Biology subjects

Yoshikawa, T.

Publications and source records attributed to Yoshikawa, T..

18 recordsLinked to original sources

bioRxiv2026

The juvenile-to-adult phase transition in wheat is independent of the winter-spring growth habit regulated by VRN1

In plants, the juvenile-to-adult (JA) phase transition occurs during the vegetative stage with drastic morphological and physiological changes. Common wheat (Triticum aestivum L.) has a molecular mechanism regulating the duration of vegetative growth in response to cold accumulation, and its sensitivity varies among varieties (winter-spring growth habit) predominantly due to VRN1 genotypes. However, the association of the growth habit with the JA phase transition remained unclear. Here, we investigated temporal changes in shoot apex and leaf morphology, and in the expression of the JA phase transition regulators miR156 and miR172, in winter and spring varieties and VRN1 near-isogenic lines (NILs) under controlled growth conditions, and leaf morphology under field growth conditions. Under controlled conditions, the results indicated that the timing of JA phase transition completion varied among spring varieties without association with VRN1 genotypes. All NILs underwent the JA phase transition at the same timing, and the expression levels of miR156 and miR172 were unrelated to VRN1 expressions during the vegetative stage. The field evaluation of leaf morphology revealed that the phase transition timing was consistent regardless of the sowing timings. These results suggested that the JA phase transition regulatory pathway and the vernalization regulator VRN1 are independent in wheat. HighlightThis study shows that the timing of the juvenile-to-adult phase transition in wheat is not affected by the expression of VRN1, the master regulator of vernalization.

plant biology↗

bioRxiv2025

Evolutionary and structural basis of SLAM utilization in morbilliviruses - Its implications for host range and cross-species transmission

Morbilliviruses, including measles virus (MV), canine distemper virus (CDV), and cetacean morbillivirus, pose a significant threat to humans and animals. While the host range of morbilliviruses is generally well-defined, severe cross-species transmission events also have been reported. Their entry into immune cells, the primary targets of morbilliviruses, relies on the signaling lymphocytic activation molecule (SLAM), a receptor whose species-specific variations influence viral host range. However, the extent to which SLAM diversity is a barrier to cross-species transmission remains poorly understood. In this study, we systematically investigated SLAM-mediated host specificity. We found that most morbilliviruses efficiently utilize SLAM from multiple host species, except for human SLAM. Among the morbilliviruses tested, only MV efficiently utilized human SLAM. Bats are natural reservoirs for many zoonotic viruses. Recent discoveries of novel morbilliviruses in bats provide new insights into morbillivirus evolution. Bats may have played a significant role in morbillivirus evolution because bat (Myotis) SLAM also functioned as an efficient receptor for multiple morbilliviruses. Unlike other morbilliviruses, MV utilized Myotis bat SLAM inefficiently. We conducted an MV adaptation experiment with Myotis bat SLAM to better understand SLAM recognition by morbilliviruses. MV readily adapted to utilize Myotis bat SLAM by acquiring a single N187Y mutation in its hemagglutinin protein, and computational structural modeling and fragment molecular orbital calculations with molecular dynamics simulations revealed key interaction changes that facilitated MVs adaptation to Myotis bat SLAM. These findings highlight the adaptability of morbilliviruses in utilizing diverse animal SLAMs. Notably, hypothetical ancestral SLAMs reconstructed in this study acted as universal receptors for all morbilliviruses. These results reinforced that morbillivirus receptor usage is primarily supported by evolutionarily conserved structural features of SLAM, highlighting a molecular basis that enables morbilliviruses to rapidly adapt to diverse animal SLAMs. Author SummaryOur study explores how viruses in the genus morbillivirus, such as measles virus, canine distemper virus, and rinderpest virus, which are notorious for deadly outbreaks in humans and animals, can jump between species. The host range of morbilliviruses is significantly influenced by a receptor molecule on cell surfaces known as the signaling lymphocytic activating molecule (SLAM). By examining SLAMs from various animals, including humans, dolphins, dogs, seals, and bats, we observed how these viruses can infect or adapt to infect different hosts. We found that in some cases slight differences in SLAM may act as initial barriers to cross-species transmission. However, these viruses rapidly overcome such barriers, showing a remarkable ability to adapt. Our research highlights the importance of monitoring these viruses to predict and prevent potential cross-species infections, which is crucial for protecting public health and animal welfare over time.

