Biology subjects

Nakamura, Y.

Publications and source records attributed to Nakamura, Y..

8 recordsLinked to original sources

bioRxiv2026

From neuropeptide and receptor annotation to ligand-receptor pairing: a sequence- and structure-based framework for mapping the neuropeptide-receptor interactome in Gryllus bimaculatus

Neuropeptides and their G protein-coupled receptors (GPCRs) control much of insect physiology and behaviour, but in Gryllus bimaculatus, an emerging model and edible insect, receptor sequence similarity hinders the mapping of which peptide each GPCR activates. We re-annotated a chromosome-scale genome (BUSCO 95.3%, from 86.7% on insecta_odb12) with comprehensive curation of 48 neuropeptide precursor families (51 loci, including seven not previously identified) and 134 candidate GPCRs (66 rhodopsin-class, 68 secretin-class), providing a near complete neuropeptide-receptor interactome catalogue. We modelled all 15,946 peptide-receptor pairs with AlphaFold3 and Boltz-2 and scored each interface with pLDDT and ipSAE. Ranking these scores, and cross-checking the top candidate for each family against a receptor phylogeny of known ligand specificity, gave a confident, phylogenetically related receptor for 27 of 35 curated receptor groups. These matches confirm the structural scorings with existing deorphanization data and propose receptors for peptides with no prior functional evidence. The annotation, curated peptide and receptor sets, and ranked complexes are available through CricketBase (https://cricket.annotation.jp), a genome browser with a structure viewer of peptide-receptor complexes, providing a resource for G. bimaculatus endocrinology and a workflow to deorphanize GPCRs in other non-model insects.

bioinformatics↗

bioRxiv2018

Age of onset in genetic prion disease and the design of preventive clinical trials

Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data from N=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.

neuroscience↗

bioRxiv2018

BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis

Human globin gene production transcriptionally \"switches\" from fetal to adult synthesis shortly after birth, and is controlled by macromolecular complexes that enhance or suppress transcription by cis-elements scattered throughout the locus. The DRED repressor is recruited to the {varepsilon}- and {gamma}-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA binding and epigenetic enzyme components (e.g. DNMT1 and LSD1) that elicit DRED function. We also describe a potent new regulator of {gamma}-globin repression: the deubiquitinase BAP1 is a component of the repressor complex whose activity maintains NCoR1 at sites in the {beta}-globin locus, and BAP1 inhibition in erythroid cells massively induces {gamma}-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate {gamma}-globin gene repression.

developmental biology↗

bioRxiv2018

CRISPR-Cas9 interrogation of a putative fetal globin repressor in human erythroid cells.

Sickle Cell Disease and {beta}-thalassemia, which are caused by defective or deficient adult {beta}-globin (HBB) respectively, are the most common serious genetic blood diseases in the world. Expression of the fetal {beta}-like globin, also known as {gamma}-globin, can ameliorate both disorders by serving in place of the adult {beta}-globin. Here we use CRISPR-Cas9 gene editing to explore a putative {gamma}-globin silencer region identified by comparison of naturally-occurring deletion mutations associated with up-regulated {gamma}-globin. We find that deletion of a 1.7 kb consensus element or select 350 bp sub-regions from bulk populations of cells increases levels of fetal hemoglobin (HbF) or {gamma}-globin. Screening of individual sgRNAs in one sub-region revealed three single guides that caused mild increases in {gamma}-globin expression. However, clonal cell lines with the 1.7 kb region deleted did not up-regulate {gamma}-globin and neither did lines with either of two of sub-regions identified in the screen deleted. These data suggest that the region is not an autonomous {gamma}-globin silencer, and thus by itself is not a suitable therapeutic target in the {beta}-hemoglobinopathies.

genetics↗

bioRxiv2018

A long-chain fatty acid elongase Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation

Mechanical damage on the skin not only affect the barrier function but also induce various immune responses, which trigger or exacerbate the inflammation in healthy individuals and patients with inflammatory skin diseases. However, how mechanical damage-induced skin inflammation is regulated remains largely unknown. Here, we show that mechanical damage due to tape stripping triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL-1, which induced production of proinflammatory cytokines and chemokines IL-1{beta} and CXCL-1 by keratinocytes in mice. We also show that a long-chain fatty acid elongase Elovl6 is expressed in keratinocytes. Mice deficient in Elovl6 had increased epidermal levels of cis-vaccenic acid (CVA); this accelerated keratinocyte death triggered by tape stripping and release of DAMPs and exacerbated skin inflammation. Our results demonstrate that Elovl6 regulates mechanical damage-triggered keratinocyte death and skin inflammation.

