Publications by authors named "Kei Sato"

215 Publications

Endovascular Treatment for Lower-extremity Arterial Thrombosis in a Patient with Congenital Afibrinogenemia and a History of Bleeding Complications.

Intern Med 2021 Jul 30. Epub 2021 Jul 30.

Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Japan.

Congenital afibrinogenemia is a rare autosomal recessive blood disorder that accompanies thrombotic complications and is associated with bleeding tendency. The management of these opposing complications remains a challenge. Endovascular treatment (EVT) for peripheral arterial thrombosis has not been described in previous studies. A 57-year-old man with congenital afibrinogenemia developed back pain and left lower leg pain. The cause of the pain was confirmed to be renal infarction and lower extremity arterial thrombosis by Doppler ultrasound and contrast-enhanced computed tomography. He was treated with EVT for the lower extremity arterial thrombosis, leading to an excellent short-term improvement without bleeding.
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http://dx.doi.org/10.2169/internalmedicine.7542-21DOI Listing
July 2021

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro.

Nat Commun 2021 07 28;12(1):4584. Epub 2021 Jul 28.

Department of Internal Medicine I, Ulm University Medical Center, Ulm, Germany.

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches.
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http://dx.doi.org/10.1038/s41467-021-24817-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319209PMC
July 2021

Clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Lung Cancer 2021 Jul 16;159:74-83. Epub 2021 Jul 16.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. Electronic address:

Objectives: The purpose of this study was to investigate the clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Methods: We retrospectively reviewed 521 cases with pathologic stage I lung adenocarcinoma resected by lobectomy and lymph node dissection. We calculated the ratio of tumor necrotic area by digital image analysis and investigated the relationship between tumor necrosis and prognosis. Furthermore, we analyzed the differentially expressed genes between cases with and without necrosis using The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset. Using whole exon sequencing data (n = 97), we examined whether tumor necrosis correlates with single nucleotide variants (SNVs) and driver mutations.

Results: Eighty four (16%) cases of the study cohort had tumor necrosis. The presence of necrosis significantly correlated with poorer prognosis (5-year overall survival: 91.9% vs. 75.4%, p < 0.001; 5-year recurrence-free survival: 86.0% vs. 59.0%, p < 0.001); however, the ratio of necrotic area did not correlate with prognosis. In multivariable analysis, invasive component size, vascular invasion, and tumor necrosis were independently associated with a higher risk of recurrence (hazard ratio, 1.652; 95% confidence interval, 1.033-2.641; p = 0.036). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as cell cycle and response to hypoxia, in cases with necrosis. The cases with tumor necrosis had more SNVs than those without tumor necrosis (p = 0.027), especially in smokers.

Conclusion: Stage I lung adenocarcinoma with tumor necrosis has worse prognosis than that without, and has distinctclinicopathological features in terms of gene expression and genetic features.
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http://dx.doi.org/10.1016/j.lungcan.2021.07.001DOI Listing
July 2021

SARS-CoV-2 B.1.617 mutations L452 and E484Q are not synergistic for antibody evasion.

J Infect Dis 2021 Jul 14. Epub 2021 Jul 14.

Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Cambridge, UK.

The SARS-CoV-2 B.1.617 variant emerged in the Indian state of Maharashtra in late 2020. There have been fears that two key mutations seen in the receptor binding domain L452R and E484Q would have additive effects on evasion of neutralising antibodies. We report that spike bearing L452R and E484Q confers modestly reduced sensitivity to BNT162b2 mRNA vaccine-elicited antibodies following either first or second dose. The effect is similar in magnitude to the loss of sensitivity conferred by L452R or E484Q alone. These data demonstrate reduced sensitivity to vaccine elicited neutralising antibodies by L452R and E484Q but lack of synergistic loss of sensitivity.
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http://dx.doi.org/10.1093/infdis/jiab368DOI Listing
July 2021

Feasibility of esophagectomy for esophageal cancer in elderly patients: a case-control study.

Langenbecks Arch Surg 2021 Jul 14. Epub 2021 Jul 14.

Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Purpose: Surgery in elderly patients with esophageal cancer is challenging due to high mortality and limited survival. This study aimed to evaluate the safety and effectiveness of curative esophagectomy in elderly patients with esophageal cancer.

Methods: This study included 77 and 112 patients with esophageal cancer aged ≥ 70 and 40-64 years, respectively, who underwent R0 esophagectomy between January 1998 and December 2016. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were compared.