microbiology↗

bioRxiv2024

Structural, genetic, and adaptive basis of superhydrophobicity in rice leaves

In most plants, leaf surfaces exhibit water-repellent properties, which protect against pathogens and weather. Plants such as lotus and rice have evolved outstanding water-repellent properties, so-called superhydrophobicity. However, the structural and genetic basis of these properties in crop plants remains unclear. In this study, we identified the genes and microstructures responsible for superhydrophobicity by analyzing water repellence in rice mutants and cultivars, as well as wild Oryza species. Analysis of the surface structure of mutant leaves revealed that the degree of water repellency in rice largely depends on the accumulation of cuticular wax. Meanwhile, although papillae differentiation contributes minorly to water repellency, it is suggested to play a crucial role in achieving superhydrophobicity. These morphological characteristics are regulated by at least five previously characterized genes. We also found that superhydrophobicity is present in ancestral species, is retained by most cultivated rice, and appears to have evolved independently of rice domestication. Understanding the mechanisms of water repellence and their applications should provide important insight into the natural design of water repellence, as well as a basis for future innovation.

plant biology↗

bioRxiv2024

Identification of novel candidate genes associated symbiotic compatibility of soybean with rhizobia under natural conditions

A robust symbiotic relationship between soybean and rhizobia can enhance the yield and quality of soybeans by reducing nitrogen fertilizer inputs, thereby contributing to sustainable agriculture. The genetic interplay between soybean cultivars and the rhizobial species colonizing their roots under natural conditions remains underexplored. This study builds on the observation that the prevalence of rhizobial species associated with the soybean cultivars Peking and Tamahomare varies significantly. Herein, we performed a quantitative trait loci (QTL) analysis of the proportion of Rhizobium species present in the root nodules of these cultivars using recombinant inbred lines derived from a cross between Peking and Tamahomare. A major QTL was identified on chromosome 18, accounting for 42% of the phenotypic variation, and was subsequently localized to a 240 kb region. The RNA-seq analysis indicated that a single gene featuring nucleotide binding site-leucine-rich repeat domains exhibited markedly different expression levels in parent cultivars within the QTL region. As this locus is distinct from the chromosomal regions containing known nodule-related genes, such as Rj or rj, it likely represents a novel gene involved in symbiosis between rhizobia and soybeans. Further research of the function and role of this new gene has potential to improve soybean yield and contribute to sustainable agriculture under low nitrogen fertilizer conditions.

plant biology↗

bioRxiv2022

Identification of inosine monophosphate dehydrogenase as a potential target for anti-monkeypox virus agents

Monkeypox virus (MPXV) is a neglected zoonotic pathogen that caused a worldwide outbreak in May 2022. Given the lack of an established therapy, the development of an anti-MPXV strategy is of vital importance. To identify drug targets for the development of anti-MPXV agents, we screened a chemical library using an MPXV infection cell assay and found that gemcitabine, trifluridine, and mycophenolic acid (MPA) inhibited MPXV propagation. These compounds showed broad-spectrum anti-orthopoxvirus activities and presented lower 90% inhibitory concentrations (0.032-1.40 M) than brincidofovir, an approved anti-smallpox agent. These three compounds have been suggested to target the post-entry step to reduce the intracellular production of virions. Knockdown of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of guanosine biosynthesis and a target of MPA, dramatically reduced MPXV DNA production. Moreover, supplementation with guanosine recovered the anti-MPXV effect of MPA, suggesting that IMPDH and its guanosine biosynthetic pathway regulate MPXV replication. By targeting IMPDH, we identified a series of compounds with stronger anti-MPXV activity than MPA. These evidences propose that IMPDH is a potential target for the development of anti-MPXV agents. ImportanceMonkeypox is a zoonotic disease caused by infection with the monkeypox virus, and a worldwide outbreak occurred in May 2022. The smallpox vaccine has recently been approved for clinical use against monkeypox in the United States. Although brincidofovir and tecovirimat are drugs approved for the treatment of smallpox by the U.S. Food and Drug Administration, their efficacy against monkeypox has not been established. Moreover, these drugs may present negative side effects. Therefore, new anti-monkeypox virus agents are needed. This study revealed that gemcitabine, trifluridine, and mycophenolic acid inhibited monkeypox virus propagation, exhibited broad-spectrum anti-orthopoxvirus activities. We also suggested inosine monophosphate dehydrogenase as a potential target for the development of anti-monkeypox virus agents. By targeting this molecule, we identified a series of compounds with stronger anti-monkeypox virus activity than mycophenolic acid.

