Search bioRxiv⌕ Search

Biology subjects

Yoshida, Y.

Publications and source records attributed to Yoshida, Y..

35 records · Page 2Linked to original sources

A Sodium-dependent Trehalose Transporter Contributes to Anhydrobiosis in Insect Cell Line, Pv11

Pv11 is the only animal cell culture that, when preconditioned with a high concentration of trehalose, can be preserved in the dry state at room temperature for more than one year while retaining the ability to resume proliferation. This extreme desiccation tolerance is referred to as anhydrobiosis. Here we identified a novel transporter that contributes to the recovery of Pv11 cells from anhydrobiosis. In general, the SLC5 family of secondary active transporters co-transport Na+ and carbohydrates including glucose. Here we identified a novel transporter STRT1 (sodium-ion trehalose transporter 1) belonging to the SLC5 family that is highly expressed in Pv11 cells and transports trehalose with Na+ dependency. This is the first report of an SLC5 family member that transports a naturally occurring disaccharide, such as trehalose. Knockout of the Strt1 gene significantly reduced the viability of Pv11 cells upon rehydration after desiccation. During rehydration, when intracellular trehalose is no longer needed, Strt1-knockout cells released the disaccharide more slowly than the parent cell line. During rehydration, Pv11 cells became roughly spherical due to osmotic pressure changes, but then returned to their original spindle shape after about 30 min. Strt1-knockout cells, however, required about 50 min to adopt their normal morphology. STRT1 probably regulates intracellular osmolality by releasing unwanted intracellular trehalose with Na+, thereby facilitating the recovery of normal cell morphology during rehydration. STRT1 likely improves the viability of dried Pv11 cells by rapidly alleviating the significant physical stresses that arise during rehydration. Significance StatementThis is the first report of an SLC5 family member, STRT1 (sodium ion trehalose transporter 1), with Na+-dependent trehalose transport activity. A Strt1-knockout cell line revealed that STRT1 likely plays an important role during anhydrobiosis in Pv11 cells: it efficiently discharges unwanted trehalose in the presence of Na+ during rehydration of dried Pv11 cells, effectively reducing intracellular osmolality and thereby restoring cell morphology to a normal state.

biochemistry↗

SLC26A2-mediated sulfate metabolism is essential for the tooth development

The sulfate transporter gene SLC26A2 is responsible for diastrophic dysplasia, which represents skeletal dysplasia in humans. This highlights the importance of sulfate metabolism in skeletal formation. SLC26A2-related chondrodysplasia is also known to exhibit abnormalities in craniofacial and tooth development. Although the function of SLC26A2 in mammals has been investigated using genetic mouse models, the essential role of SLC26A2 during craniofacial and tooth development has not been elucidated. In this study, we demonstrate the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. Analysis of Slc26a2 expression reveals that it is predominantly expressed in dental tissues, including odontoblasts and ameloblasts, during tooth development. Slc26a2 knockout mice (Slc26a2-KO-{Delta}exon2) exhibit a retrognathic upper jaw, small upper incisors, and hypoplasia of upper molars. Additionally, upper incisors and molars in Slc26a2-KO-{Delta}exon2 mice display flattened odontoblasts and nuclei that lack intracellular polarity. In contrast, tooth phenotype is not remarkable in lower incisors and molars. Furthermore, the expression of odontoblast differentiation markers, Dspp and Dmp1, is significantly decreased in the upper molars of Slc26a2-deficient mice. Ex vivo organ culture of tooth germs by implantation of Slc26a2-deficient tooth germs under the kidney capsule reveals hypoplasia of the dentin matrix as well as tooth root shortening. In vitro studies using human dental pulp stem cells (hDPSCs) show that the expression levels of Dspp and Dmp1 in shSlc26a2 knockdown cells are significantly decreased compared to control cells. Collectively, our data demonstrate that SLC26A2-mediated sulfate metabolism is essential for tooth development. This study may provide insight into the mechanisms underlying tooth abnormalities in patients with recessively inherited chondrodysplasias caused by mutations in the SLC26A2 gene.

developmental biology↗

Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for SARS-CoV-2 3CL Protease

The pandemic of coronavirus disease 2019 (COVID-19) has urgently necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report the new class of covalent inhibitors for 3CLpro possessing chlorofluoroacetamide (CFA) as a cysteine reactive warhead. Based on the aza-peptide scaffold, we synthesized the series of CFA derivatives in enantiopure form and evaluated their biochemical efficiencies. The data revealed that 8a (YH-6) with R configuration at the CFA unit strongly blocks the SARS-CoV-2 replication in the infected cells and this potency is comparable to that of nirmatrelvir. The X-ray structural analysis shows that 8a (YH-6) forms a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong antiviral activity and sufficient pharmacokinetics property of 8a (YH-6) suggest its potential as a lead compound for treatment of COVID-19.

