Biology subjects

Sato, T.

Publications and source records attributed to Sato, T..

At least 127 records · Page 7Linked to original sources

bioRxiv2020

Expression of ACE2 and TMPRSS2 proteins in the upper and lower aerodigestive tracts of rats

Objective Patients with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibit not only respiratory symptoms but also symptoms of chemo-sensitive disorders and kidney failure. Cellular entry of SARS-CoV-2 depends on the binding of its spike protein to a cellular receptor named angiotensin-converting enzyme 2 (ACE2), and the subsequent spike protein-priming by host cell proteases, including transmembrane protease serine 2 (TMPRSS2). Thus, high expression of ACE2 and TMPRSS2 are considered to enhance the invading capacity of SARS-CoV-2.Methods To elucidate the underlying histological mechanisms of the aerodigestive disorders caused by SARS-CoV-2, we investigated the expression of ACE2 and TMPRSS2 proteins in the aerodigestive tracts of the tongue, hard palate with partial nasal tissue, larynx with hypopharynx, trachea, esophagus, lung, and kidney of rats through immunohistochemistry.Results Strong co-expression of ACE2 and TMPRSS2 proteins was observed in the nasal respiratory epithelium, trachea, bronchioles, alveoli, kidney, and taste buds of the tongue. Remarkably, TMPRSS2 expression was much stronger in the peripheral alveoli than in the central alveoli. These results coincide with the reported clinical symptoms of COVID-19, such as the loss of taste, loss of olfaction, respiratory dysfunction, and acute nephropathy.Conclusions A wide range of organs have been speculated to be affected by SARS-CoV-2 depending on the expression levels of ACE2 and TMPRSS2. Differential distribution of TMPRSS2 in the lung indicated the COVID-19 symptoms to possibly be exacerbated by TMPRSS2 expression. This study might provide potential clues for further investigation of the pathogenesis of COVID-19.Level of Evidence NACompeting Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2020

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium towards a reparative state.

developmental biology↗

bioRxiv2020

2MV/cm Pulsed Electric Fields Promote Transthyretin Amyloid Disintegration

Exposing transthyretin amyloid to 1000 sub-nanosecond 2 MV/cm pulsed electric fields (PEFs) promotes both amyloid disassembly and amyloid-derived transthyretin disintegration. The process produced no change in pH, and the resulting temperature increase was less than 1 {degrees}C. We conclude that PEFs physical effects facilitate amyloid disassembly, rather than thermal or chemical effects, and provoke amyloid-derived transthyretin disintegration, the latter of which is reported here for the first time.

biophysics↗

bioRxiv2020

The Superior Frontal Longitudinal Tract: Connection between the Dorsal Premotor and the Dorsolateral Prefrontal Cortices

The structural connection between the dorsal premotor (PMd) and the lateral prefrontal cortices (DLPFC) has been revealed, in a few studies, as the frontal longitudinal system (FLS). This study conducted a tractography analysis and a limited, postmortem, white-fiber dissection to investigate the superior FLS tract (SFLT) and analyze both its symmetry and termination point patterns. An analysis of spatial location, termination points, laterality, and correlation with the subjects gender or handedness was performed. SFLT was constructed in 100% of right and 88% of left hemispheres. The tracts exhibited variable patterns in different subjects in their posterior terminations. Additionally, the SFLT was found to possess a complex spatial relationship with the adjacent bundles. The SFLT was revealed successfully in two right hemispheres, where the posterior terminations were found to originate in the PMd, and its posterior terminations being totally separate from the superior longitudinal fasciculus.

neuroscience↗

bioRxiv2019

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/floxmice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.

cancer biology↗

bioRxiv2019

Calling Somatic SNVs and Indels with Mutect2

Mutect2 is a somatic variant caller that uses local assembly and realignment to detect SNVs and indels. Assembly implies whole haplotypes and read pairs, rather than single bases, as the atomic units of biological variation and sequencing evidence, improving variant calling. Beyond local assembly and alignment, Mutect2 is based on several probabilistic models for genotyping and filtering that work well with and without a matched normal sample and for all sequencing depths.

bioinformatics↗

bioRxiv2019

Integrative genomic and epigenomic analyses identify a distinct role of c-Myc and L-Myc for lineage determination in small cell lung cancer

Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.

cancer biology↗

bioRxiv2019

Lin28a/let-7 Pathway Modulates the Hox Code via Polycomb Regulation during Axial Patterning in Vertebrates

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 reciprocal regulatory pathway is critical for vertebral specification. Lin28a-/- mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posterior Hox genes. The accumulation of let-7-family microRNAs in Lin28a-/- mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7-family microRNAs. These results suggest that Lin28/let-7 pathway is possibly involved in the modulation of the "Hox code" via Polycomb regulation during axial patterning in vertebrates.

developmental biology↗

bioRxiv2019

Ablation of Arf-expressing cells ameliorates cigarette smoke-induced lung dysfunction in mice.

Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing senescent cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing senescent cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.

physiology↗

bioRxiv2019

Timing and duration of phenological subsidies: toward a mechanistic understanding of impacts on community structure and ecosystem processes in stream food chains

Phenological resources are common across many ecological communities, and can strongly affect community dynamics. Recent field manipulation experiments in stream food chains found that seasonal timing and duration of terrestrial prey inputs affected the feeding behavior, growth, and maturation of fish predators, caused predator-mediated indirect effects on aquatic prey, and modified trophic-cascading effects on litter processing. These experiments described impacts of resource phenological changes over a few month period, and long-term impacts of continued changes in resource phenology are unknown. Here we develop a mathematical model to extrapolate long-term predictions about the effects of changes in resource phenology from the results of field manipulation experiments. The model predicts that advanced timing generally decreases aquatic prey and litter processing and prolonged duration will either increase or decrease aquatic prey and litter processing depending on the total amount and pre-disturbed timing and duration of terrestrial prey inputs. Importantly, our modeling approach clarifies the mechanisms by which stage-specific responses of life history processes in fish, such as growth, maturation, and reproduction, respond to phenological changes in terrestrial prey inputs and mediate indirect effects on aquatic prey and litter processing. Stage-specific responses of life history processes are an integral part of the mechanisms with which to predict the consequences of phenological species interactions at the community and ecosystem levels.

ecology↗

bioRxiv2019

The effects of resource subsidy duration on detritus-based stream ecosystems: a stream mesocosm experiment

Most of the resource subsidies are temporally variable, and studies have revealed that ecological processes can be mediated by the temporal attributes of subsidies, such as timing and frequency. Less studies have, however, examined the effects of the subsidy duration, an another major temporal attribute, on consumer populations, communities and ecosystem functions. Using an outdoor mesocosm experiment, we demonstrated that, even with the same total amounts, the prolonged subsidy let large-stage fish effectively monopolize the subsidy over small-stage fish, while the pulsed subsidy allowed small-stage fish to increase the ingestion rate of the subsidy. This effect resulted in causing weaker indirect positive effects on in-situ benthic prey and a leaf breakdown rate with the prolonged subsidy than with the pulsed-subsidy although it depended on dominant benthic prey species having different edibility. Increasing evidences have shown that global warming would not only advance, but also prolong the growing seasons, which may, in turn, make subsidies more prolonged. The ecological significance of the subsidy duration might be common in nature, and should be incorporated to better understand ecological processes in spatially and temporally coupled ecosystems.

ecology↗

bioRxiv2019

Larger, but not better, implicit motor adaptation ability inherent in medicated Parkinson’s disease patients: a smart-device-based study

Generating appropriate motor commands is an essential brain function. To achieve proper motor control in diverse situations, predicting future states of the environment and body and modifying the prediction are indispensable. The internal model is a promising hypothesis about brain function for generating and modifying the prediction. Although several findings support the involvement of the cerebellum in the internal model, recent results support the influence of other related brain regions on the internal model. A representative example is the motor adaptation ability in Parkinsons disease (PD) patients. Although this ability provides some hints about how dopamine deficits affect the internal model, previous findings are inconsistent; some reported a deficit in the motor adaptation ability in PD patients, but others reported that the motor adaptation ability of PD patients is comparable to that of healthy controls. A possible factor causing this inconsistency is the difference in task settings, which yield different cognitive strategies in each study. Here, we demonstrate a larger, but not better, motor adaptation ability in PD patients than healthy controls while reducing the involvement of cognitive strategies and concentrating on implicit motor adaptation abilities. This study utilizes a smart-device-based experiment that enables motor adaptation experiments anytime and anywhere with less cognitive strategy involvement. The PD patients showed a significant response to insensible environmental changes, but the response was not necessarily suitable for adapting to the changes. Our findings support compensatory or paretic cerebellar functions in PD patients from the perspective of motor adaptation.

neuroscience↗

bioRxiv2019

Cooperating lineage factors SOX2 and BRN2 govern the transcriptional program of the neural subtype of lung squamous cell carcinoma

Molecular characterization of lung squamous cell carcinoma (LUSC), a major subtype of lung cancer, has not sufficiently improved its non-stratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution, and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed neural subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic co-occupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the neural LUSC. Forced expression of p63 downregulated Brn2 in the neural LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted.

cancer biology↗

bioRxiv2019

Comparison of odor responses of homologous medial and lateral glomeruli mapped in the olfactory bulb of the mouse

Olfactory sensory neurons expressing same-type odorant receptors typically project to a pair of glomeruli in the medial and lateral sides of the olfactory bulbs (OBs) in rodents. However, their functional properties remain unclear, because the majority of medial glomeruli are hidden in the septal OB. Recently, trace amine-associated odorant receptors were identified that project to a pair of glomeruli uniquely located in the dorsal OB. We measured the odorant-induced calcium responses of these glomeruli simultaneously and found that they exhibited similar temporal response patterns. However, the medial glomeruli had significantly larger respiration-locked calcium fluctuations than the lateral glomeruli. This trend was observed with/without odorant stimulation in postsynaptic neurons but not in presynaptic sensory axon terminals. This indicates that the medial rather than the lateral OB map enhances the respiration-locked rhythm and transfers this information to higher brain centers.\n\nImpact StatementThis study used in vivo calcium imaging to document the odor-evoked responses in paired glomeruli, demonstrating that activation in medial glomeruli more strongly impacts respiratory-linked odor processing.