microbiology↗

bioRxiv2022

Potential anti-monkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments

Monkeypox virus (MPXV) is a zoonotic orthopoxvirus that causes smallpox-like symptoms in humans and caused an outbreak in May 2022 that led the WHO to declare global health emergency. In this study, from a screening of approved-drug libraries using an MPXV infection cell system, atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 M, which is more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted post-entry process to impair intracellular virion accumulation. Inhibitors of dihydroorotate dehydrogenase, an atovaquones target enzyme, showed conserved anti-MPXV activities. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by seven days at clinically relevant drug concentrations. Moreover, atovaquone and molnupiravir exhibited pan-Orthopoxvirus activity against vaccinia and cowpox viruses. These data suggest that atovaquone would be potential candidates for treating monkeypox.

microbiology↗

bioRxiv2021

Deep learning-based chest X-ray age serves as a novel biomarker for cardiovascular aging

Chest X-ray (CXR) is one of the most commonly performed medical imaging tests. Although aging, sex and disease status have been known to cause changes in CXR findings, the extent of these effects has not been fully characterized. Here, we present a deep neural network (DNN) model trained using more than 100,000 CXRs to estimate the patients age and sex solely from CXRs. Our DNN exhibited high performance in terms of estimating age and sex, with Pearsons correlation coefficient between the actual and estimated age of above 0.9 and an area under the ROC curve of 0.98 for sex estimation. The difference between the actual and estimated age is large in CXRs with abnormal findings, suggesting that the estimated age ("CXR age") can be a biomarker for disease status. Furthermore, by applying our DNN to CXRs of consecutive 1,562 hospitalized heart failure patients, we demonstrated that an elevated CXR age is not only associated with aging-related diseases, such as hypertension and atrial fibrillation, but also a worse outcome of heart failure. Given these results, our new concept "CXR age" serves as a novel biomarker for cardiovascular aging and can help clinicians to predict, prevent, and manage cardiovascular diseases.

bioinformatics↗

bioRxiv2021

Phase Gradients and Anisotropy of the Suprachiasmatic Network

Biological neural networks operate at several levels of granularity, from the individual neuron to local neural circuits to networks of thousands of cells. The daily oscillation of the brains master clock in the suprachiasmatic nucleus (SCN) rests on a yet to be identified network of connectivity among its ~20,000 neurons. The SCN provides an accessible model to explore neural organization at several levels of organization. To relate cellular to local and global network behaviors, we explore network topology by examining SCN slices in three orientations using immunochemistry, light and confocal microscopy, real-time imaging, and mathematical modeling. Importantly, the results reveal small local groupings of neurons that form intermediate structures, here termed "phaseomes" which can be identified through stable local phase differences of varying magnitude among neighboring cells. These local differences in phase are distinct from the global phase relationship - that between individual cells and the mean oscillation of the overall SCN. The magnitude of the phaseomes local phase differences are associated with a global phase gradient observed in the SCNs rostral-caudal extent. Modeling results show that a gradient in connectivity strength can explain the observed gradient of phaseome strength, an extremely parsimonious explanation for the heterogeneous oscillatory structure of the SCN. Significance statementOscillation is a fundamental property of information sensing and encoding in the brain. Using real time imaging and modeling, we explore encoding of time by examining circadian oscillation in single neurons, small groups of neurons, and the entire nucleus, in the brains master: the suprachiasmatic nucleus (SCN). New insights into the network organization underlying circadian rhythmicity include the discovery of intermediate structures, termed phaseomes, characterized by neurons which are stably out of phase with their neighbors. Modeling indicates that the pattern of phaseomes across the tissue encompasses a gradient in connectivity strength from the rostral to caudal aspects of the nucleus. Anisotropy in network organization emerges from comparisons of phaseomes and connectivity gradients in sagittal, horizontal and coronal slices.