Results: The proportions of comorbid diseases (85.7% vs. 57.1%; P < 0.001), the American Society of Anesthesiologists score (1/2/3; 2.6%/94.8%/2.6% vs. 42.9%/57.1%/0%; P < 0.001), the preoperative systemic inflammation score (SIS) (0/1/2; 20.8%/48.1%/31.2% vs. 38.4%/38.4%/23.2%; P = 0.036), and postoperative complications (Clavien-Dindo grade ≥ III) (33.8% vs. 20.5%; P = 0.041) were significantly higher in the elderly group than those in the non-elderly group. However, long-term overall survival (OS) and relapse-free survival were not significantly different between the groups. On multivariate analysis, SIS (hazard ratio, 3.06; P = 0.037) and severe postoperative complications (hazard ratio, 2.01; P = 0.039) were significantly correlated with OS in the elderly group.

Conclusions: As SIS and severe postoperative complications lead to poor prognosis after R0 esophagectomy in elderly patients, selecting appropriate patients for esophagectomy and preventing severe postoperative complications is essential.
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http://dx.doi.org/10.1007/s00423-021-02271-0DOI Listing
July 2021

SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity.

Cell Host Microbe 2021 07 15;29(7):1124-1136.e11. Epub 2021 Jun 15.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan; CREST, Japan Science and Technology Agency, Saitama 3220012, Japan. Electronic address:

Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
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http://dx.doi.org/10.1016/j.chom.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205251PMC
July 2021

High postoperative neutrophil-lymphocyte ratio and low preoperative lymphocyte-monocyte ratio predict poor prognosis in gastric cancer patients receiving gastrectomy with positive lavage cytology: a retrospective cohort study.

Langenbecks Arch Surg 2021 Jun 17. Epub 2021 Jun 17.

Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama City, Kanagawa, 236-0004, Japan.

Background: Long-term outcomes in gastric cancer patients with positive lavage cytology (CY1) are generally poor. This multi-institutional retrospective cohort study aims to evaluate the clinical significance of the neutrophil-lymphocyte ratio (NLR) and the lymphocyte-monocyte ratio (LMR) in CY1 gastric cancer patients.

Methods: A total of 121 CY1 gastric cancer patients without other non-curative factors, who underwent macroscopically curative resection, were enrolled in this study. The cutoff values of preoperative NLR (pre-NLR), postoperative NLR (post-NLR), preoperative LMR (pre-LMR), and postoperative LMR (post-LMR) were defined by the Contal and O'Quigley method as 2.3, 3.0, 2.5, and 3.2, respectively. A Cox proportional hazard model was used to identify the independent prognostic factors among NLR, LMR, and other clinicopathological factors.

Results: There were significant differences in the overall survival (OS) between the two groups: high post-NLR groups vs. low post-NLR group (median survival time, months) (10.9 vs. 22.8, P = 0.006) and high pre-LMR group vs. low pre-LMR group (21.3 vs. 11.0, P = 0.001). The LMR value elevated significantly after gastrectomy (P = 0.020), although not in the NLR value (P = 0.733). On multivariate analysis, high post-NLR (hazard ratio = 1.506; 95% confidence interval = 1.047-2.167; P = 0.027), low pre-LMR (1.773; 1.135-2.769, 0.012), and no postoperative chemotherapy (1.558; 1.053-2.305, 0.027) were found to be independent prognostic factors for adverse OS.

Conclusions: Because a combination of high post-NLR and low pre-LMR may be an adverse prognostic marker in resectable CY1 gastric cancer patients, it is necessary to conduct a prospective trial to confirm a useful perioperative chemotherapeutic regimen for these patients.
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http://dx.doi.org/10.1007/s00423-021-02233-6DOI Listing
June 2021

Ischemic Stroke as a Warning Sign of Impending Aneurysmal Rupture: A Report of Two Cases.

NMC Case Rep J 2021 Apr 2;8(1):85-88. Epub 2021 Apr 2.

Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.

Ischemic stroke associated with intracranial aneurysm is rare but potentially happens because of emboli originating from aneurysm sac or aneurysmal thrombosis extension to the parent artery. We describe two patients who present subarachnoid hemorrhage (SAH) soon after ischemic stroke. Case 1. A 51-year-old woman with a history of multiple endovascular therapy for ruptured basilar top aneurysm presented with double vision. Magnetic resonance imaging (MRI) revealed infarcts in the right thalamus and left occipital cortex. Four days after ischemic stroke, she suffered from sudden onset headache, computed tomography (CT) showed diffuse SAH with intraventricular hemorrhage. Case 2. A 62-year-old man presented with right facial palsy and sensory disorder. MRI revealed an infarct in the left pons. Four days after ischemic stroke, he became comatose and CT showed diffuse SAH. Both cases develop ischemic stroke adjacent to the aneurysms and subsequently cause devasting aneurysm rupture, suggesting ischemic stroke as a warning sign of aneurysm rupture. In such cases, early treatment of the aneurysm should be considered.
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http://dx.doi.org/10.2176/nmccrj.cr.2020-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116920PMC
April 2021

Elucidation of the Complicated Scenario of Primate APOBEC3 Gene Evolution.

