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Background: Blood supply to the remnant stomach should be preserved during pancreatectomy in patients with a history of gastrectomy. Moreover, ischemic complications should be considered when performing pancreatoduodenectomy in patients with celiac axis and superior mesenteric artery (SMA) stenosis. However, whether these surgical procedures can be safely performed remains unclear., Case Presentation: A 75-year-old man had a history of laparoscopic proximal gastrectomy (PG) with double-flap technique for gastric cancer and laparoscopic sigmoidectomy for sigmoid cancer treated 4 years ago. Follow-up computed tomography (CT) revealed an irregular nodular tumor measuring 13 mm in the pancreatic head. The patient was diagnosed with resectable pancreatic head cancer without lymph node metastasis (cT1cN0M0, cStageIA) according to the Union for International Cancer Control, 8th edition. As a standard pancreatic cancer treatment, two courses of preoperative chemotherapy with gemcitabine plus S-1 were administered. CT after preoperative chemotherapy identified no significant changes in tumor size but revealed SMA stenosis due to atherosclerosis. Blood flow to the left-sided colon was supplied from the middle colic artery via the SMA because of the past sigmoidectomy with inferior mesenteric artery detachment. Therefore, SMA stent placement was performed 1 day preoperatively. Subsequently, pylorus-preserving pancreatoduodenectomy (PPPD) was performed, preserving the remnant stomach with the right gastroepiploic (RGE) artery and vein. After resection, indocyanine green fluorescence imaging confirmed a good blood supply to the remnant stomach. The operation time was 467 min, and the blood lost was 442 mL. Histopathologically, the tumor was diagnosed as moderate adenocarcinoma and pT1cN0M0, Stage IA. The postoperative course was uneventful. The patient was discharged on postoperative day 23. S-1 as adjuvant chemotherapy was administered on postoperative day 63. The patient has been alive without recurrence for 7 months., Conclusions: We performed PPPD preserving blood supply for pancreatic head cancer in a patient with benign SMA stenosis and a history of PG and sigmoidectomy. Blood supply was preserved through preoperative SMA stent placement and a surgical procedure preserving the RGE vessels. Furthermore, S-1 adjuvant chemotherapy was successfully initiated. These multimodal therapies contributed to a favorable clinical outcome., Competing Interests: Declarations. Ethics approval and consent to participate: The present study was conducted in accordance with the ethical standards of our institution. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Purpose: The acute kidney injury (AKI) onset owing to vancomycin (VCM) is reported that depend on the area under the blood concentration-time curve (AUC) and occur comparison early phase (early AKI). This study aimed to investigate the occurrence of early AKI in patients treated with VCM and new indicators to avoid early AKI., Methods: Adult patients who received VCM treatment for more than 4 days and whose trough values measured at least once on or after day 4 and serum creatinine before day 7 from the initiation of VCM administration between August 2021 and September 2022 at the Yamanashi Prefectural Central Hospital were enrolled. Early AKI (defined as AKI occurring within day 7 from VCM administration) and the association between each AUC (0-24, 24-48, 48-72, 0-48, 24-72, 0-72) were investigated. Furthermore, each AUC cut-off value for early AKI was calculated., Result: In total, 164 patients were enrolled; early AKI developed in 21 patients and most frequently occurred on day 4. All stratified AUC were associated with early AKI development. The AUC cut-off values were AUC 0-24 : 470.8 μg/mL⋅h; AUC 24-48 : 473.0 μg/mL⋅h; AUC 48-72 : 489.7 μg/mL⋅h; AUC 0-48 : 910.2 μg/mL⋅h; AUC 24-72 : 1039.2 μg/mL⋅h; and AUC 0-72 : 1544.0 μg/mL⋅h., Conclusion: The possibility of AKI development owing to the AUC accumulation of VCM was observed (accumulation toxicity). Concentration control through early-phase blood concentration measurements and a transition to AUC 0-48 <910.2 μg/mL⋅h may reduce the early-phase AKI onset., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Dispersal increases the costs of feeding and predation risk in the new environment and is reported to be biased toward habitats similar to the natal region in some mammals. The benefits and costs of dispersal often differ between sexes, and most mammals show male-biased dispersal in relation to a polygamous mating system. Japanese serow is generally a solitary and monogamous species. However, recent studies have shown that the sociality of serows on Mt. Asama differs between habitat types. In the mountain forests with low forage availability, solitary habits and social monogamy were observed, while, in alpine grasslands, female grouping and social polygyny were observed, which is probably due to abundant forage availability. We investigated the effects of habitat characteristics and sociality on the dispersal of serows using fecal and tissue samples from two different habitats on Mt. Asama. The F st value between the two areas was significantly positive, and the mean relatedness within areas was significantly higher than that between areas, which suggests limited gene flow and natal habitat-biased dispersal. Bayesian clustering analysis showed unidirectional gene flow from forest to grassland, which was probably due to the high forage availability of the grassland. Analyses of the assignment index and mean relatedness did not show male-biased dispersal, even in the grassland, where serows were polygynous. Thus, polygyny in the grassland is not linked to male-biased dispersal. In summary, our study suggests that dispersal patterns in Japanese serows are affected by habitat rather than social differences.

