contributes to maintenance of quality of life (QOL) of the elderly.

The development and application of concepts is a critical component of cognition. Although concepts can be formed on the basis of simple perceptual or semantic features, conceptual representations can also capitalize on similarities across feature relationships. By representing these types of higher-order relationships, concepts can simplify the learning problem and facilitate decisions. Despite this, little is known about the neural mechanisms that support the construction and deployment of these kinds of higher-order concepts during learning. To address this question, we combined a carefully designed associative learning task with computational model-based functional magnetic resonance imaging (fMRI). Participants were scanned as they learned and made decisions about sixteen pairs of cues and associated outcomes. Associations were structured such that individual cues shared feature relationships, operationalized as shared patterns of cue pair-outcome associations. In order to capture the large number of possible conceptual representational structures that participants might employ and to evaluate how conceptual representations are used during learning, we leveraged a well-specified Bayesian computational model of category learning [1]. Behavioral and model-based results revealed that participants who displayed a tendency to link experiences in memory benefitted from faster learning rates, suggesting that the use of the conceptual structure in the task facilitated decisions about cue pair-outcome associations. Model-based fMRI analyses revealed that trial-by-trial integration of cue information into higher-order conceptual representations was supported by an anterior temporal (AT) network of regions previously implicated in representing complex conjunctions of features and meaning-based information.

The present study tested the clinical efficiency (item grouping, internal consistency of the subscales, construct validity, and clinical feasibility) of a widely used pain assessment system, the Mandarin version of the American Pain Society Patient Outcome Questionnaire (APS-POQ-R-C), in Chinese patients. We also attempted to investigate the current quality of pain management provided in orthopedic inpatient units in China and provide baseline data. First, we investigated the test-retest reliability of APS-POQ-R-C. In total, 236 orthopedic patients were evaluated. Our results showed that APS-POQ-R-C has satisfactory internal consistency and construct validity, although some items are not appropriate for orthopedic patients. Test-retest reliability outcomes indicated that APS-POQ-R-C is a satisfactory battery with acceptable validity and reliability, and is therefore recommended for pain management in future studies.

We recently reported that the over-expression of skin fibroblast-derived neutral endopeptidase (NEP) plays a pivotal role in impairing the three-dimensional architecture of dermal elastic fibers during the biological mechanism of ultraviolet (UV)-induced skin wrinkling. In that process, a UVB-associated epithelial-mesenchymal cytokine interaction as well as a direct UVA-induced cellular stimulation are associated with the up-regulation of NEP in human fibroblasts. In this study, we characterized the mode of action of ubiquinol10 which may abrogate the up-regulation of NEP by dermal fibroblasts, resulting in a reported in vivo anti-wrinkling action, and compared that with 3 other anti-oxidants, astaxanthin (AX), riboflavin (RF) and flavin mononucleotide (FMN). Post-irradiation treatment with all 4 of those anti-oxidants elicited an interrupting effect on the UVB-associated epithelial-mesenchymal cytokine interaction leading to the up-regulation of NEP in human fibroblasts but with different modes of action. While AX mainly served as an inhibitor of the secretion of wrinkle-inducing cytokines, such as interleukin-1α (IL-1α) and granulocyte macrophage colony stimulatory factor (GM-CSF) in UVB-exposed epidermal keratinocytes, ubiquinol10, RF and FMN predominantly interrupted the IL-1α and GM-CSF-stimulated expression of NEP in dermal fibroblasts. On the other hand, as for the UVA-associated mechanism, similar to the abrogating effects reported for AX and FMN, ubiquinol10 but not RF had the potential to abrogate the increased expression of NEP and matrix-metalloproteinase-1 in UVA-exposed human fibroblasts. Our findings strongly support the in vivo anti-wrinkling effects of ubiquinol10 and AX on human and animal skin and provide convincing proof of the UV-induced wrinkling mechanism that essentially focuses on the over-expression of NEP by dermal fibroblasts as an intrinsic causative factor.

Definitive chemoradiotherapy (CRT) is a less invasive therapy for esophageal squamous cell carcinoma (ESCC). Five-year survival rate of locally advanced ESCC patients by definitive CRT were 37%. We previously reported that tumor-specific cytotoxic T-lymphocyte (CTL) activation signatures were preferentially found in long-term survivors. However, it is unknown whether the CTL activation is actually driven by CRT. We compared gene expression profiles among pre- and post-treatment biopsy specimens of 30 ESCC patients and 121 pre-treatment ESCC biopsy specimens. In the complete response (CR) cases, 999 overexpressed genes including at least 234 tumor-specific CTL-activation associated genes such as IFNG, PRF1, and GZMB, were found in post-treatment biopsy specimens. Clustering analysis using expression profiles of these 234 genes allowed us to distinguish the immune-activated cases, designating them as I-type, from other cases. However, despite the better CR rate in the I-type, overall survival was not significantly better in both these 30 cases and another 121 cases. Further comparative study identified a series of epithelial to mesenchymal transition-related genes overexpressed in the early relapse cases. Importantly, the clinical outcome of CDH2-negative cases in the I-type was significantly better than that of the CDH2-positive cases in the I-type. Furthermore, NK cells, which were activated by neutrophils-producing S100A8/S100A9, and CTLs were suggested to cooperatively enhance the effect of CRT in the CDH2-negative I-type. These results suggested that CTL gene activation may provide a prognostic advantage in ESCCs with epithelial characteristics.

Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-β enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs.

A mutation that confers white plumage with black eyes was identified in the Minohiki breed of Japanese native chicken (Gallus gallus domesticus). The white plumage, with a few partially pigmented feathers, was not associated with the tyrosinase gene, and displayed an autosomal recessive mode of inheritance against the pigmented phenotype. All F1 offspring derived from crosses with mottled chickens (mo/mo), which show characteristic pigmented feathers with white tips, had plumage with a mottled-like pattern. This result indicates that the white plumage mutation is a novel allele at the mo locus; we propose the gene symbol mo(w) for this mutant allele. Furthermore, the F1 hybrid between the mo(w) /mo(w) chicken and the panda (s/s) mutant of Japanese quail (Coturnix japonica), whose causative gene is the endothelin receptor B2 (EDNRB2) gene, showed a mo(w)/mo(w) chicken-like plumage, suggesting the possibility that the mutations in parental species are alleles of the same gene, EDNRB2. Nucleotide sequencing of the entire coding region of EDNRB2 revealed a non-synonymous G1008T substitution, which causes Cys244Phe amino acid substitution in exon 5 (which is part of the extracellular loop between the putative fourth and fifth transmembrane domains of EDNRB2) in the mutant chicken. This Cys244Phe mutation was also present in individuals of four Japanese breeds with white plumage. We also identified a non-synonymous substitution leading to Arg332His substitution that was responsible for the mottled (mo/mo) plumage phenotype. These results suggest that the EDN3 (endothelin 3)-EDNRB2 signaling is essential for normal pigmentation in birds, and that the mutations of EDNRB2 may cause defective binding of the protein with endothelins, which interferes with melanocyte differentiation, proliferation, and migration.

Vast quantities of data on human behavior are being created by our everyday internet usage. Building upon a recent study by Preis, Moat, Stanley, and Bishop (2012), we used search engine query data to construct measures of the time-perspective of nations, and tested these measures against per-capita gross domestic product (GDP). The results indicate that nations with higher per-capita GDP are more focused on the future and less on the past, and that when these nations do focus on the past, it is more likely to be the distant past. These results demonstrate the viability of using nation-level data to build psychological constructs.

Phosphatidylinositol-3,4,5-trisphosphate (PIP3) is highly regulated in a spatiotemporal manner and plays multiple roles in individual cells. However, the local dynamics and primary functions of PIP3 in developing neurons remain unclear because of a lack of techniques for manipulating PIP3 spatiotemporally. We addressed this issue by combining optogenetic control and observation of endogenous PIP3 signaling. Endogenous PIP3 was abundant in actin-rich structures such as growth cones and "waves", and PIP3-rich plasma membranes moved actively within growth cones. To study the role of PIP3 in developing neurons, we developed a PI3K photoswitch that can induce production of PIP3 at specific locations upon blue light exposure. We succeeded in producing PIP3 locally in mouse hippocampal neurons. Local PIP3 elevation at neurite tips did not induce neurite elongation, but it was sufficient to induce the formation of filopodia and lamellipodia. Interestingly, ectopic PIP3 elevation alone activated membranes to form actin-based structures whose behavior was similar to that of growth-cone-like "waves". We also found that endocytosis regulates effective PIP3 concentration at plasma membranes. These results revealed the local dynamics and primary functions of PIP3, providing fundamental information about PIP3 signaling in neurons.

BACKGROUND: Surgical samples have long been used as important subjects for cancer research. In accordance with an increase of neoadjuvant therapy, biopsy samples have recently become imperative for cancer transcriptome. On the other hand, both biopsy and surgical samples are available for expression profiling for predicting clinical outcome by adjuvant therapy; however, it is still unclear whether surgical sample expression profiles are useful for prediction via biopsy samples, because little has been done about comparative gene expression profiling between the two kinds of samples. METHODOLOGY AND FINDINGS: A total of 166 samples (77 biopsy and 89 surgical) of normal and malignant lesions of the esophagus were analyzed by microarrays. Gene expression profiles were compared between biopsy and surgical samples. Artificially induced epithelial-mesenchymal transition (aiEMT) was found in the surgical samples, and also occurred in mouse esophageal epithelial cell layers under an ischemic condition. Identification of clinically significant subgroups was thought to be disrupted by the disorder of the expression profile through this aiEMT. CONCLUSION AND SIGNIFICANCE: This study will evoke the fundamental misinterpretation including underestimation of the prognostic evaluation power of markers by overestimation of EMT IN past cancer research, and will furnish some advice for the near future as follows: 1) Understanding how long the tissues were under an ischemic condition. 2) Prevalence of biopsy samples for in vivo expression profiling with low biases on basic and clinical research. 3) Checking cancer cell contents and normal- or necrotic-tissue contamination in biopsy samples for prevalence.

A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (tau), quantitative trait locus (QTL) analysis was performed using F(2) mice obtained from an F(1) cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For tau, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.