biochemistry↗

A novel hamster model of SARS-CoV-2 respiratory infection using a pseudotyped virus

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a biosafety level (BSL)-3 pathogen; therefore, its research environment is strictly limited. Pseudotyped viruses that mimic SARS-CoV-2 have been widely used for in vitro evaluation because they are available in BSL-2 containment laboratories; however, in vivo application is inadequate. Therefore, animal models that can be instigated with animal BSL-2 will increase opportunities for in vivo evaluations. MethodsHamsters (6-to 10-week-old males) were intratracheally inoculated with luciferase-expressing vesicular stomatitis virus (VSV)-based SARS-CoV-2 pseudotyped virus. The lungs were harvested 24 h after inoculation, and luminescence was measured using an in vivo imaging system. ResultsLung luminescence after inoculation with the SARS-CoV-2 pseudotyped virus increased in a dose-dependent manner. VSV-G (envelope [G]) pseudotyped virus also induced luminescence; however, a 100-fold concentration was required to reach a level similar to that of the SARS-CoV-2 pseudotyped virus. ConclusionsThe SARS-CoV-2 pseudotyped virus is applicable to SARS-CoV-2 respiratory infections in a hamster model. Because of the single-round infectious virus, the model can be used to study the steps from viral binding to entry, which will be useful for future research regarding SARS-CoV-2 entry without using live SARS-CoV-2 or transgenic animals.

microbiology↗

Darwin's bark spider shares a spidroin repertoire with Caerostris extrusa but achieves extraordinary silk toughness through gene expression

Spider silk is a protein-based material whose toughness suggests possible novel applications. A particularly fascinating example of silk toughness is provided by Darwins bark spider (Caerostris darwini) found in Madagascar. This spider produces extraordinarily tough silk, with an average toughness of 350 MJ/m and over 50% extensibility, and can build river-bridging webs with a size of 2.8 m2. Recent studies have suggested that specific spidroins expressed in C. darwini are responsible for the mechanical properties of its silk. Therefore, a more comprehensive investigation of spidroin sequences, silk thread protein contents, and phylogenetic conservation among closely related species is required. Here, we conducted genomic, transcriptomic, and proteomic analyses of C. darwini and its close relative Caerostris extrusa. A variety of spidroins and low-molecular-weight proteins were found in the dragline silk of these species; all of the genes encoding these proteins were conserved in both genomes, but their genes were more expressed in C. darwini. The potential to produce very tough silk is common in the genus Caerostris, and our results may suggest the existence of plasticity allowing silk mechanical properties to be changed by optimizing related gene expression in response to the environment.

molecular biology↗

CZON-cutter: a CRISPR-Cas9 system with multiplexed organelle imaging in a simple unicellular alga

The simple cellular structure of the unicellular alga Cyanidioschyzon merolae consists of one nucleus, one mitochondrion, one chloroplast, and one peroxisome per cell and offers unique advantages to investigate mechanisms of organellar proliferation and the cell cycle. Here, we describe an engineered clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system, CZON-cutter, for simultaneous genome editing and organellar visualization. We engineered a C. merolae strain expressing a nuclear-localized Cas9-Venus nuclease to target editing at a locus defined by a single-guide RNA (sgRNA). We then successfully edited the algal genome and visualized the mitochondrion and peroxisome in transformants by fluorescent protein reporters with different excitation wavelengths. Fluorescent protein labeling of organelles in living transformants allows validation of phenotypes associated with organellar proliferation and the cell cycle, even when the edited gene is essential. Combined with the exceptional biological features of C. merolae, CZON-cutter will be instrumental for investigating cellular and organellar division in a high-throughput manner. SummaryAn engineered CRISPR-Cas9 system, named CZON-cutter, for simultaneous genome editing and fluorescent protein labeling of organelles in Cyanidioschyzon merolae can be used to validate intracellular function of a particular gene, even if it is essential.

molecular biology↗

Multicomponent nature underlies the extraordinary mechanical properties of spider dragline silk

