A transcriptional program underlying the circannual rhythms of gonadal development in medaka.

To cope with seasonal environmental changes, organisms have evolved approximately 1-y endogenous circannual clocks. These circannual clocks regulate various physiological properties and behaviors such as reproduction, hibernation, migration, and molting, thus providing organisms with adaptive advantages. Although several hypotheses have been proposed, the genes that regulate circannual rhythms and the underlying mechanisms controlling long-term circannual clocks remain unknown in any organism. Here, we show a transcriptional program underlying the circannual clock in medaka fish (Oryzias latipes). We monitored the seasonal reproductive rhythms of medaka kept under natural outdoor conditions for 2 y. Linear regression analysis suggested that seasonal changes in reproductive activity were predominantly determined by an endogenous program. Medaka hypothalamic and pituitary transcriptomes were obtained monthly over 2 y and daily on all equinoxes and solstices. Analysis identified 3,341 seasonally oscillating genes and 1,381 daily oscillating genes. We then examined the existence of circannual rhythms in medaka via maintaining them under constant photoperiodic conditions. Medaka exhibited approximately 6-mo free-running circannual rhythms under constant conditions, and monthly transcriptomes under constant conditions identified 518 circannual genes. Gene ontology analysis of circannual genes highlighted the enrichment of genes related to cell proliferation and differentiation. Altogether, our findings support the "histogenesis hypothesis" that postulates the involvement of tissue remodeling in circannual time-keeping.

Luminescence Color and Intensity Changes of Nitridorhenium(V) Complexes Induced by Protonation/Deprotonation on the Bidentate Azolylpyridine Ligands.

Tricyanidonitridorhenium(V) complexes with azolylpyridines, namely, [ReN(CN)3(H-N2py)]- (1-H, H-N2py = 2-(3-pyrazolyl)pyridine) and [ReN(CN)3(L)]2- (2-a, L = 2-[1,2,3]-triazol-4-yl-pyridine anion (N3py-), and 3-a, that is, L = 2-(tetrazol-5-yl)-pyridine anion (N4py-)), were newly synthesized and characterized. The structures of the new complexes were determined by single-crystal X-ray analysis. The 1-H complex includes two geometrical isomers in which an isomer is the conformation with the pyridyl (py) and pyrazolyl (pyrz) moieties of H-N2py occupying the trans site to the nitrido (the ax site) and the trans site to the cyanido (the eq site), respectively, in a bidentate fashion; the other isomer is the py and pyrz moieties coordinated to the eq and ax sites. In 2-a and 3-a, the triazolyl (trz) and tetrazoly (tetrz) moieties in N3py- and N4py- occupy the eq site, and the py moieties in N3py- and N4py- coordinate to the ax site. The complex 1-H is deprotonated upon the addition of 1,8-diazabicyclo[5.4.0]undec-7-one or NaOH to produce [ReN(CN)3(N2py)]2- (1-a), and 2-a is protonated upon the addition of p-toluene sulfonic acid (TsOH) to give [ReN(CN)3(H-N3py)]- (2-H) in DMSO. The protonation reaction does not occur for 3-a with TsOH in DMSO. All the complexes show one-electron redox waves of the Re(VI)/Re(V) and azolylpyridine ligand-centered processes in 0.1 M (n-C4H9)4NPF6-DMSO. All the complexes exhibit photoluminescence in DMSO and in the crystalline phase at 296 K. The emissive excited states of the complexes in DMSO were assigned to MLCT with a spin triplet nature. The emission band shifts to shorter and longer wavelengths upon protonation and deprotonation of the coordinated azolylpyridines, respectively. The emission color and intensity changes of 2-H and 2-a in the presence of acidic and basic vapors were investigated.

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior.

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.

Home-measured pulse pressure is a predictor of cardiovascular disease in type 2 diabetes: The KAMOGAWA-HBP study.