Animals exhibit dynamic collective behaviors, as observed in flocks of birds, schools of fish, and crowds of humans. The collective behaviors of animals have been investigated in the fields of both biology and physics. In the laboratory, researchers have used various model animals such as the fruit fly and zebrafish for approximately a century, but it has remained a major challenge to study large-scale complex collective behavior orchestrated by these genetically tractable model animals. This paper presents a protocol to create an experimental system of collective behaviors in Caenorhabditis elegans. The propagated worms climb on the lid of the Petri plate and show collective swarming behavior. The system also controls worm interactions and behaviors by changing the humidity and light stimulation. This system allows us to examine the mechanisms underlying collective behaviors by changing environmental conditions and examining the effects of individual-level locomotion on collective behaviors using mutants. Thus, the system is useful for future research in both physics and biology.

Many organisms living along the coastlines synchronize their reproduction with the lunar cycle. At the time of spring tide, thousands of grass puffers (Takifugu alboplumbeus) aggregate and vigorously tremble their bodies at the water's edge to spawn. To understand the mechanisms underlying this spectacular semilunar beach spawning, we collected the hypothalamus and pituitary from male grass puffers every week for 2 months. RNA sequencing (RNA-seq) analysis identified 125 semilunar genes, including genes crucial for reproduction (e.g., gonadotropin-releasing hormone 1 [gnrh1], luteinizing hormone β subunit [lhb]) and receptors for pheromone prostaglandin E (PGE). PGE 2 is secreted into the seawater during the spawning, and its administration activates olfactory sensory neurons and triggers trembling behavior of surrounding individuals. These results suggest that PGE 2 synchronizes lunar-regulated beach-spawning behavior in grass puffers. To further explore the mechanism that regulates the lunar-synchronized transcription of semilunar genes, we searched for semilunar transcription factors. Spatial transcriptomics and multiplex fluorescent in situ hybridization showed co-localization of the semilunar transcription factor CCAAT/enhancer-binding protein δ (cebpd) and gnrh1, and cebpd induced the promoter activity of gnrh1. Taken together, our study demonstrates semilunar genes that mediate lunar-synchronized beach-spawning behavior. VIDEO ABSTRACT., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101 and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioural rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

A 93-year-old woman was diagnosed with Lysinibacillus fusiformis bacteremia complicated with coma blisters. Initial gram staining for L. fusiformis indicated the presence of gram-negative rods; however, subsequent staining of colonies from Mueller-Hinton agar revealed the presence of gram-positive and gram-negative rods with spherical endospores, and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (VITEK ® MS and microflex® LT/SH) definitively identified the organism as L. fusiformis. The two-week administration of piperacillin/tazobactam and ampicillin resulted in an improvement of the patient's general condition, and the skin lesions gradually improved., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Shortening of tensor fasciae latae is one factor that causes a functional leg length discrepancy. A shoe lift has been used to correct the compensatory posture resulting from the discrepancy. Despite the potential therapeutic benefit of a shoe lift, the mechanism by which it exerts its effect is unclear., Objective: To investigate the effect of a shoe lift on tensor fasciae latae length during standing with an artificial functional leg length discrepancy using ultrasonic shear wave elastography., Methods: Twenty-two healthy individuals performed static standing under three conditions: drop of the pelvis and flexion of the leg resulting from fixing in the hip abduction position using a hip orthosis (functional leg length discrepancy condition); drop of the pelvis by the orthosis, but no flexion of the leg due to a shoe lift (shoe lift condition); and normal bilateral standing condition. The shear elastic modulus of tensor fasciae latae was calculated using ultrasonic shear wave elastography., Results: The shear elastic modulus was significantly lower in the functional leg length discrepancy condition than in the shoe lift and normal conditions (p= 0.038)., Conclusions: Using a shoe lift for the functional leg length discrepancy can result in a functional hip position that elongates tensor fasciae latae.

Pyruvate dehydrogenase kinases (PDHKs) are fascinating drug targets for numerous diseases, including diabetes and cancers. In this report, we describe the result of our structure-based drug design from tricyclic lead compounds that led to the discovery of highly potent PDHK2 and PDHK4 dual inhibitors in enzymatic assay. The C3-position of the tricyclic core was explored, and the PDHK2 X-ray structure with a representative compound revealed a novel ATP lid conformation in which the phenyl ring of Phe326 mediated the interaction of the Arg258 sidechain and the compound. Compounds with amide linkers were designed to release the ATP lid by forming an intramolecular pi-pi interaction, and these compounds showed single-digit nM IC 50 values in an enzymatic assay. We also explored the C4-position of the tricyclic core to reproduce the interaction observed with the C3-position substitution, and the pyrrolidine compound showed the same level of IC 50 values. By optimizing an interaction with the Asn255 sidechain through a docking simulation, compounds with 2-carboxy pyrrole moiety also showed single-digit nM IC 50 values without having a cation-pi interaction with the Arg258 sidechain., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Circadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, cardiovascular disease, and cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target AKT and its relevant signaling pathways. As expected, analysis of the major ingredients targeting AKT signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of AKT, and triple knockdown of AKT isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption., (© 2021. The Author(s).)