J Virol 2021 05 24;95(12). Epub 2021 May 24.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan

APOBEC3 proteins play pivotal roles in defenses against retroviruses, including HIV-1, as well as retrotransposons. Presumably due to the evolutionary arms race between the hosts and retroelements, APOBEC3 genes have rapidly evolved in primate lineages through sequence diversification, gene amplification and loss, and gene fusion. Consequently, modern primates possess a unique set or "repertoire" of APOBEC3 genes. The APOBEC3 gene repertoire of humans has been well investigated. There are three types of catalytic domains (Z domain; A3Z1, A3Z2, and A3Z3), 11 Z domains, and 7 independent genes, including 4 genes encoding double Z domains. However, the APOBEC3 gene repertoires of nonhuman primates remain largely unclear. Here, we characterize APOBEC3 gene repertoires among primates and investigated the evolutionary scenario of primate APOBEC3 genes using phylogenetic and comparative genomics approaches. In the 21 primate species investigated, we identified 145 APOBEC3 genes, including 69 double-domain type APOBEC3 genes. We further estimated the ages of the respective APOBEC3 genes and revealed that APOBEC3B, APOBEC3D, and APOBEC3F are the youngest in humans and were generated in the common ancestor of Catarrhini. Notably, invasion of the LINE1 retrotransposon peaked during the same period as the generation of these youngest APOBEC3 genes, implying that LINE1 invasion was one of the driving forces of the generation of these genes. Moreover, we found evidence suggesting that sequence diversification by gene conversions among APOBEC3 paralogs occurred in multiple primate lineages. Together, our analyses reveal the hidden diversity and the complicated evolutionary scenario of APOBEC3 genes in primates. In terms of virus-host interactions and coevolution, the APOBEC3 gene family is one of the most important subjects in the field of retrovirology. APOBEC3 genes are composed of a repertoire of subclasses based on sequence similarity, and a paper by LaRue et al. provides the standard guideline for the nomenclature and genomic architecture of APOBEC3 genes. However, it has been more than 10 years since this publication, and new information, including RefSeq, which we used in this study, is accumulating. Based on accumulating knowledge, APOBEC3 genes, particularly those of primates, should be refined and reannotated. This study updates knowledge of primate APOBEC3 genes and their genomic architectures. We further inferred the evolutionary scenario of primate APOBEC3 genes and the potential driving forces of APOBEC3 gene evolution. This study will be a landmark for the elucidation of the multiple aspects of APOBEC3 family genes in the future.
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http://dx.doi.org/10.1128/JVI.00144-21DOI Listing
May 2021

Conflicting and ambiguous names of overlapping ORFs in the SARS-CoV-2 genome: A homology-based resolution.

Virology 2021 06 17;558:145-151. Epub 2021 Mar 17.

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.

At least six small alternative-frame open reading frames (ORFs) overlapping well-characterized SARS-CoV-2 genes have been hypothesized to encode accessory proteins. Researchers have used different names for the same ORF or the same name for different ORFs, resulting in erroneous homological and functional inferences. We propose standard names for these ORFs and their shorter isoforms, developed in consultation with the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. We recommend calling the 39 codon Spike-overlapping ORF ORF2b; the 41, 57, and 22 codon ORF3a-overlapping ORFs ORF3c, ORF3d, and ORF3b; the 33 codon ORF3d isoform ORF3d-2; and the 97 and 73 codon Nucleocapsid-overlapping ORFs ORF9b and ORF9c. Finally, we document conflicting usage of the name ORF3b in 32 studies, and consequent erroneous inferences, stressing the importance of reserving identical names for homologs. We recommend that authors referring to these ORFs provide lengths and coordinates to minimize ambiguity caused by prior usage of alternative names.
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http://dx.doi.org/10.1016/j.virol.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967279PMC
June 2021

Sarbecovirus ORF6 proteins hamper induction of interferon signaling.

Cell Rep 2021 03 12;34(13):108916. Epub 2021 Mar 12.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan; CREST, Japan Science and Technology Agency, Saitama 3220012, Japan. Electronic address:

The presence of an ORF6 gene distinguishes sarbecoviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 from other betacoronaviruses. Here we show that ORF6 inhibits induction of innate immune signaling, including upregulation of type I interferon (IFN) upon viral infection as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and that ORF6 inhibits nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Our findings suggest that ORF6 contributes to the poor IFN activation observed in individuals with coronavirus disease 2019 (COVID-19).
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http://dx.doi.org/10.1016/j.celrep.2021.108916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953434PMC
March 2021

Comprehensive Investigation on the Interplay between Feline APOBEC3Z3 Proteins and Feline Immunodeficiency Virus Vif Proteins.