immunology↗

bioRxiv2017

A randomized comparison of different hormone replacement protocols for thawed blastocyst transfer

BackgroundThere are no randomized controlled trials evaluating the pregnancy rates after thawed blastocyst transfers in patients treated with various hormone replacement regimens.\n\nMethodsA prospective randomized controlled trial was conducted to evaluate the outcomes in three different hormone replacement protocols for thawed blastocyst transfer. A total of 330 women (median age 38.2 years) who were undergoing IVF at our clinic were enrolled.\n\nResultsSerum estradiol (E2) levels were 267.71 pg/ml in Premarin group, 391.22 pg/ml in Estrogel group and 495.12 pg/ml in Estrana tape group. Therefore, serum E2 levels in Estrana tape group were higher than those of the other two groups (P<0.01). The pregnancy rate in the Estrogel group was higher than that in the Premarin group (30.0% versus 17.3%, P=0.026, odds ratio 2.05, 95% confidence interval: 1.09-3.87). Furthermore, the pregnancy rate in the Estrana tape group was higher than that in the Estrogel group (43.6% versus 30.0%, P=0.036, odds ratio 1.81, 95% confidence interval: 1.04-3.14).\n\nConclusionThe serum E2 levels contributed to differences observed in the pregnancy rate among the three different protocols. Thus, Estrana tape has an advantage as a hormone replacement protocol for thawed blastocyst transfer.

clinical trials↗

bioRxiv2017

Abnormally high levels of serum α-klotho result in a poor outcome for clinical pregnancy-A prospective cohort study-

BackgroundThe klotho protein has been extensively studied. However, there are no studies examining the association between serum alpha klotho levels and the clinical outcome of post-clinical pregnancy.\n\nMethodsWe conducted a prospective cohort study in 42 patients (median age 37.4 years) to evaluate the association between serum alpha klotho levels during the follicular phase of preimplantation and the clinical outcome data of post-clinical pregnancy. The patients provided informed consent at our clinic. The serum alpha klotho levels were evaluated using a human soluble alpha klotho assay kit. The fetal chromosomal abnormalities were investigated at our clinic. We also assessed the clinical outcomes of post-clinical pregnancies.\n\nResultsThe serum alpha klotho level during the follicular phase of preimplantation for non-pregnant women was 544.31 pg/ml (mean). The clinical pregnancy rate was 38.1%. There were chromosomal abnormalities observed in four unborn children (9.5%; Down syndrome, etc). The serum alpha klotho levels during the follicular phase of preimplantation in the chromosomal abnormalities group were higher than in the group without chromosomal abnormalities (P=0.029, abnormalities group 659.26 pg/ml [mean] versus control 530.23 pg/ml [mean]). A multiple logistic regression analysis showed the chromosomal abnormalities rates in unborn children were positively influenced by serum alpha klotho levels during the follicular phase of preimplantation (p=0.0008) and the patients age (p=0.008).\n\nConclusionPrevious studies have demonstrated that increased alpha klotho levels in human serum are positively correlated with health. However, abnormally high levels of serum alpha klotho during the follicular phase of preimplantation may predict a poor outcome for clinical pregnancy.

genetics↗

bioRxiv2017

Can the location of a trophectoderm biopsy contribute to human blastocyst development ?

The influence of the location of a trophectoderm biopsy in human blastocysts on the development of those blastocysts has not yet been investigated. In our prospective study (n=92), our multivariate logistic regression analysis indicated that blastocoel development was influenced by the location of the trophectoderm biopsy (p=0.049) and by the type of human blastocyst used (fresh or thawed) (p=0.037), regardless of the patients age (p=0.507) and the number of days for the human blastocyst in the pretrophectoderm biopsy (p=0.239). Therefore, when a trophectoderm biopsy is close to the inner cell mass (ICM) in human blastocysts, it improves the progress of blastocoel development.\n\nClinical evidence suggests that the progress of blastocoel development is a predictor of clinical outcomes after single blastocyst transfer. Therefore, when the trophectoderm biopsy is done from near the ICM, improvement of clinical outcomes after single blastocyst transfer may be expected.

developmental biology↗