E1A is an adenoviral protein which is expressed at the early phase after viral infection and contains four conserved regions (CR1, CR2, CR3 and CR4). Our previous work suggests that E1A facilitates the formation of cyclin A-CDK2 complex and thereby enhances CDK2 activity. However, the molecular function of E1A in CDK2 activation has been unclear. Here, we studied the mechanism of enhancement of CDK2 activity by E1A, using the E1A variant forms which selectively contain CR domains. We isolated four E1A variant forms, i.e. 13S (containing CR1, CR2, CR3, CR4), 12S (CR1, CR2, CR4), 10S (CR2, CR4) and 9S (CR4), derived from HEK293 cells which express E1A. 13S promoted G2/M-phase arrest, upon CDK2 hyper-activation by co-expressing a stabilized cyclin A mutant, most strongly among those E1A variant forms. Concomitantly, the specific activity of the 13S-associated CDK2 was highest among them. 10S exhibited lower affinity for CDK2 than the 13S while the affinity for CDK2 was comparable between 13S and 12S. Nonetheless, 12S did not enhance the CDK2 specific activity. On the other hand, a mutation in CR2 domain, which is essential for binding to p107, suppressed both the binding and activation of CDK2. These results suggest that CR1 domain, in addition to CR2 domain via p107 interaction, is important for binding to CycA-CDK2 complex while CR3 domain facilitates CDK2 activation. Since the function of CR3 in cell cycle regulation has been relatively unknown, we propose the enhancement of CDK2 activity as a novel function of CR3 domain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

At high latitudes, approximately 10% of people suffer from depression during the winter season, a phenomenon known as seasonal affective disorder (SAD). Shortened photoperiod and/or light intensity during winter season are risk factors for SAD, and bright light therapy is an effective treatment. Interestingly, reduced retinal photosensitivity along with the mood is observed in SAD patients in winter. However, the molecular basis underlying seasonal changes in retinal photosensitivity remains unclear, and pharmacological intervention is required. Here we show photoperiodic regulation of dopamine signaling and improvement of short day-attenuated photosensitivity by its pharmacological intervention in mice. Electroretinograms revealed dynamic seasonal changes in retinal photosensitivity. Transcriptome analysis identified short day-mediated suppression of the Th gene, which encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine biosynthesis. Furthermore, pharmacological intervention in dopamine signaling through activation of the cAMP signaling pathway rescued short day-attenuated photosensitivity, whereas dopamine receptor antagonists decreased photosensitivity under long-day conditions. Our results reveal molecular basis of seasonal changes in retinal photosensitivity in mammals. In addition, our findings provide important insights into the pathogenesis of SAD and offer potential therapeutic interventions.

The seed coat of mature black soybean, Glycine max, accumulates a high amount of cyanidin 3-O-glucoside (Cy3G), which is the most abundant anthocyanin in nature. In the pod, it takes two months for the seed coat color change from green to black. However, immature green beans rapidly adopt a black color within one day when the shell is removed. We analyzed the components involved in the color change of the seed coat and detected a new precursor of Cy3G, namely 5,7,3',4'-tetrahydroxyflav-2-en-3-ol 3-O-glucoside (2F3G). Through quantitative analysis using purified and synthetic standard compounds, it was clarified that during this rapid color change, an increase in the Cy3G content was observed along with the corresponding decrease in the 2F3G content. Chemical conversion from 2F3G to Cy3G at pH 5 with air and ferrous ion was observed. Our findings allowed us to propose a new biosynthetic pathway of Cy3G via a colorless glucosylated compound, 2F3G, which was oxidized to give Cy3G.

Chartelline C, a marine alkaloid, possesses a unique core scaffold including indolenine β-lactam and imidazole moieties linked by an unsaturated 10-membered ring. A new synthetic approach for the construction of the indolenine β-lactam was planned, based on the inherent reactivity of chartelline A with NaOMe, triggered by bromination of bromoenamide, and proceeding through an N -acyl imine. However, the N -acyl imine intermediate was not observed. Instead, the corresponding bromoindolenine was obtained, which led to the desired indolenine β-lactam in 92% yield.

Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Alpha-linolenic acid (ALA), a polyunsaturated fatty acid, is involved in bioregulatory functions. In recent years, the health-promoting effects of vegetable-derived edible oils rich in ALA have attracted attention. ALA has a variety of physiological effects such as anti-arteriosclerotic and antiallergic properties, but is prone to oxidation. Therefore, safety concerns exist with regard to adverse effects on humans induced by its oxides. However, the effects on neuronal cells induced by oxidized ALA-rich oils, such as perilla and linseed oils, have not been fully investigated. This information is very important from the viewpoint of food safety. In this study, we investigated the effects of oxidized perilla and linseed oils, which are rich in ALA, on the toxicity of neuronal SH-SY5Y cells. Perilla and linseed oils were significantly oxidized compared with other edible vegetable oils. These oxidized oils induce neuronal cell death and apoptosis via caspase-dependent and -independent pathways through reactive oxygen species (ROS) generation. Furthermore, they suppressed neurite outgrowth. These results suggest that oxidized perilla and linseed oils have the potential to cause neuronal loss and ROS-mediated apoptosis, and thus may affect the onset and progression of neurodegenerative disorders and other diseases.