Dragline silk of golden orb-weaver spiders (Nephilinae) is noted for its unsurpassed toughness, combining extraordinary extensibility and tensile strength, suggesting industrial application as a sustainable biopolymer material. To pinpoint the molecular composition of dragline silk and the roles of its constituents in achieving its mechanical properties, we report a multiomics approach combining high-quality genome sequencing and assembly, silk gland transcriptomics, and dragline silk proteomics of four Nephilinae spiders. We observed the consistent presence of the MaSp3B spidroin unique to this subfamily, as well as several non-spidroin SpiCE proteins. Artificial synthesis and combination of these components in vitro showed that the multicomponent nature of dragline silk, including MaSp3B and SpiCE, along with MaSp1 and MaSp2, is essential to realize the mechanical properties of spider dragline silk.

molecular biology↗

The dynamics of cell-free DNA from urine and blood after a full marathon

PurposeCell-free DNA (cfDNA) has been investigated as a minimally invasive biomarker for many diseases, particularly cancer. An increase in cfDNA has been observed during exercise. Neutrophil extracellular traps (NETs) may be the origin of cfDNA in response to acute exercise, but the mechanisms of generation of cfDNA during exercise remain unclear. In this study we investigated the dynamics of serum and urinary cfDNA levels and determined the relevance of other biomarkers to serum and urinary cfDNA levels and fragment size after a full marathon. MethodsSamples were collected from 23 healthy male subjects. Blood and urine samples were collected before and immediately, two hours, and one day after the full marathon. The measurements included serum and urinary cfDNA, creatine kinase, myoglobin, creatinine, white blood cells, platelets, and lactoferrin from blood, and amylase, albumin, and creatinine from urine. ResultsSerum and urinary cfDNA levels increased after a full marathon. Creatine kinase, myoglobin, and creatinine in blood, and albumin and creatinine in urine also increased significantly after a full marathon. Serum cfDNA showed peak values about 180 bp after the full marathon. Values over 1000 bp were present at two hours post-marathon. Urinary cfDNA showed peak values from 35 bp to 50 bp after the full marathon. Values over 1000 bp appeared at Immediately and two hours post marathon. ConclusionThis study revealed that both serum and urinary cfDNA levels transiently increased after a full marathon. In addition, these cfDNA fragment varied in size.

physiology↗

Molecular effects of mannanase-hydrolyzed coprameal to intestinal immunity in the Pacific white shrimp (Litopenaeus vannamei )

To mitigate disease outbreak, an alternative approach through enhancing shrimp immunity was explored. Mannan oligosaccharides (MOS) have been previously reported to enhance shrimp immune system. Here, coprameal samples were digested with mannanase to yield MOS, namely, mannanase-hydrolyzed coprameal (MCM) and feasibility of MCM as shrimp immunostimulant in grow-out ponds was determined. Pacific white shrimp (Litopenaeus vannamei) were fed with the commercial diet containing 1% MCM as the MCM-supplemented group and compared to the non-MCM control diet. There was no significant difference in survival rates between the MCM-supplemented and the control groups throughout the 4-month-period of the trial (p > 0.05). Gene expression analysis in shrimp intestines revealed that the transcript levels of antimicrobial peptides (anti-lipopolysaccharide factor isoform 1 (alf1), penaeidin (pen3a) and crustin (crus)) and lysozymes (lyz) were not significantly different in the MCM-supplemented group. Meanwhile, C-type lectin and toll-like receptor transcript levels, whose gene products play roles as pattern recognition proteins, were significantly higher in a group fed with MCM for 2- and 4-month periods than those of the control group (p < 0.05). The increased transcript levels of C-type lectin and toll-like receptor provide evidence for potential implementation of MCM as feed supplement to modulate shrimp immune system.

molecular biology↗

Ion mechanism and parameter analysis of anodal-first waveforms for selective stimulation of C-fiber nerves

Few investigations have been conducted on selective stimulation of small-radius unmyelinated C nerves (C), which is critical to both recoveries of damaged nerves and pain suppressions. The purpose of this study is to understand how an anodal pulse in an anodal-first stimulation could improve C-selectivity over myelinated nociceptive A{delta} nerves (A{delta}), and further clarify the landscape of the solution space. The Hodgkin-Huxley (HH) model and the Mclntyre-Richardson-Grill (MRG) model were used for modelling C and A{delta}, respectively to analyze the underlying ion dynamics and the influence of relevant stimulation waveforms, including monopolar, polarity-symmetric, and asymmetric pulses. Results showed that polarity-asymmetric waveforms with preceding anodal stimulations benefit C-selectivity most, underlain by the decrease of the potassium ion current of C. The optimal parameters for C-selectivity have been identified in the low frequency band, which will benefit remarkably the designs of nociceptive nerve selective stimulation.

neuroscience↗

Comparative analysis of antigen-specific anti-SARS-CoV-2 antibody isotypes in COVID-19 patients