neuroscience↗

bioRxiv2020

Regulation of the plastochron by three MANY-NODED DWARF genes in barley

The plastochron, the time interval between the formation of two successive leaves, is an important determinant of plant architecture. We genetically and phenotypically investigated many-noded dwarf (mnd) mutants in barley. The mnd mutants exhibited a shortened plastochron and a decreased leaf blade length, and resembled previously reported plastochron1 (pla1), pla2, and pla3 mutants in rice. In addition, the maturation of mnd leaves was accelerated, similar to pla mutants in rice. Several barley mnd alleles were derived from three loci--MND1, MND4, and MND8. Although MND4 coincided with a cytochrome P450 family gene that is a homolog of rice PLA1, we clarified that MND1 and MND8 encode an N-acetyltransferase-like protein and a MATE transporter-family protein, which are respectively orthologs of rice GW6a and maize BIGE1 and unrelated to PLA2 or PLA3. Expression analyses of the three MND genes revealed that MND1 and MND4 were expressed in limited regions of the shoot apical meristem and leaf primordia, but MND8 did not exhibit a specific expression pattern around the shoot apex. In addition, the expression levels of the three genes were interdependent among the various mutant backgrounds. Genetic analyses using the double mutants mnd4mnd8 and mnd1mnd8 indicated that MND1 and MND4 regulate the plastochron independently of MND8, suggesting that the plastochron in barley is controlled by multiple genetic pathways involving MND1, MND4, and MND8. Correlation analysis between leaf number and leaf blade length indicated that both traits exhibited a strong negative association among different genetic backgrounds but not in the same genetic background. We propose that MNDs function in the regulation of the plastochron and leaf growth and revealed conserved and diverse aspects of plastochron regulation via comparative analysis of barley and rice. Author summaryThe number of leaves produced during a plants lifetime is major determinant of plant architecture and affects the efficiency of photosynthesis and crop productivity. The leaf number is dependent on the temporal pattern of leaf initiation at the shoot apical meristem, which is termed the plastochron. The genetic factors involved in plastochron regulation have been identified in several plant species. However, whether the functions of plastochron-related genes and their genetic pathways are universal or diversified among different plant species is unclear. In this study, we investigated many-noded dwarf (mnd) mutants in barley, which exhibited a shortened plastochron and a decreased leaf blade length. The mutant alleles used in this study were derived from three loci, MND4, MND1, and MND8, which encode a cytochrome P450 family protein, an N-acetyltransferase-like protein, and a MATE transporter-family protein, respectively. Phenotypic and expression analyses revealed that these three MND genes affect the leaf production rate and leaf maturation program, but their expression levels were interdependent. In addition, the plastochron and leaf growth are closely related but independently regulated. We also analyzed the expression patterns and knockout mutants of rice MND orthologs to clarify whether their biological functions are conserved in rice and barley. This study provides insight into the genetic mechanisms of plastochron control in grass species.

plant biology↗

bioRxiv2020

Role of an atypical cadherin gene, Cdh23 in prepulse inhibition and its implication in schizophrenia

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest LOD score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression-QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