Spontaneously Diabetic Torii (SDT) rats are a well-known animal model of non-obese type 2 diabetes mellitus. Although this animal model has been studied extensively over the last decade, the incidence rates of Leydig cell hyperplasia and tumors in this model have not been reported. In this study, pathophysiological analyses of the testes were performed on male SDT rats, to understand the effect of insulin treatment on the development of Leydig cell hyperplasia and tumors and the expression of integrins and extracellular matrix proteins. Testicular Leydig cell hyperplasia and tumors were observed in SDT rats at 64 weeks of age but were rarely identified in Sprague-Dawley (SD) rats of the same age. Insulin treatment decreased plasma glucose and HbA1c levels, and interestingly, decreased the number of hyperplastic Leydig cell foci and Leydig cell tumors in treated animals. A similar reduction in the expression of Ki67 in these Leydig cell foci was also observed. In addition, insulin treatment decreased the expression of integrin α5, integrin β1, integrin αvβ3, fibronectin, and vitronectin in hyperplastic Leydig cell foci. These results suggest that insulin might decrease the incidence of Leydig cell hyperplasia by reducing Leydig cell proliferation and the expression of integrins and extracellular matrix proteins through the reduction of serum glucose concentrations in these animals., Competing Interests: Yoshitomi Nakane, Yusuke Kemmochi, Naoto Ogawa, and Tomohiko Sasase are employees of Japan Tobacco Inc. Takeshi Ohta, Yoshikazu Higami, and Fumio Fukai have no conflict of interest., (©2020 The Japanese Society of Toxicologic Pathology.)

At higher latitudes, vertebrates exhibit a seasonal cycle of reproduction in response to changes in day-length, referred to as photoperiodism. Extended day-length induces thyroid-stimulating hormone in the pars tuberalis of the pituitary gland. This hormone triggers the local activation of thyroid hormone in the mediobasal hypothalamus and eventually induces gonadal development. In avian species, light information associated with day-length is detected through photoreceptors located in deep-brain regions. Within these regions, the expressions of multiple photoreceptive molecules, opsins, have been observed. However, even though the Japanese quail is an excellent model for photoperiodism because of its robust and significant seasonal responses in reproduction, a comprehensive understanding of photoreceptors in the quail brain remains undeveloped. In this study, we initially analyzed an action spectrum using photoperiodically induced expression of the beta subunit genes of thyroid-stimulating hormone in quail. Among seven wavelengths examined, we detected maximum sensitivity of the action spectrum at 500 nm. The low value for goodness of fit in the alignment with a template of retinal1-based photopigment, assuming a spectrum associated with a single opsin, proposed the possible involvement of multiple opsins rather than a single opsin. Analysis of gene expression in the septal region and hypothalamus, regions hypothesized to be photosensitive in quail, revealed mRNA expression of a mammal-like melanopsin in the infundibular nucleus within the mediobasal hypothalamus. However, no significant diurnal changes were observed for genes in the infundibular nucleus. Xenopus-like melanopsin, a further isoform of melanopsin in birds, was detected in neither the septal region nor the infundibular nucleus. These results suggest that the mammal-like melanopsin expressed in the infundibular nucleus within the mediobasal hypothalamus could be candidate deep-brain photoreceptive molecule in Japanese quail. Investigation of the functional involvement of mammal-like melanopsin-expressing cells in photoperiodism will be required for further conclusions., Competing Interests: The authors have declared that no competing interests exist.

Masking is a direct behavioral response to environmental changes and plays an important role in the temporal distribution of activity. However, the mechanisms responsible for masking remain unclear. Here we identify thermosensors and a possible neural circuit regulating temperature-dependent masking behavior in mice. Analysis of mice lacking thermosensitive transient receptor potential (TRP) channels (Trpv1/3/4 and Trpm2/8) reveals that temperature-dependent masking is impaired in Trpm2- and Trpm8-null mice. Several brain regions are activated during temperature-dependent masking, including the preoptic area (POA), known as the thermoregulatory center, the suprachiasmatic nucleus (SCN), which is the primary circadian pacemaker, the paraventricular nucleus of the thalamus (PVT), and the nucleus accumbens (NAc). The POA, SCN, PVT are interconnected, and the PVT sends dense projections to the NAc, a key brain region involved in wheel-running activity. Partial chemical lesion of the PVT attenuates masking, suggesting the involvement of the PVT in temperature-dependent masking behavior.