BACKGROUND AND AIMS: Pulse pressure (PP) is a prognostic predictor of cardiovascular mortality. This retrospective cohort study aimed to investigate the association between home PP measurements and cardiovascular disease in patients with type 2 diabetes. METHODS AND RESULTS: Home blood pressure was measured for 14 consecutive days in 1082 patients with type 2 diabetes, and pulse pressure was calculated. A 10 mmHg increase in morning PP was associated with a 1.30-fold increase in the risk of cardiovascular disease. The risk of cardiovascular disease was 1.88 times higher in the morning in the higher PP group than in the lower PP group. In the receiver operating characteristic analysis, the areas under the curve (95% confidence interval) corresponding to the PP (morning, evening, and clinic) for new-onset cardiovascular disease were 0.63 (0.58-0.69), 0.62 (0.57-0.67), and 0.59 (0.54-0.64), respectively. The area under the curve for PP measured in the morning was significantly greater than that for PP measured in the clinic (P = 0.032). CONCLUSION: Home-measured PP is a better predictor of new-onset cardiovascular disease than clinic-measured PP, in patients with type 2 diabetes.

Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock.

The circadian clock provides organisms with the ability to adapt to daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for clock functions in fungi and animals, but the posttranslational modifications that affect the plant clock are less understood. Here, using chemical biology strategies, we show that the Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved in posttranslational modification in the plant clock. Chemical screening demonstrated that an animal CDC7/CDK9 inhibitor, PHA767491, lengthens the Arabidopsis circadian period. Affinity proteomics using a chemical probe revealed that PHA767491 binds to and inhibits multiple CKL proteins, rather than CDC7/CDK9 homologs. Simultaneous knockdown of Arabidopsis CKL-encoding genes lengthened the circadian period. CKL4 phosphorylated transcriptional repressors PSEUDO-RESPONSE REGULATOR 5 (PRR5) and TIMING OF CAB EXPRESSION 1 (TOC1) in the TTFL. PHA767491 treatment resulted in accumulation of PRR5 and TOC1, accompanied by decreasing expression of PRR5- and TOC1-target genes. A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks.

Effect to Therapy of Sodium-Iodine Symporter Expression by Alpha-Ray Therapeutic Agent via Sodium/Iodine Symporter.

This study confirmed the effect of sodium/iodine symporter (NIS) expression on existing drugs by in vitro and in vivo tests using cultured cell lines. The tumor growth inhibitory effect of sodium astatide ([211At]NaAt) was evaluated by in vitro and in vivo tests using human thyroid cancer cells (K1, K1/NIS and K1/NIS-DOX). NIS expression in cancer cells was controlled using the Tet-On system. [131I]NaI was used as control existing drug. From the results of the in vitro studies, the mechanism of [211At]NaAt uptake into thyroid cancer cells is mediated by NIS, analogous to [131I]NaI, and the cellular uptake rate correlates with the expression level of NIS. [211At]NaAt's ability to inhibit colony formation was more than 10 times that of [131I]NaI per becquerel (Bq), and [211At]NaAt's DNA double-strand breaking (DSB) induction was more than ten times that of [131I]NaI per Bq, and [211At]NaAt was more than three times more cytotoxic than [131I]NaI (at 1000 kBq each). In vivo studies also showed that the tumor growth inhibitory effect of [211At]NaAt depended on NIS expression and was more than six times that of [131I]NaI per Bq.

Effect of matcha consumption on gut microbiota in healthy Japanese individuals: study protocol for a double-blind crossover interventional study.

This study compares and clarifies the changes in intestinal flora resulting from the continuous consumption of two types of matcha. Healthy adults will consume two types of matcha tea for four weeks, and differences in the intestinal microflora before and after drinking will be compared. Gut microbiota will be identified using next-generation sequencing. Phylogenetic classification of the enterobacteria will be performed based on sequence similarities. The relative proportions of the classified enterobacteria to the total nucleotide sequences will be compared between the samples obtained from the two groups consuming different matcha. The continuous consumption of matcha may improve dysbiosis and prevent atherosclerosis. The effects may vary according to the type of matcha used. Trial registration: The study was registered with university hospital medical information network (UMIN) (UMIN000040303), and all participants gave their written informed consent. Registered 1 November 2020, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000045982.

α-Emitting cancer therapy using 211 At-AAMT targeting LAT1.

