Biology subjects

Tada, H.

Publications and source records attributed to Tada, H..

6 recordsLinked to original sources

bioRxiv2026

Autopsy-based longitudinal multi-organ high-dimensional profiling reveals lineage plasticity in TRK-inhibitor-resistant secretory breast carcinoma

Secretory breast carcinoma (SBC) is typically indolent, yet mechanisms underlying aggressiveness and therapeutic resistance to tropomyosin receptor kinase inhibitors (TRKi) remain unclear. Autopsy-based longitudinal multi-organ high-dimensional profiling of metastatic TRKi-resistant SBC demonstrated histopathological heterogeneity, including secretory and squamous components, arising from a shared clonal origin. Integrated genomic and transcriptomic analyses revealed hierarchical transcriptional rewiring consistent with a lineage-plastic state, suggesting a potential link to tumor aggressiveness and therapeutic resistance.

pathology↗

bioRxiv2024

Nitric oxide regulates phagocytosis through S-nitrosylation of Rab5

Phagocytosis is mediated mainly by immune cells, such as macrophages, monocytes and neutrophils, that function to clear large pathogens including bacteria. The small GTP-binding protein Rab5 is crucial for clathrin-dependent endocytosis as well as phagocytosis. However, the role and mechanism of Rab5 activation during phagocytosis are poorly understood. Here we report that nitric oxide (NO), a novel regulator of Rab5, regulates phagocytosis through S-nitrosylation of Rab5. NO can promote phagocytosis by activating Rab5 in cultured cells, and it potently S-nitrosylates active Rab5 compared to inactive Rab5. Moreover, we demonstrate that two cysteine residues in the C terminus of Rab5 are S-nitrosylated and are important for phagocytosis. Experiments involving mice also showed that NO activates Rab5 and increases levels of S-nitrosylated Rab5 and that NO is involved in phagocytic bacterial clearance mediated by peritoneal macrophages. These data suggest that NO promotes S-nitrosylation of Rab5 to act as a novel Rab5 activator and a key regulator of phagocytosis. HighlightsO_LINO promotes phagocytosis C_LIO_LINO directly activates Rab5 and increases Rab5 S-nitrosylation C_LIO_LIS-nitrosylation C-terminal Rab5 cysteines residues is involved in phagocytosis C_LIO_LINO increases Rab5 S-nitrosylation and activity to promote bacterial clearance in vivo C_LI

biochemistry↗

bioRxiv2023

Bi-allelic variants in WDR47 lead to neuronal loss causing a rare neurodevelopmental syndrome with corpus callosum dysgenesis in humans.

The corpus callosum (CC) is the largest interhemispheric connection that is largely formed by the axons of layer 2/3 callosal projection neurons (CPNs) through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps may prevent the proper development of the corpus callosum resulting in a spectrum of disorders collectively referred to as corpus callosum dysgenesis (CCD). Here, we report four unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly, cerebellar abnormalities and hydrocephalus. Using a combination of in vitro and in vivo mouse models and complementation assays, we show that independently from its previously identified functions in neuronal migration and axonal extension, WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further provide evidence that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.

neuroscience↗

bioRxiv2022

Age-associated sleep-wake patterns are altered with Prdm13 signaling in the dorsomedial hypothalamus and dietary restriction in mice

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here we demonstrated that dorsomedial hypothalamus-specific PR-domain containing protein 13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during sleep deprivation (SD). These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep alterations, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated sleep fragmentation and excessive sleepiness during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

physiology↗

bioRxiv2019

Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease

BackgroundFamilial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency - homozygous loss-of-function (LoF) variants -- in the ATP-binding cassette transporter G5 (ABCG5) or G8 (ABCG8) genes, and have substantially elevated plasma sitosterol and low-density lipoprotein cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8, as occurs in heterozygous carriers of LoF variants, on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.\n\nMethodsWe first recruited nine sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8, and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29,361) versus controls (n=357,326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency less than 0.1% in ABCG5 or ABCG8.\n\nResultsIn sitosterolemia families, seven pedigrees harbored causative LoF variants in ABCG5 and two pedigrees in ABCG8. Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared to non-carriers. Within the large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 were approximately 0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (24.7 mg/dL; 95% confidence interval [CI] 14 to 35; P=1.1x10-6), and were at two-fold increased risk of CAD (odds ratio 2.06, 95% CI 1.27 to 3.35; P=0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.\n\nConclusionsAlthough familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of a LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a two-fold increase in risk of CAD.

genetics↗

bioRxiv2019

Processing of a single ribonucleotide embedded into DNA by human nucleotide excision repair and DNA polymerase η

DNA polymerases often incorporate non-canonical nucleotide, i.e., ribonucleoside triphosphates into the genomic DNA. Aberrant accumulation of ribonucleotides in the genome causes various cellular abnormalities. Here, we show the possible role of human nucleotide excision repair (NER) and DNA polymerase {eta} (Pol {eta}) in processing of a single ribonucleotide embedded into DNA. We found that the reconstituted NER system can excise the oxidized ribonucleotide on the plasmid DNA. Taken together with the evidence that Pol {eta} accurately bypasses a ribonucleotide, i.e., riboguanosine (rG) or its oxidized derivative (8-oxo-rG) in vitro, we further assessed the mutagenic potential of the embedded ribonucleotide in human cells lacking NER or Pol {eta}. A single rG on the supF reporter gene predominantly induced large deletion mutations. An embedded 8-oxo-rG caused base substitution mutations at the 3-neighboring base rather than large deletions in wild-type cells. The disruption of XPA, an essential factor for NER, or Pol {eta} leads to the increased mutant frequency of 8-oxo-rG. Furthermore, the frequency of 8-oxo-rG-mediated large deletions was increased by the loss of Pol {eta}, but not XPA. Collectively, our results suggest that base oxidation of the embedded ribonucleotide enables processing of the ribonucleotide via alternative DNA repair and damage tolerance pathways.

genetics↗