The blue-breasted quail (Coturnix chinensis), the smallest species of quail with short generation interval and excellent reproductive performance, is a potential avian research model. A normal series of skeletal development of avian embryos could be served as a reference standard in the fields of developmental biology and teratological testing as well as in the investigation of mutation with skeletal abnormalities and in the study of the molecular mechanisms of skeletal development through genome manipulation. Furthermore, ossification sequence shows a species-specific pattern and has potential utility in phylogeny. However, data on the skeletal development of blue-breasted quail embryos are scarce. Here, we established a series of normal stages for the skeletal development of blue-breasted quail embryos. Cartilage and ossified bones of blue-breasted quail embryos were stained blue and red with Alcian blue 8GX and Alizarin red S, respectively. The time and order of chondrification and calcification of their skeletons were documented every 24 hr from 3 to 17 days of incubation, and a 15-stage series of skeletal development was created. Moreover, a comparative study with the Japanese quail (Coturnix japonica) demonstrated that ossification sequence differed significantly between these two species., (© 2019 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

Organisms use changes in photoperiod for seasonal reproduction to maximize the survival of their offspring. Birds have sophisticated seasonal mechanisms and are therefore excellent models for studying these phenomena. Birds perceive light via deep-brain photoreceptors and long day-induced thyroid-stimulating hormone (TSH, thyrotropin) in the pars tuberalis of the pituitary gland (PT), which cause local thyroid hormone activation within the mediobasal hypothalamus. The local bioactive thyroid hormone controls seasonal gonadotropin-releasing hormone secretion and subsequent gonadotropin secretion. In mammals, the eyes are believed to be the only photoreceptor organ, and nocturnal melatonin secretion triggers an endocrine signal that communicates information about the photoperiod to the PT to regulate TSH. In contrast, in Salmonidae fish the input pathway to the neuroendocrine output pathway appears to be localized in the saccus vasculosus. Thus, comparative analysis is an effective way to uncover the universality and diversity of fundamental traits in various organisms.

Chickens and Japanese quail (Coturnix japonica) have traditionally been the primary avian models in developmental biology research. Recently, the blue-breasted quail (Coturnix chinesis), the smallest species in the order Galliformes, has been proposed as an excellent candidate model in avian developmental studies owing to its precocious and prolific properties. However, data on the embryonic development of blue-breasted quail are scarce. Here, we developed a normal developmental series for the blue-breasted quail based on developmental features. The blue-breasted quail embryos take 17 days to reach the hatching period at 37.7°C. We documented specific periods of incubation in which significant development occurred, and created a 39-stage developmental series. The developmental series for the blue-breasted quail was almost identical to that for chickens and Japanese quail in the earlier stages of development (stages 1-16). Our staging series is especially useful at later stages of development (stages 34-39) of blue-breasted quail embryos as a major criterion of staging in this phase of development was the weight of embryos and the length of third toes., (© 2018 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

The master circadian pacemaker in mammals resides in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized to ambient light/dark cycles (i.e., photoentrainment). Melanopsin (Opn4) and classical rod-cone photoreceptors are believed to provide all the photic input necessary for circadian photoentrainment. Although the UVA-sensitive photopigment Opn5 is known to be expressed in retinal ganglion cells, its physiological role remains unclear and a potential role for Opn5 in the photoentrainment of the master clock has not been addressed. Here we report impaired photoentrainment and phase shifting to UVA light in Opn5-null mice. However, triple-knockout mice lacking all known functional circadian photoreceptors (i.e., rods, cones, and melanopsin) failed to entrain to UVA-light/dark cycles, despite the presence of Opn5, demonstrating that Opn5 alone is not sufficient for photoentrainment of the SCN clock. Since Opn5 is involved in the regulation of the retinal circadian clock, disrupted retinal function may cause impaired circadian photoentrainment in Opn5-null mice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

In this study, we report on phase retrieval by the maximum likelihood method with conjugate gradient method (CG-MAL) using through-focus images in Lorentz transmission electron microscopy (LTEM). The method was evaluated using 32 simulated and experimentally obtained through-focus images of magnetic bubbles; these images were collected under a defocus range from approximately -3 mm to 3 mm. Consequently, we obtained the magnetic domain structures of the magnetic bubbles in both the simulation and the LTEM experiment. Furthermore, the CG-MAL method showed better convergence behavior than other iterative phase retrieval methods. Therefore, the method can also be widely and effectively applied to the observation of magnetic domain structures other than magnetic bubbles when highly defocused through-focus images are used.

Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA Dietary administration of DHEA to mice shortened free-running circadian period and accelerated re-entrainment to advanced light-dark (LD) cycles, thereby reducing jet-lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

2-(1,3-Benzothiazol-2-yl)-4-methoxy-6-(1,4,5-triphenyl-1H-imidazol-2-yl)phenol (BTImP) is an excited-state intramolecular proton transfer (ESIPT) fluorophore, containing an acid-stimuli-responsive intramolecular hydrogen bond (H-bond) that can switch from the central phenolic proton to the imidazole (Im) or benzothiazole (BT) nitrogen atoms. Here, we demonstrate that BTImP shows full-color (red, green, blue, and white) emission upon the addition of different concentrations of HClO 4 or, with time, after the addition of HBF 4 . It also shows thermally dependent color changes from pink through white to blue in a narrow temperature range of 25-60 °C. 1 H and 15 N NMR measurements suggest that, after the green fluorescent BTImP is protonated at its Im nitrogen atom, a conjugate base anion coordinates to the imidazolium (HIm + ) proton, forming two types of complexes with different coordination states. One state shows a significantly Stokes-shifted red emission resulting from ESIPT at the BT side, whereas the other shows a typical Stokes-shifted blue emission, probably caused by interaction of the anion with the phenolic proton, which breaks the H-bond on the BT side. BF 4 - and ClO 4 - are effective in forming such a blue emitter, whereas Cl - and PF 6 - are not; this behavior depends on whether the anion can fit into the bidentate binding site consisting of HIm + and the phenolic hydroxy group., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic-bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors.

Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Na v 1.2, Na v 1.6 and Na v 1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD). In the presence of VTD, however, crambescin B carboxylic acid diminished VTD-induced sustained and tail currents through the three VSSC subtypes in a dose-dependent manner, whereas TTX inhibited both the peak current and the VTD-induced sustained and tail currents through all subtypes of VSSC tested. We thus concluded that crambescin B carboxylic acid does not block VSSC in a similar manner to TTX but modulate the action of VTD, thereby causing an apparent block of VSSC in the cell-based assay., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Crush syndrome is a devastating condition leading to multiple organ failure. The mechanisms by which local traumatic injuries affect distant organs remain unknown. ETS-GS is a novel water-soluble, stable anti-oxidative agent composed of vitamin E derivative. Given that one of the main pathophysiological effects in crush syndrome is massive ischemia-reperfusion, reactive oxygen species (ROS) generated from the injured extremities would be systemically involved in distant organ damage. We investigated whether ETS-GS could suppress inflammatory response and improve mortality in a rat model of crush injury. Crush injury was induced by compression of bilateral hindlimbs for 6 h followed by release of compression. Seven-day survival was significantly improved by ETS-GS treatment. To estimate anti-oxidative and anti-inflammatory effects of ETS-GS, serum was collected 6 and 20 h after the injury. ETS-GS treatment significantly dampened the up-regulation of malondialdehyde and reduction of superoxide dismutase in the serum, which were induced by crush injury. Serum levels of interleukin 6 and high mobility group box 1 were significantly decreased in the ETS-GS group compared with those in the control group. Lung damage shown by hematoxylin-eosin staining at 20 h after the injury was ameliorated by the treatment. Ex vivo imaging confirmed that ETS-GS treatment reduced ROS generation in both the lung and the muscle following crush injury. The administration of ETS-GS could suppress ROS generation, systemic inflammation, and the subsequent organ damage, thus improving survival in a rat model of crush injury. These findings suggest that ETS-GS can become a novel therapeutic agent against crush injury.

The acquisition of drug resistance mediated by the interaction of tumor cells with the extracellular matrix (ECM), commonly referred to as cell adhesion-mediated drug resistance (CAM-DR), has been observed not only in hematopoietic tumor cells but also in solid tumor cells. We have previously demonstrated that a 22-mer peptide derived from fibronectin, FNIII14, can inhibit cell adhesion through the inactivation of β1 integrin; when coadministered with cytarabine, FNIII14 completely eradicates acute myelogenous leukemia by suppressing CAM-DR. In this study, we show that our FNIII14 peptide also enhances chemotherapy efficacy in solid tumors. Coadministration of FNIII14 synergistically enhances the cytotoxicity of doxorubicin and aclarubicin in mammary tumor and melanoma cells, respectively. The solid tumor cell chemosensitization induced by FNIII14 is dependent upon the upregulation and activation of the pro-apoptotic protein, Bim. Furthermore, the metastasis of tumor cells derived from ventrally transplanted mammary tumor grafts is suppressed by the coadministration of FNIII14 and doxorubicin. These results suggest that the coadministration of our FNIII14 peptide with chemotherapy could achieve efficient solid tumor eradication by increasing chemosensitivity and decreasing metastasis. The major causes of tumor recurrence are the existence of chemotherapy-resistant primary tumor cells and the establishment of secondary metastatic lesions. As such, coadministering FNIII14 with anti-cancer drugs could provide a promising new approach to improve the prognosis of patients with solid tumors., Competing Interests: The authors have declared that no competing interests exist.

Near-infrared (NIR) fluorescent imaging is a powerful tool for the non-invasive visualization of the inner structure of living organisms. Recently, NIR fluorescence imaging at 1000-1400 nm (second optical window) has been shown to offer better spatial resolution compared with conventional NIR fluorescence imaging at 700-900 nm (first optical window). Here we report lead sulfide (PbS) quantum dots (QDs) and their use for in vivo NIR fluorescence imaging of cerebral venous thrombosis in septic mice. Highly fluorescent PbS QDs with a 1100 nm emission peak (QD1100) were prepared from lead acetate and hexamethyldisilathiane, and the surface of QD1100 was coated with mercaptoundecanoic acid so as to be soluble in water. NIR fluorescence imaging of the cerebral vessels of living mice was performed after intravascular injection (200-300 μL) of QD1100 (3 μM) from a caudal vein. By detecting the NIR fluorescence of QD1100, we achieved non-invasive NIR fluorescence imaging of cerebral blood vessels through the scalp and skull. We also achieved NIR fluorescence imaging of cerebral venous thrombosis in septic mice induced by the administration of lipopolysaccharide (LPS). From the NIR fluorescence imaging, we found that the number of thrombi in septic mice was significantly increased by the administration of LPS. The formation of thrombi in cerebral blood vessels in septic mice was confirmed by enzyme-linked immunosorbent assay (ELISA). We also found that the number of thrombi significantly decreased after the administration of heparin, an inhibitor of blood coagulation. These results show that NIR fluorescence imaging with QD1100 is useful for the evaluation of the pathological state of cerebral blood vessels in septic mice.