α-Methyl-l-tyrosine (AMT) has a high affinity for the cancer-specific l-type amino acid transporter 1 (LAT1). Therefore, we established an anti-cancer therapy, with 211 At-labeled α-methyl-l-tyrosine (211 At-AAMT) as a carrier of 211 At into tumors. 211 At-AAMT had high affinity for LAT1, inhibited tumor cell growth, and induced DNA double-stranded breaks in vitro. We evaluated the accumulation of 211 At-AAMT in vivo and the role of LAT1. Treatment with 0.4 MBq/mouse 211 At-AAMT inhibited tumor growth in the PANC-1 tumor model and 1 MBq/mouse 211 At-AAMT inhibited metastasis in the lung of the B16F10 metastasis model. Our results suggested that 211 At would be useful for anti-cancer therapy and that LAT1 is suitable as a target for radionuclide therapy.

The quail genome: insights into social behaviour, seasonal biology and infectious disease response.

BACKGROUND: The Japanese quail (Coturnix japonica) is a popular domestic poultry species and an increasingly significant model species in avian developmental, behavioural and disease research. RESULTS: We have produced a high-quality quail genome sequence, spanning 0.93 Gb assigned to 33 chromosomes. In terms of contiguity, assembly statistics, gene content and chromosomal organisation, the quail genome shows high similarity to the chicken genome. We demonstrate the utility of this genome through three diverse applications. First, we identify selection signatures and candidate genes associated with social behaviour in the quail genome, an important agricultural and domestication trait. Second, we investigate the effects and interaction of photoperiod and temperature on the transcriptome of the quail medial basal hypothalamus, revealing key mechanisms of photoperiodism. Finally, we investigate the response of quail to H5N1 influenza infection. In quail lung, many critical immune genes and pathways were downregulated after H5N1 infection, and this may be key to the susceptibility of quail to H5N1. CONCLUSIONS: We have produced a high-quality genome of the quail which will facilitate further studies into diverse research questions using the quail as a model avian species.

Synthesis, Structures, and Photoluminescent Properties of Tricyanidonitridorhenium(V) Complexes with Bipyridine-Type Ligands.

Tricyanidonitridorhenium(V) complexes with 2,2'-bipyridine (bpy) derivatives in which the 4 and 4' positions were substituted by X, [ReN(CN)3(X2bpy)]- (X = NMe2, NH2, OMe, Me, Cl, and Br), were newly synthesized and characterized. The structures of the new complexes were determined by single-crystal X-ray analysis. UV-vis spectra of the complexes in dimethyl sulfoxide (DMSO) showed that the peak maximum wavelengths of rhenium-to-π* bpy-type-ligand charge transfer were in the range of 474-542 nm. Cyclic voltammograms in n-(C4H9)4NPF6-DMSO showed one-electron oxidation and reduction waves corresponding to the Re(VI/V) and X2bpy0/- processes, respectively. The new complexes and [ReN(CN)3bpy]- showed photoluminescence in the crystalline phase at 295 and 80 K and in DMSO at 295 K. The origin of the emission in DMSO was attributed to the triplet nature of the rhenium-to-π* bpy-type-ligand charge-transfer transition. Density functional theory calculations showed that the highest occupied and lowest unoccupied molecular orbitals were primarily localized on the dxy orbital of the rhenium and π* orbitals of the bpy-type ligand, respectively.

[A Case of Thymic Carcinoma of Postoperative Liver and Mediastinal Lymph Node Metastases Where Long-Term Survival Was Achieved through Multidisciplinary Treatment].

The patient was a 67-year-old man. At the age of 60, he underwent resection of thymic carcinoma with partial resection of the right upper lobe of the lung because of invasive thymic carcinoma. The pathological diagnosis was Masaoka stage Ⅲ squamous cell carcinoma. Follow-up examination 2 years after surgery showed metastases to the mediastinall ymph node and liver. After undergoing radiotherapy of 50 Gy to the mediastinal lymph node metastasis, partial hepatectomy was performed for metastatic liver cancer. Post-operation, he received 4 courses of combination therapy of carboplatin and paclitaxel. Five years post-hepatectomy, the patient developed liver metastasis again and underwent hepatectomy for local control. Postoperative recurrent cases of thymic carcinoma generally have poor prognosis. We describe a patient with thymic carcinoma of postoperative liver and mediastinal lymph node metastases who achieved long-term survival through multidisciplinary treatment.