genetics↗

bioRxiv2020

A highly attenuated vaccinia virus strain LC16m8-based vaccine for severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) caused by Dabie bandavirus (formerly SFTS virus [SFTSV]) is an emerging hemorrhagic infectious disease with a high case-fatality rate. One of the best strategies for preventing SFTS is to develop a vaccine, which is expected to induce both humoral and cellular immunity. We applied a highly attenuated but still immunogenic vaccinia virus strain LC16m8 (m8) as a recombinant vaccine for SFTS. Recombinant m8s expressing SFTSV nucleoprotein (m8-N), envelope glycoprotein precursor (m8-GPC), and both N and GPC (m8-N+GPC) in the infected cells were generated. Both m8-GPC- and m8-N+GPC-infected cells were confirmed to produce SFTSV-like-particles (VLP) in vitro, and the N was incorporated in the VLP produced by the infection of cells with m8-N+GPC. Specific antibodies to SFTSV were induced in mice inoculated with each of the recombinant m8s, and the mice were fully protected from lethal challenge with SFTSV at both 103 TCID50 and 105 TCID50. In mice that had been immunized with vaccinia virus strain Lister in advance of m8-based SFTSV vaccine inoculation, protective immunity against the SFTSV challenge was also conferred. The pathological analysis revealed that mice immunized with m8-GPC or m8-N+GPC did not show any histopathological changes without any viral antigen-positive cells, whereas the control mice showed focal necrosis with inflammatory infiltration with SFTSV antigen-positive cells in tissues after SFTSV challenge. The passive serum transfer experiments revealed that sera collected from mice inoculated with m8-GPC or m8-N+GPC but not with m8-N conferred protective immunity against lethal SFTSV challenge in naive mice. On the other hand, the depletion of CD8-positive cells in vivo did not abrogate the protective immunity conferred by m8-based SFTSV vaccines. Based on these results, the recombinant m8-GPC and m8-N+GPC were considered promising vaccine candidates for SFTS. Author SummarySevere fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with a high case-fatality rate (approximately 5% to >40%). Indigenous SFTS has been reported in China, Japan, South Korea, and Vietnam. Thus, the development of an effective vaccine for SFTS is urgently needed. Vaccinia virus (VAC) was previously used as a vaccine for smallpox. Unfortunately, after these strains, the so-called second generation of VAC used during the eradication campaign was associated with severe adverse events, and the third generation of VAC strains such as LC16m8 (m8) and modified vaccinia Ankara (MVA) was established. m8 is confirmed to be highly attenuated while still maintaining immunogenicity. m8 is licensed for use in healthy people in Japan. At the present time, approximately 100,000 people have undergone vaccination with m8 without experiencing any severe postvaccine complications. At present, third-generation VAC strains are attractive for a recombinant vaccine vector, especially for viral hemorrhagic infectious diseases, such as Ebola virus disease, Lassa fever, Crimean-Congo hemorrhagic fever, and SFTS. We investigated the practicality of an m8-based recombinant vaccine for SFTS as well as other promising recombinant VAC-based vaccines for viral hemorrhagic infectious diseases.

microbiology↗

bioRxiv2019

Endogenization and excision of human herpesvirus 6 in human genomes

The genome of human herpesvirus 6 (HHV-6) is integrated within the nuclear genome of about 1% of humans, but how this came about is not clear. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). piRNAs block integration of transposons in the germline, so piRNA-mediated repression of HHV-6 integration has been suspected. Whether integrated HHV-6 can reactive into an infectious virus is also uncertain. In vitro, recombination of the viral genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected single DR "scar" has not been described in vivo. We analyzed whole-genome sequencing (WGS) data from 13,040 subjects, including 7,485 from Japan. We found an association between integrated HHV-6 and polymorphisms on chr22q in Japanese subjects. However, association with the reported MOV10L1 polymorphism was driven by physical linkage to a single ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. We resolved the junction of the human chromosome with this viral genome using long read sequencing. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a single DR, supporting in vivo excision and viral reactivation. Using WGS data from North American families, we show that the incidence of HHV-6 integration into the germline is lower than its prevalence, and that integrated HHV-6 is not associated with the reported variant in MOV10L1. Together these results explain the recently reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact non-retroviral genome known to be present in human germlines. SIGNIFICANCE STATEMENT Human herpesvirus 6 (HHV-6) infects most people during childhood, usually only causing fever and rash. Reactivation of HHV-6 has been linked to a number of neurological diseases including encephalitis, Alzheimers disease and multiple sclerosis. However, about 1% of people are born with the HHV-6 genome present within their genome, included in the end "cap" of one of their 46 chromosomes. Little is known about how and when HHV-6 genomes entered human genomes, whether or not they still do, and whether or not this poses risk for virus reactivation. We looked for HHV-6 in genome sequences from over 13,000 people. Most HHV-6 variants present in human genomes have been co-evolving with human chromosomes for many generations, and new integration events are rare. Surprisingly, in almost three fourths of Japanese people with HHV-6 in their genome, HHV-6 integrated in the same end of the same chromosome - 22q. Persistence of the HHV-6 genome within the short "cap" that preserves the end of chromosome 22q suggests that the integrated viral sequence may have taken on a useful function for this chromosome. We also found that some human genomes harbor only one part of the HHV-6 genome. This part is the same part that remains after experimental viral reactivation, during which most of the virus is cut out of the genome. This warrants assessment of the risk that integration of HHV-6 into inherited human genomes is not irreversible, and possibly leads to production of infectious virus.