Synthesis of both enantiomers of crambescin B carboxylic acid is described. A cis-enyne starting material was epoxidized under the conditions of Katsuki asymmetric epoxidation to give 95% ee of the epoxide, which was transformed to crambescin B carboxylic acid via bromocation-triggered cascade cyclization as the key step. Enantiomerically pure crambescin A and C carboxylic acids were also synthesized from the product of the cascade reaction. Structure-activity relationship (SAR) studies against voltage-gated sodium channel (VGSC) inhibition using those synthetic compounds revealed that the natural enantiomer of crambescin B carboxylic acid was most active and comparable to tetrodotoxin, and the unalkylated cyclic guanidinium structure is indispensible, while the carboxylate moiety is not important. The absolute stereochemistry of crambescin A was determined by a comparison of the methyl ester derived from natural crambescin A with that derived from the stereochemically defined crambescin A carboxylic acid synthesized in this study.

Objective: We investigated the associations between DSM-IV mental disorders and subsequent arthritis onset, with and without mental disorder comorbidity adjustment. We aimed to determine whether specific types of mental disorders and increasing numbers of mental disorders were associated with the onset of arthritis later in life., Method: Data were collected using face-to-face household surveys, conducted in 19 countries from different regions of the world (n=52,095). Lifetime prevalence and age at onset of 16 DSM-IV mental disorders were assessed retrospectively with the World Health Organization (WHO) Composite International Diagnostic Interview (WHO-CIDI). Arthritis was assessed by self-report of lifetime history of arthritis and age at onset. Survival analyses estimated the association of initial onset of mental disorders with subsequent onset of arthritis., Results: After adjusting for comorbidity, the number of mood, anxiety, impulse-control, and substance disorders remained significantly associated with arthritis onset showing odds ratios (ORs) ranging from 1.2 to 1.4. Additionally, the risk of developing arthritis increased as the number of mental disorders increased from one to five or more disorders., Conclusion: This study suggests links between mental disorders and subsequent arthritis onset using a large, multi-country dataset. These associations lend support to the idea that it may be possible to reduce the severity of mental disorder-arthritis comorbidity through early identification and effective treatment of mental disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

TSH secreted from the pars distalis (PD) of the pituitary gland stimulates the thyroid gland. In contrast, TSH secreted from the pars tuberalis (PT) of the pituitary gland regulates seasonal reproduction. The ontogeny of thyrotrophs and the regulatory mechanisms of TSH are apparently different between the PD and the PT. Interestingly, fish do not have an anatomically distinct PT, and the saccus vasculosus (SV) of fish is suggested to act as a seasonal sensor. Thus, it is possible that the SV is analogous to the PT. Here we examined the ontogeny of the pituitary gland and SV using rainbow trout. A histological analysis demonstrated the development of the pituitary anlage followed by that of the SV. Lhx3 and Pit-1, which are required for the development of PD thyrotrophs, clearly labeled the pituitary anlage. The common glycoprotein α-subunit (CGA) and TSH β-subunit (TSHB) genes were also detected in the pituitary anlage. In contrast, none of these genes were detected in the SV anlage. We then performed a microarray analysis and identified parvalbumin (Pvalb) as a marker for SV development. Because Pvalb expression was not detected in the pituitary anlage, no relationship was observed between the development of the SV and the pituitary gland. In contrast to embryos, Lhx3, Pit-1, CGA, and TSHB were all expressed in the adult SV. These results suggest that the morphological differentiation of SV occurs during the embryonic stage but that the functional differentiation into a seasonal sensor occurs in a later developmental stage.

Spinal cord herniation (SCH) is a rare disease characterized by herniation of the thoracic spinal cord through an anterior dural defect, presenting with progressive myelopathy. A case of a 69-year-old woman who presented with Brown-Sequard syndrome and a bone defect, in which an osteophyte created a hemisphere-like cavity with spinal cord herniation, is presented. The strangled spinal cord was released, and the defect was closed microsurgically using an artificial dural patch to prevent re-herniation. Postoperatively, the patient experienced gradual improvement in neurologic function. The SCH mechanism and surgical strategy are discussed.