Serological tests for detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in blood are expected to identify individuals who have acquired immunity against SARS-CoV-2 and indication of seroprevalence of SARS-CoV-2 infection. Many serological tests have been developed to detect antibodies against SARS-CoV-2. However, these tests have considerable variations in their specificity and sensitivity, and whether they can predict levels of neutralizing activity is yet to be determined. This study aimed to investigate the kinetics and neutralizing activity of various antigen-specific antibody isotypes against SARS-CoV-2 in serum of coronavirus disease 2019 (COVID-19) patients confirmed via polymerase chain reaction test. We developed IgG, IgM and IgA measurement assays for each antigen, including receptor-binding domain (RBD) of spike (S) protein, S1 domain, full length S protein, S trimer and nucleocapsid (N) domain, based on enzyme-linked immunosorbent assay. The assays of the S protein for all isotypes showed high specificity, while the assays for all isotypes against N protein showed lower specificity. The sensitivity of all antigen-specific antibody isotypes depended on the timing of the serum collection and all of them, except for IgM against N protein, reached more than 90% at 15-21 days post-symptom onset. The best correlation with virus neutralizing activity was found for IgG against RBD (RBD-IgG), and levels of RBD-IgG in sera from four severe COVID-19 patients increased concordantly with neutralizing activity. Our results provide valuable information regarding the selection of serological test for seroprevalence and vaccine evaluation studies.

immunology↗

A novel Mn-dependent peroxidase contributes to tardigrade anhydrobiosis

Tardigrades are microscopic animals that are capable of tolerating extreme environments by entering a desiccated ametabolic state known as anhydrobiosis. While antioxidative stress genes, antiapoptotic pathways and tardigrade-specific intrinsically disordered proteins have been implicated in the anhydrobiotic machinery, conservation of these mechanisms is not universal within the phylum Tardigrada, suggesting the existence of overlooked components. Here, we show that a novel Mn-dependent peroxidase is an important factor in tardigrade anhydrobiosis. Through comparative time-series transcriptome analysis of Ramazzottius varieornatus specimens exposed to desiccation or ultraviolet light, we first identified several novel gene families without similarity to existing sequences that are induced rapidly after stress exposure. Among these, a single gene family with multiple orthologs that is highly conserved within the phylum Tardigrada and enhances oxidative stress tolerance when expressed in human cells was identified. Crystallographic study of this protein suggested Zn or Mn binding at the active site, and we further confirmed that this protein has Mn-dependent peroxidase activity in vitro. Our results demonstrated novel mechanisms for coping with oxidative stress that may be a fundamental mechanism of anhydrobiosis in tardigrades. Furthermore, localization of these sets of proteins in the Golgi apparatus suggests an indispensable role of the Golgi stress response in desiccation tolerance.

molecular biology↗

Synergistic anticancer effect of plasma-activated infusion and salinomycin by targeting autophagy and mitochondrial morphology

Non-thermal atmospheric plasma (NTAP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines showed much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anti-cancer stem cell agent, mutually operated as adjuvants. Combined administration of PAI and Sal was much more effective than single agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 in a rapid and transient manner. PAI also suppressed the ambient autophagic flux by activating the mammalian target of rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.

cancer biology↗

Cas9-mediated Genome Editing Reveals a Significant Contribution of Calcium Signaling Pathways to Anhydrobiosis in Pv11

Pv11 is an insect cell line established from the midge Polypedilum vanderplanki that exhibits an extreme desiccation tolerance known as anhydrobiosis. Pv11 has also an anhydrobiotic ability which is induced by trehalose treatment. Here we report the successful construction of the genome editing system for Pv11 cells and its application for identifying the signaling pathways in the anhydrobiosis. Using the Cas9-mediated gene knock-in system, we established GCaMP3-stably expressing Pv11 cells to monitor intracellular Ca2+ mobilization. Intriguingly, trehalose treatment evoked a transient increase of cytosolic Ca2+ concentration, and further experiments indicated the contribution of the calmodulin - calcineurin - NFAT pathway to the tolerance for trehalose treatment as well as the desiccation tolerance, while the calmodulin - calmodulin Kinase - CREB pathway conferred only the desiccation tolerance on Pv11 cells. Thus, our results show the critical contribution of the trehalose-induced Ca2+ surge to the anhydrobiosis and the temporal different roles of each signaling pathway.

molecular biology↗

Evaluation of SARS-CoV-2 neutralizing antibodies using a vesicular stomatitis virus possessing SARS-CoV-2 spike protein

SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is now classified in the genus Coronavirus with closely related SARS-CoV. SARS-CoV-2 is highly pathogenic in humans and is classified as a biosafety level (BSL)-3 pathogen, which makes manipulating it relatively difficult due to its infectious nature. To circumvent the need for BSL-3 laboratories, an alternative assay was developed that avoids live virus and instead uses a recombinant VSV expressing luciferase and possesses the full length or truncated spike proteins of SARS-CoV-2. Furthermore, to measure SARS-CoV-2 neutralizing antibodies under BSL2 conditions, a chemiluminescence reduction neutralization test (CRNT) for SARS-CoV-2 was developed. The neutralization values of the serum samples collected from hospitalized patients with COVID-19 or SARS-CoV-2 PCR-negative donors against the pseudotyped virus infection evaluated by the CRNT were compared with antibody titers determined from an immunofluorescence assay (IFA). The CRNT, which used whole blood collected from hospitalized patients with COVID-19, was also examined. As a result, the inhibition of pseudotyped virus infection was specifically observed in both serum and whole blood and was also correlated with the results of the IFA. In conclusion, the CRNT for COVID-19 is a convenient assay system that can be performed in a BSL-2 laboratory with high specificity and sensitivity for evaluating the occurrence of neutralizing antibodies against SARS-CoV-2.

microbiology↗

Autologous adipose-derived stem cell transplantation enhances healing of wound with exposed bone in a rat model

ObjectivesSoft tissue wounds with exposed bone often require extended healing times and can be associated with severe complications. We describe the ability of artificial dermis with autogenic adipose-derived stem cells (ADSCs) to promote the healing of wounds with exposed bone in a rat model.\n\nMethodsAdipose tissues harvested from the bilateral inguinal regions of Wistar rats were used as ADSCs. Rats were randomly divided into control and ADSC groups to investigate the efficacy of ADSC transplantation for wound healing (n=20 per group). Soft tissue defects were created on the heads of the rats and were covered with artificial dermis with or without the seeded ADSCs. Specimens from these rats were evaluated using digital image analysis, histology, immunohistochemistry, cell labeling, and real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR).\n\nResultsThe average global wound area was significantly smaller in the ADSC group than in the control group on days 3, 7, and 14 after surgery (p<0.05). After 14 days, the blood vessel density in the wound increased by 1.6-fold in the ADSC group compared with that in the control group (p<0.01). Real-time RT-PCR results showed higher Fgfb and Vegf expression levels at all time points, and higher Tgfb1 and Tgfb3 expression levels until 14 days after surgery, in the ADSC group than in the control group (p<0.05).\n\nConclusionsIn wounds with exposed bone, autogenic ADSCs can promote vascularization and wound healing. Use of this cell source has multiple benefits, including convenient clinical application and lack of ethical concerns.

animal behavior and cognition↗

Comparative genomics of the tardigrades Hypsibius dujardini and Ramazzottius varieornatus

Tardigrada, a phylum of meiofaunal organisms, have been at the center of discussions of the evolution of Metazoa, the biology of survival in extreme environments, and the role of horizontal gene transfer in animal evolution. Tardigrada are placed as sisters to Arthropoda and Onychophora (velvet worms) in the superphylum Ecdysozoa by morphological analyses, but many molecular phylogenies fail to recover this relationship. This tension between molecular and morphological understanding may be very revealing of the mode and patterns of evolution of major groups. Similar to bdelloid rotifers, nematodes and other animals of the water film, limno-terrestrial tardigrades display extreme cryptobiotic abilities, including anhydrobiosis and cryobiosis. These extremophile behaviors challenge understanding of normal, aqueous physiology: how does a multicellular organism avoid lethal cellular collapse in the absence of liquid water? Meiofaunal species have been reported to have elevated levels of HGT events, but how important this is in evolution, and in particular in the evolution of extremophile physiology, is unclear. To address these questions, we resequenced and reassembled the genome of Hypsibius dujardini, a limno-terrestrial tardigrade that can undergo anhydrobiosis only after extensive pre-exposure to drying conditions, and compared it to the genome of Ramazzottius varieornatus, a related species with tolerance to rapid desiccation. The two species had contrasting gene expression responses to anhydrobiosis, with major transcriptional change in H. dujardini but limited regulation in R. varieornatus. We identified few horizontally transferred genes, but some of these were shown to be involved in entry into anhydrobiosis. Whole-genome molecular phylogenies supported a Tardigrada+Nematoda relationship over Tardigrada+Arthropoda, but rare genomic changes tended to support Tardigrada+Arthropoda.

genomics↗