The underlying mechanisms of vertebrate seasonal reproduction.

Animals make use of changes in photoperiod to adapt their physiology to the forthcoming breeding season. Comparative studies have contributed to our understanding of the mechanisms of seasonal reproduction in vertebrates. Birds are excellent models for studying these phenomena because of their rapid and dramatic responses to changes in photoperiod. Deep brain photoreceptors in birds perceive and transmit light information to the pars tuberalis (PT) in the pituitary gland, where the thyroid-stimulating hormone (TSH) is produced. This PT-TSH locally increases the level of the bioactive thyroid hormone T3 via the induction of type 2 deiodinase production in the mediobasal hypothalamus, and an increased T3 level, in turn, controls seasonal gonadotropin-releasing hormone secretion. In mammals, the eyes are the only photoreceptive structure, and nocturnal melatonin secretion encodes day-length information and regulates the PT-TSH signaling cascade. In Salmonidae, the saccus vasculosus plays a pivotal role as a photoperiodic sensor. Together, these studies have uncovered the universality and diversity of fundamental traits in vertebrates.

Seasonal changes in color perception.

In temperate zones, organisms experience dynamic fluctuations in environment including changes in color. To cope with such seasonal changes in the environment, organisms adapt their physiology and behavior. Although color perception has been believed to be fixed throughout life, there is increasing evidence for the alteration in opsin gene expression induced by environmental stimuli in a number of animals. Very recently, dynamic seasonal plasticity in color perception has been reported in the seasonally breeding medaka fish. Interestingly, seasonal changes in human color perception have also been reported. Therefore, plasticity of color perception, induced by environmental stimuli, might be a common phenomenon across various species.

Synthesis, Structures, and Proton Self-Exchange Reaction of µ3-Oxido/Hydroxido Bridged Trinuclear Uranyl(VI) Complexes with Tridentate Schiff-Base Ligands.

New µ3-hydroxido/oxido bridged trinuclear uranyl(VI) complexes with 3,5-di-t-butyl-N-salicylidene-2-aminophenolato (dbusap2-) ligands, Et3NH[(UO2)3(µ3-OH)(dbusap)3] (Et3NH[1]) and (Et3NH)2[(UO2)3(µ3-O)(dbusap)3] ((Et3NH)2[2]) were synthesized and characterized. Single-crystal X-ray structures of both complexes were determined. The oxygen atom on µ3-hydroxido center in [1]- is sp3 hybridized with an average U-(µ3-O)-U bond angle of 109.7(5)°; the µ3-oxido atom in [2]2- is sp2 hybridized with an average U-(µ3-O)-U bond angle of 118.0(10)°. U-(µ3-O) distances in [1]- are long (average of 2.43(1) Å) compared with those in [2]2- (average of 2.23(2) Å). The optimized geometries of the [(UO2)3(µ3-OH)]5+ core in [(UO2)3(µ3-OH)(sap)3]- and the [(UO2)3(µ3-O)]4+ core in [(UO2)3(µ3-O)(sap)3]2- (where sap = N-salicylidene-2-aminophenolato) from density functional theory (DFT) calculations resemble those in [1]- and [2]2-, respectively. The U-(µ3-O) bond in [2]2- is significantly shorter than that in [1]-, because of the greater negative charge on the central µ3-oxido. A reversible structural conversion between [2]2- and [1]- was conducted by protonation and deprotonation of the µ3-oxido/hydroxido group. The activation enthalpy and entropy of the proton self-exchange reaction between [1]- and [2]2- determined from the temperature dependence of 1H NMR coalescence are ΔH⧧ = 23 ± 2 kJ mol-1 and ΔS⧧ = -77 ± 5 J K-1 mol-1.

Molecular and Neuroendocrine Mechanisms of Avian Seasonal Reproduction.