A quinoxalinone derivative capable of lactam-lactim tautomerization was designed as a new fluorescence probe for sensing of cation (M(+) = Li(+) and Na(+)) and anion (X(-) = F(-), Cl(-), Br(-), and CH3COO(-)) in organic solvents. In THF, the minor lactam tautomer exhibited a weak fluorescence band at 425 nm with a typical Stokes shift of ∼4400 cm(-1), whereas the major lactim tautomer exhibited an intense fluorescence band at 520 nm with large Stokes shift of ∼8900 cm(-1) due to excited-state intramolecular proton transfer (ESIPT). The presence of either cations or anions was found to promote lactim-to-lactam conversion, resulting in the lowering of the ESIPT fluorescence. The lone pairs on the alkylamide oxygen and the quinoxalinone ring nitrogen of the lactam were found to bind Li(+) to form a 1:2 coordination complex, which was confirmed by single crystal X-ray structural analysis and fluorescent titrations. In addition, the N-H bond of the lactam was able to recognize anions via N-H···X hydrogen bonding interactions. Where X = F(-) or CH3COO(-), further addition of these anions caused deprotonation of the lactam to generate an anionic state, consistent with the crystal structure of the anion prepared by mixing tetrabutylammonium fluoride and the quinoxalinone derivative in THF. Dual cation-anion-sensing responses were found to depend on the ion-recognition procedure. The anionic quinoxalinone derivative and its Li(+) complex, which are formed by the addition of CH3COO(-) and Li(+), respectively, displayed different fluorescence enhancement behavior due to the two anions exchanging with each other.

In temperate zones, animals restrict breeding to specific seasons to maximize the survival of their offspring. Birds have evolved highly sophisticated mechanisms of seasonal regulation, and their testicular mass can change 100-fold within a few weeks. Recent studies on Japanese quail revealed that seasonal gonadal development is regulated by central thyroid hormone activation within the hypothalamus, depending on the photoperiodic changes. By contrast, the mechanisms underlying seasonal testicular regression remain unclear. Here we show the effects of short day and low temperature on testicular regression in quail. Low temperature stimulus accelerated short day-induced testicular regression by shutting down the hypothalamus-pituitary-gonadal axis and inducing meiotic arrest and germ cell apoptosis. Induction of T3 coincided with the climax of testicular regression. Temporal gene expression analysis over the course of apoptosis revealed the suppression of LH response genes and activation of T3 response genes involved in amphibian metamorphosis within the testis. Daily ip administration of T3 mimicked the effects of low temperature stimulus on germ cell apoptosis and testicular mass. Although type 2 deiodinase, a thyroid hormone-activating enzyme, in the brown adipose tissue generates circulating T3 under low-temperature conditions in mammals, there is no distinct brown adipose tissue in birds. In birds, type 2 deiodinase is induced by low temperature exclusively in the liver, which appears to be caused by increased food consumption. We conclude that birds use low temperature-induced circulating T3 not only for adaptive thermoregulation but also to trigger apoptosis to accelerate seasonal testicular regression.

The crystal structures and redox properties of p-benzoquinone (BQ)-fused [18]crown-6 1 and bis-BQ-fused [18]crown-6 2 were examined. The anion radicals of these BQ molecules were stabilized by addition of metal ions, through effective electrostatic interactions between the negatively charged BQ moiety and positively charged ion-capturing [18]crown-6 unit. The electrostatic interactions and solvation energy played important roles in determining the magnitudes of anodic redox shifts in the reduction potentials. Regular π-stacking of BQ units and regular arrays of [18]crown-6 units were observed in crystal 2, in which one-dimensional π-electron columns were separated by ionic channels. The hydroquinone-fused [18]crown-6 molecule 3 and a new BQ- and phenol-fused [18]crown-6 derivative 4 were obtained as single crystals. The molecular conformations of [18]crown-6 in crystal 3 and hydrated crystal 3⋅H2 O were different from each other., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Simple organic salts such as (Li(+))(m-IBA) (1), (Na(+))(m-IBA) (2), (K(+))(m-IBA) (3), (Rb(+))(m-IBA) (4), and (Cs(+))(m-IBA) (5) (m-IBA = m-iodobenzoate) were shown to form a mesophase before crystal melting or decomposition. The crystals were obtained in the hydrated form, e.g., 1·(H2O), 2·(H2O), 3·0.5(H2O), 4·(H2O), and 5·(H2O); they were then converted into dehydrated forms by increasing the temperature to ∼450 K. Optically anisotropic-layered mesophases were observed in unhydrated crystals 2, 3, 4, and 5, whereas an optically isotropic mesophase (e.g., rotator phase) was found for crystal 1. The single-crystal X-ray structural analysis of the hydrated crystals revealed an inorganic-organic alternate layer structure, which is consistent with the average molecular orientation in the layered mesophase. The m-IBA anions formed a π-stacking columnar structure in the hydrated crystals, while one- or two-dimensional M(+)∼O networks were observed in the inorganic layers. Our results showed that the M(+)∼O interactions and their connectivity are strongly influenced by the size of the cations. The reconstruction of the M(+)∼O networks by removing H2O molecules was crucial for the formation of the mesophases. A strong response of both the real and imaginary parts of the dielectric constant was observed around the solid-mesophase phase-transition temperatures of crystals 1-5, with the ionic conductions playing a critical role.