genetics↗

bioRxiv2019

Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses.\n\nA novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further.\n\nThe IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10-22), and increased risk of future MS (OR = 2.22, p = 2x10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04.\n\nIn conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

immunology↗

bioRxiv2019

Genetic risks of schizophrenia identified in a matched case-control study

BackgroundGenetic association studies of schizophrenia may be confounded by the pathological heterogeneity and multifactorial nature of this disease. We demonstrated previously that combinations of the three functional single nucleotide polymorphisms (SNPs) rs10770141 of tyrosine hydroxylase (TH) gene, rs4680 of catechol-O-methyltransferase (COMT) gene, and rs1800497 of dopamine D2 receptor (DRD2) gene may be associated with schizophrenia onset, and we tested those associations herein. Methods: We conducted a secondary study of 2,542 individuals in age- and sex-matched case-control populations. The schizophrenia diagnosis was based on the DSM-IV. To reduce the influence of confounders (age and sex), we performed a propensity score matching analysis. Genotyping and associative analyses of rs10770141, rs4680, and rs1800497 with schizophrenia were performed. Results: We analyzed 1,271 schizophrenics (male/female: 574/698; age 47.4{+/-}13.9 years) and 1,271 matched controls (male/female: 603/669; age 46.5{+/-}13.4 years). The estimated odds ratios (ORs) were 1.245 (p<0.001) for rs4680, 1.727 (p<0.0001) for rs1800497, and 1.788 (p<0.0001) for rs10770141. Double SNP analyses revealed the ORs of 2.010 (p<0.0001) for the combination of rs4680*rs1800497, 1.871 (p<0.001) for rs1800497*rs10770141, and 1.428 (p=0.068) for rs4680*rs1800497. Among the individuals with any of the three double SNP risk combinations (which accounted for 35.8% of the involved patients), the estimated OR was 2.224 (p<0.0001). Conclusions: In this validation study, the combinations of functional polymorphisms related to dopaminergic genes were associated with the development of schizophrenia. Analyzing combinations of functional polymorphisms with the control of possible confounders may provide new insights for association research.

genetics↗

bioRxiv2019

Deep learning detects virus presence in cancer histology

Oncogenic viruses like human papilloma virus (HPV) or Epstein Barr virus (EBV) are a major cause of human cancer. Viral oncogenesis has a direct impact on treatment decisions because virus-associated tumors can demand a lower intensity of chemotherapy and radiation or can be more susceptible to immune check-point inhibition. However, molecular tests for HPV and EBV are not ubiquitously available.\n\nWe hypothesized that the histopathological features of virus-driven and non-virus driven cancers are sufficiently different to be detectable by artificial intelligence (AI) through deep learning-based analysis of images from routine hematoxylin and eosin (HE) stained slides. We show that deep transfer learning can predict presence of HPV in head and neck cancer with a patient-level 3-fold cross validated area-under-the-curve (AUC) of 0.89 [0.82; 0.94]. The same workflow was used for Epstein-Barr virus (EBV) driven gastric cancer achieving a cross-validated AUC of 0.80 [0.70; 0.92] and a similar performance in external validation sets. Reverse-engineering our deep neural networks, we show that the key morphological features can be made understandable to humans.\n\nThis workflow could enable a fast and low-cost method to identify virus-induced cancer in clinical trials or clinical routine. At the same time, our approach for feature visualization allows pathologists to look into the black box of deep learning, enabling them to check the plausibility of computer-based image classification.

cancer biology↗

bioRxiv2019

Characterization of the untranslated region of lymphocytic choriomeningitis virus S segment

