Structure–activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists

Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate neurokinin-3 receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties

Development of Radiation Hard N+-on-P Silicon Microstrip Sensors for Super LHC

Radiation tolerance up to 1015 1-MeV neq/cm2 is required for the silicon microstrip sensors to be operated at the Super LHC experiment. As a candidate for such sensors, we are investigating non-inverting n+-on-p sensors. We manufactured sample sensors of 1 times 1 cm in 4" and 6" processes with implementing different interstrip electrical isolation structures. Industrial high resistive p-type wafers from FZ and MCZ growth are tested. They are different in crystal orientations lang100rang and lang111rang with different wafer resistivities. The sensors were irradiated with 70-MeV protons and characterized in views of the leakage current increase, noise figures, electrical strip isolation, full depletion voltage evolution, and charge collection efficiency

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

新たなイントラクライン機構を用いた加齢性眼疾患治療へ --眼局所のホルモンの加齢変化とサーカディアンリズムが鍵--. 京都大学プレスリリース. 2022-02-14.Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD+)-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD+ availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction

Effects of behavioural activation on the neural circuit related to intrinsic motivation

[Background] Behavioural activation is an efficient treatment for depression and can improve intrinsic motivation. Previous studies have revealed that the frontostriatal circuit is involved in intrinsic motivation; however, there are no data on how behavioural activation affects the frontostriatal circuit. [Aims] We aimed to investigate behavioural activation-related changes in the frontostriatal circuit. [Method] Fifty-nine individuals with subthreshold depression were randomly assigned to either the intervention or non-intervention group. The intervention group received five weekly behavioural activation sessions. The participants underwent functional magnetic resonance imaging scanning on two separate occasions while performing a stopwatch task based on intrinsic motivation. We investigated changes in neural activity and functional connectivity after behavioural activation. [Results] After behavioural activation, the intervention group had increased activation and connectivity in the frontostriatal region compared with the non-intervention group. The increased activation in the right middle frontal gyrus was correlated with an improvement of subjective sensitivity to environmental rewards. [Conclusions] Behavioural activation-related changes to the frontostriatal circuit advance our understanding of psychotherapy-induced improvements in the neural basis of intrinsic motivation. [Declaration of interest] None.This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from Japan Society for the Promotion of Science, JSPS (grants 16H06395 and 16H06399), and grant 23118004 from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was partially supported by the programme for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) by Japan Agency for Medical Research and Development, AMED (grant 15dm0207012h0002) and Integrated Research on Depression, Dementia and Development Disorders by AMED (grant 16dm0107093h0001). The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation or review of the manuscript or decision to submit the manuscript for publication

LP narrowing: a new strategy for finding all solutions of nonlinear equations

Abstract-As solution techniques to solve numerical constraint satisfaction problems, consistency techniques such as box consistency are well-known. In this paper, the idea of the box consistency is applied to the problem of finding all solutions of nonlinear equations. A new algorithm is proposed, where boxes that appear in the algorithmic process are narrowed using linear programming such that no solution is lost. It is shown that all solutions can be found very efficiently by the proposed algorithm

Immunolocalization of murine type VI 3β-hydroxysteroid dehydrogenase in the adrenal gland, testis, skin, and placenta.

The enzyme 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD) is essential for the biosynthesis of all active steroid hormones, such as those secreted from the adrenal gland, testis, ovary, skin and placenta. The 3β-HSD enzymes exist in multiple isoforms in humans and rodents. To date, six different isoforms have been identified in the mouse, and these isoforms are speculated to play different roles in different tissues. We previously showed that the murine type VI 3β-HSD isoform (Hsd3b6) is expressed specifically in the aldosterone-producing zona glomerulosa cells within the adrenal gland and that its overexpression causes abnormally increased aldosterone synthesis, revealing a crucial (or rate-limiting) role of this enzyme in steroidogenesis. However, potential contributions of this enzyme to the steroid hormone synthesis outside the adrenal glands are poorly understood. This paucity of knowledge is partly because of the lack of isoform-specific antibody that can be used for immunohistochemistry. Here, we report the development and characterization of specific antibody to Hsd3b6 and show the results of immunohistochemistry for the adrenal gland, testis, ovary, skin and placenta. As expected, Hsd3b6 immunoreactivities within the adrenal gland were essentially confined to the zona glomerulosa cells, where aldosterone is produced. By contrast, no immunopositive cells were observed in the zona fasciculata, which is where corticosterone is produced. In the gonads, while the ovaries did not show any detectable immunoreactivity to Hsd3b6, the testes displayed intense immunoreactivities within the interstitial Leydig cells, where testosterone is produced. In the skin, positive immunoreactivities to Hsd3b6 were only seen in the sebaceous glands, suggesting a specific role of this enzyme in sebaceous function. Moreover, in the placenta, Hsd3b6 was specifically found in the giant trophoblast cells surrounding the embryonic cavity, which suggests a role for this enzyme in local progesterone production that is required for proper embryonic implantation and/or maintenance of pregnancy. Taken together, our data revealed that Hsd3b6 is localized in multiple specific tissues and cell types, perhaps thereby involved in biosynthesis of a number of tissue-specific steroid hormones with different physiological roles

Characteristics of stx-Converting Phages of EHEC O157

In this communication, we analyzed primarily an O157 strain isolated during the EHEC outbreak in Tokyo and revealed that all stx-converting phages examined were lambdoid and induced with ultraviolet light or norfloxacin and that an optimal dosage required for induction and patterns of time course in VT-specific DNA synthesis and toxin release were essentially similar to those in an O157 Sakai strain as described in the previous report. But the relationship appears to be rather remote between stx-converting phages lysogenized in O157 strains prevalent in Sakai city, west of Japan and those in O157 strains prevalent in Tokyo and Nagano, east of Japan in 1996, since the immunity is different from each other. Thus, stx-converting phages derived from the same hosts or the same prevalent area are related to each other but lower degree of relatedness is observed for those derived from different years and areas. These results may be accounted for by a hypothesis of the presence of a cassette of lysis genes associated with an stx gene that is mutually exchangeable by recombination between these phages.継続後誌:近畿大学先端技術総合研究所紀要 = Memoirs of Institute of Advanced Technology, Kinki Universit

Adjusting the Structure of a Peptide Nucleic Acid (PNA) Molecular Beacon and Promoting Its DNA Detection by a Hybrid with Quencher-Modified DNA

In this study, we performed an elaborate adjustment of the structure of peptide nucleic acid (PNA) molecular beacons as probes for detecting nucleic acids. We synthesized the PNA beacons with various numbers of Glu, Lys, and dabcyl (Dab) quenchers in them, and we investigated their fluorescence changes (F1/1/F0) with and without full-match DNA. As the numbers of Glu/Lys or Dab increased, the F1/1/F0 tended to decrease. Among the different beacons, the PNA beacon with one Glu and one Lys (P1Q1) showed the largest F1/1/F0. On the other hand, a relatively large F1/1/F0 was obtained when the number of Glu/Lys and the number of Dab were the same, and the balance between the numbers of Glu/Lys and Dab seemed to affect the F1/1/F0. We also investigated the DNA detection by the prehybrid of P1Q1, which consists of the T790M base sequence, [P1Q1(T790M)], with quencher-modified DNA (Q-DNA). We examined the DNA detection with single-base mismatch by P1Q1(T790M), and we clarified that there was difficulty in detecting the sequence with P1Q1 alone, but that the sequence was successfully detected by the prehybrid of P1Q1 with the Q-DNA