neuroscience↗

bioRxiv2019

Jomon genome sheds light on East Asian population history

Anatomical modern humans reached East Asia by >40,000 years ago (kya). However, key questions still remain elusive with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of East Eurasia may shed light on the detail picture of peopling to East Eurasia. Here, we analyze the whole-genome sequence of a 2.5 kya individual (IK002) characterized with a typical Jomon culture that started in the Japanese archipelago >16 kya. The phylogenetic analyses support multiple waves of migration, with IK002 forming a lineage basal to the rest of the ancient/present-day East Eurasians examined, likely to represent some of the earliest-wave migrants who went north toward East Asia from Southeast Asia. Furthermore, IK002 has the extra genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration from Southeast Asia to the Japanese archipelago. This study highlight the power of ancient genomics with the isolated population to provide new insights into complex history in East Eurasia.

genomics↗

bioRxiv2019

Exploring deep-time relationships between cultural and genetic evolution in Northeast Asia

Culture evolves in ways that are analogous to, but distinct from, genomes. Previous studies examined similarities between cultural variation and genetic variation (population history) at small scales within language families, but few studies empirically investigated such parallels across language families using diverse cultural data. We report an analysis comparing culture and genomes from in and around Northeast Asia spanning 11 language families. We extract and summarize the variation in language (grammar, phonology, lexicon), music (song structure, performance style), and genomes (genome-wide SNPs) and test for correlations. We find that grammatical structure correlates with population history. Recent contact and shared descent fail to explain the signal, suggesting relationships that arose before the formation of current families. Our results suggest that grammar might be a cultural indicator of population history, while also demonstrating differences among cultural and genetic relationships that highlight the complex nature of human history.

evolutionary biology↗

bioRxiv2018

Anti-tumor effects of antimicrobial peptides, targets of the innate immune system, against hematopoietic tumors in Drosophila mxc mutants

The innate immune response is the first line of defense against microbial infections. In Drosophila, three immune pathways induce the synthesis of antimicrobial peptides (AMPs) in the fat body. Recently, it has been reported that certain cationic AMPs exhibit selective cytotoxicity against human cancer cells. However, little is known about their anti-tumor effects. Drosophila mxcmbn1 mutants exhibit malignant hyperplasia in a larval hematopoietic organ called the lymph gland (LG). Here, using RNA-Seq analysis, we found that many immunoresponsive genes, including AMP genes, were up-regulated in the mutants. Down-regulation of these pathways by either a Toll or an imd mutation enhanced the tumor phenotype of the mxc mutants. Conversely, ectopic expression of each of five different AMPs in the fat body significantly suppressed the LG hyperplasia phenotype in the mutants. Thus, we propose that the Drosophila innate immune system can suppress progression of hematopoietic tumors by inducing AMP gene expression. Overexpression of any one of these five AMPs resulted in enhanced apoptosis in the mutant LGs, while no apoptosis signals were detected in controls. We observed that two AMPs, Drosomycin and Defensin, were taken up by circulating hemocyte-like cells, which were associated with LG regions showing reduced cell-to-cell adhesion in the mutants; another AMP, diptericin, was directly localized on the tumors without intermediating hemocytes. These results lead us to conclude that the AMPs have a specific cytotoxic effect that enhance apoptosis exclusively in the tumor cells.\n\nSummary statementAntimicrobial peptides can be associated with tumor cells generated in a hematopoietic tissue in Drosophila mxc mutants and have an anti-tumor effect in suppressing their growth.

developmental biology↗

bioRxiv2018

A transgenic mutant mouse line accompanied by the complete deletion of interleukin-33 showed insulin and leptin resistances

Interleukin (IL) -33 has been identified as a member of the IL-1 family. Members of the IL-1 family have been reported to be involved in the regulation of energy homeostasis and glucose metabolism. Homozygous transgenic mutant mice of FLP14 line, that we previously generated, unexpectedly developed mature-onset obesity and diabetes. Through genetic investigations, we found that insertion of the transgenes had resulted in complete deletion of the Il33 gene. These obese male homozygous mutant mice exhibited hyperphagia with hyperleptinemia and insulin resistance caused by increased hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. As a result of examining preobese male homozygous mutant mice to investigate with the exclusion of the effect of obesity, hyperphagia with hyperleptinemina and insulin resistance caused by decreased glucose uptake in skeletal muscle were already observed, but the increased hepatic glucose production was not. To investigate whether the insulin resistance was caused by deletion of the Il33 gene, we treated these preobese homozygous mutant mice with recombinant IL-33 protein and noted a significant improvement in insulin resistance. Thus, insulin resistance in these homozygous mutant mice was caused, at least in part, by IL-33 deficiency, suggesting a favorable role of IL-33 for glucose metabolism in the skeletal muscle.

molecular biology↗