Lymphocytic choriomeningitis virus (LCMV) is a prototypic arenavirus. The viral genome consists of two RNA segments, L and S. The 5- and 3-termini of both L and S segments are highly conserved among arenaviruses. These regions consist of 19 complementary base pairs and are essential for viral genome replication and transcription. In addition to these 19 nucleotides in the 5- and 3-termini, there are untranslated regions (UTRs) composed of 58 and 41 nucleotide residues in the 5 and 3 UTRs, respectively, in the LCMV S segment. Their functional roles, however, have yet to be elucidated. In this study, a reverse genetics and a minigenome system for the LCMV strain WE were established and used to analyze the function of these regions. The results obtained from these analyses, plus RNA secondary structure prediction, revealed that not only these 19 nucleotides but also the 20th-40th and 20th-38th nucleotides located downstream of the 19 nucleotides in the 5- and 3-termini, respectively, are heavily involved in viral genome replication and transcription. Furthermore, the introduction of mutations in these regions depressed viral propagation in vitro and enhanced attenuation in vivo. Conversely, recombinant LCMVs (rLCMVs), which had various deletions in the other UTRs, propagated as well as wild-type LCMV in vitro but were attenuated in vivo. Most mice previously infected with rLCMVs with mutated UTRs, when further infected with a lethal dose of wild-type LCMV, survived. These results suggest that rLCMVs with mutated UTRs could be candidates for an LCMV vaccine.\n\nIMPORTANCEThe function of untranslated regions (UTRs) of the arenavirus genome has not well been studied except for the 19 nucleotides of the 5- and 3-termini. In this study the function of the UTRs of the LCMV S segment was analyzed. It was found that not only the 19 nucleotides of the 5- and 3-termini but also the 20th-40th and 20th-38th nucleotides located downstream of the 19 nucleotides in the 5- and 3-termini, respectively, were involved in viral genome replication and transcription. Furthermore, other UTRs in the S segment were involved in virulence in vivo. The introduction of mutations to these regions makes it possible to establish attenuated LCMV and potentially develop LCMV vaccine candidates.

microbiology↗

bioRxiv2019

Investigation of betaine as a novel psychotherapeutic for schizophrenia

Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine treatments. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with \"betaine deficit-oxidative stress pathology\". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. In conclusion, the present study underscores the potential benefit of betaine in a subset of schizophrenia.

neuroscience↗

bioRxiv2017

Genomic and proteomic analysis of Human herpesvirus 6 reveals distinct clustering of acute versus inherited forms and reannotation of reference strain

Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). To date, only two complete genomes are available for HHV-6B. Using a custom capture panel for HHV-6B, we report near-complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). We also report partial genome sequences from 10 strains of iciHHV-6A. Although the overall sequence diversity of HHV-6 is limited relative to other human herpesviruses, our sequencing identified geographical clustering of HHV-6B sequences from active infections, as well as evidence of recombination among HHV-6B strains. One strain of active HHV-6B was more divergent than any other HHV-6B previously sequenced. In contrast to the active infections, sequences from iciHHV-6 cases showed reduced sequence diversity. Strikingly, multiple iciHHV-6B sequences from unrelated individuals were found to be completely identical, consistent with a founder effect. However, several iciHHV-6B strains intermingled with strains from active pediatric infection, consistent with the hypothesis that intermittent de novo integration into host germline cells can occur during active infection Comparative genomic analysis of the newly sequenced strains revealed numerous instances where conflicting annotations between the two existing reference genomes could be resolved. Combining these findings with transcriptome sequencing and shotgun proteomics, we reannotated the HHV-6B genome and found multiple instances of novel splicing and genes that hitherto had gone unannotated. The results presented here constitute a significant genomic resource for future studies on the detection, diversity, and control of HHV-6.\n\nAuthor SummaryHHV-6 is a ubiquitous large DNA virus that is the most common cause of febrile seizures and reactivates in allogeneic stem cell patients. It also has the unique ability among human herpesviruses to be integrated into the genome of every cell via integration in the germ line, a condition called inherited chromosomally integrated (ici)HHV-6, which affects approximately 1% of the population. To date, very little is known about the comparative genomics of HHV-6. We sequenced 61 isolates of HHV-6B from active infections, 64 strains of iciHHV-6B, and 10 strains of iciHHV-6A. We found geographic clustering of HHV-6B strains from active infections. In contrast, iciHHV-6B had reduced sequence diversity, with many identical sequences of iciHHV-6 found in individuals not known to share recent common ancestry, consistent with a founder effect from a remote common ancestor with iciHHV-6. We also combined our genomic analysis with transcriptome sequencing and shotgun proteomics to correct previous misannotations of the HHV-6 genome.

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