Animals living outside tropical zones experience seasonal changes in the environment and accordingly, adapt their physiology and behavior in reproduction, molting, and migration. Subtropical birds are excellent models for the study of seasonal reproduction because of their rapid and dramatic response to changes in photoperiod. For example, testicular weight typically changes by more than a 100-fold. In birds, the eyes are not necessary for seasonal reproduction, and light is instead perceived by deep brain photoreceptors. Functional genomic analysis has revealed that long day (LD)-induced thyrotropin from the pars tuberalis of the pituitary gland causes local thyroid hormone (TH) activation within the mediobasal hypothalamus. This local bioactive TH, triiodothyronine (T3), appears to regulate seasonal gonadotropin-releasing hormone (GnRH) secretion through morphological changes in neuro-glial interactions. GnRH, in turn, stimulates gonadotropin secretion and hence, gonadal development under LD conditions. In marked contrast, low temperatures accelerate short day (SD)-induced testicular regression in winter. Interestingly, low temperatures increase circulating levels of T3 to support adaptive thermogenesis, but this induction of T3 also triggers the apoptosis of germ cells by activating genes involved in metamorphosis. This apparent contradiction in the role of TH has recently been clarified. Central activation of TH during spring results in testicular growth, while peripheral activation of TH during winter regulates adaptive thermogenesis and testicular regression.

Comparative analysis reveals the underlying mechanism of vertebrate seasonal reproduction.

Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms.

[Animals' clever adaptation strategy for seasonal changes in environment].

Organisms living outside of tropical zones experience seasonal changes in environment. Organisms are using day length as a calendar to change their physiology and behavior such as seasonal breeding, hibernation, migration, and molting. A comparative biology approach revealed underlying mechanisms of vertebrate seasonal reproduction. Here we review the current understanding of vertebrate seasonal reproduction. We Aso describe the involvement of tissue-specific post-translational modification in functional diversification of a hormone.

C-H activation generates period-shortening molecules that target cryptochrome in the mammalian circadian clock.

The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting-edge C-H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm-changing activity along with the components that trigger opposite modes of action. The first period-shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism.

A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation.

Patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) display multiple symptoms, such as chronic widespread pain, fatigue, sleep disturbance, and cognitive dysfunction. Abnormal pain sensation may be the most serious of these symptoms; however, its pathophysiology remains unknown. To provide insights into the molecular basis underlying abnormal pain in CFS and FMS, we used a multiple continuous stress (CS) model in rats, which were housed in a cage with a low level of water (1.5 cm in depth). The von Frey and Randall-Seritto tests were used to evaluate pain levels. Results showed that mechanical allodynia at plantar skin and mechanical hyperalgesia at the anterior tibialis (i.e., muscle pain) were induced by CS loading. Moreover, no signs of inflammation and injury incidents were observed in both the plantar skin and leg muscles. However, microglial accumulation and activation were observed in L4-L6 dorsal horn of CS rats. Quantification analysis revealed a higher accumulation of microglia in the medial part of Layers I-IV of the dorsal horn. To evaluate an implication of microglia in pain, minocycline was intrathecally administrated (via an osmotic pump). Minocycline significantly attenuated CS-induced mechanical hyperalgesia and allodynia. These results indicated that activated microglia were involved in the development of abnormal pain in CS animals, suggesting that the pain observed in CFS and FMS patients may be partly caused by a mechanism in which microglial activation is involved.

Thyroid hormone and seasonal regulation of reproduction.

Organisms living outside the tropics use changes in photoperiod to adapt to seasonal changes in the environment. Several models have contributed to an understanding of this mechanism at the molecular and endocrine levels. Subtropical birds are excellent models for the study of these mechanisms because of their rapid and dramatic response to changes in photoperiod. Studies of birds have demonstrated that light is perceived by a deep brain photoreceptor and long day-induced thyrotropin (TSH) from the pars tuberalis (PT) of the pituitary gland causes local thyroid hormone activation within the mediobasal hypothalamus (MBH). The locally generated bioactive thyroid hormone, T3, regulates seasonal gonadotropin-releasing hormone (GnRH) secretion, and hence gonadotropin secretion. In mammals, the eyes are the only photoreceptor involved in photoperiodic time perception and nocturnal melatonin secretion provides an endocrine signal of photoperiod to the PT to regulate TSH. Here, I review the current understanding of the hypothalamic mechanisms controlling seasonal reproduction in mammals and birds.