J Virol 2021 Jun 10;95(13):e0017821. Epub 2021 Jun 10.

Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

As the hosts of lentiviruses, almost 40 species of felids (family ) are distributed around the world, and more than 20 feline species test positive for feline immunodeficiency virus (FIV), a lineage of lentiviruses. These observations suggest that FIVs globally infected a variety of feline species through multiple cross-species transmission events during a million-year history. Cellular restriction factors potentially inhibit lentiviral replication and limit cross-species lentiviral transmission, and cellular APOBEC3 deaminases are known as a potent restriction factor. In contrast, lentiviruses have evolutionary-acquired viral infectivity factor (Vif) to neutralize the APOBEC3-mediated antiviral effect. Because the APOBEC3-Vif interaction is strictly specific for viruses and their hosts, a comprehensive investigation focusing on Vif-APOBEC3 interplay can provide clues that will elucidate the roles of this virus-host interplay on cross-species transmission of lentiviruses. Here, we performed a comprehensive investigation with 144 patterns of a round robin test using 18 feline genes, an antiviral gene in felid, and 8 FIV Vifs and derived a matrix showing the interplay between feline APOBEC3Z3 and FIV Vif. We particularly focused on the interplay between the APOBEC3Z3 of three felids (domestic cat, ocelot, and Asian golden cat) and an FIV Vif (strain Petaluma), and revealed that residues 65 and 66 of the APOBEC3Z3 protein of multiple felids are responsible for the counteraction triggered by FIV Petaluma Vif. Altogether, our findings can be a clue to elucidate not only the scenarios of the cross-species transmissions of FIVs in felids but also the evolutionary interaction between mammals and lentiviruses. Most of the emergences of new virus infections originate from the cross-species transmission of viruses. The fact that some virus infections are strictly specific for the host species indicates that certain "species barriers" in the hosts restrict cross-species jump of viruses, while viruses have evolutionary acquired their own "arms" to overcome/antagonize/neutralize these hurdles. Therefore, understanding of the molecular mechanism leading to successful cross-species viral transmission is crucial for considering the menus of the emergence of novel pathogenic viruses. In the field of retrovirology, APOBEC3-Vif interaction is a well-studied example of the battles between hosts and viruses. Here, we determined the sequences of 11 novel feline genes and demonstrated that all 18 different feline APOBEC3Z3 proteins tested exhibit anti-feline immunodeficiency virus (FIV) activity. Our comprehensive investigation focusing on the interplay between feline APOBEC3 and FIV Vif can be a clue to elucidate the scenarios of the cross-species transmissions of FIVs in felids.
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http://dx.doi.org/10.1128/JVI.00178-21DOI Listing
June 2021

Frequent post-operative monitoring of colorectal cancer using individualised ctDNA validated by multiregional molecular profiling.

Br J Cancer 2021 Apr 3;124(9):1556-1565. Epub 2021 Mar 3.

Division of Biomedical Research and Development, Iwate Medical University Institute for Biomedical Sciences, Iwate, Japan.

Background: Circulating tumour DNA (ctDNA) is known as a tumour-specific personalised biomarker, but the mutation-selection criteria from heterogeneous tumours remain a challenge.

Methods: We conducted multiregional sequencing of 42 specimens from 14 colorectal tumours of 12 patients, including two double-cancer cases, to identify mutational heterogeneity to develop personalised ctDNA assays using 175 plasma samples.

Results: "Founder" mutations, defined as a mutation that is present in all regions of the tumour in a binary manner (i.e., present or absent), were identified in 12/14 tumours. In contrast, "truncal" mutations, which are the first mutation that occurs prior to the divergence of branches in the phylogenetic tree using variant allele frequency (VAF) as continuous variables, were identified in 12/14 tumours. Two tumours without founder and truncal mutations were hypermutators. Most founder and truncal mutations exhibited higher VAFs than "non-founder" and "branch" mutations, resulting in a high chance to be detected in ctDNA. In post-operative long-term observation for 10/12 patients, early relapse prediction, treatment efficacy and non-relapse corroboration were achievable from frequent ctDNA monitoring.

Conclusions: A single biopsy is sufficient to develop custom dPCR probes for monitoring tumour burden in most CRC patients. However, it may not be effective for those with hypermutated tumours.
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http://dx.doi.org/10.1038/s41416-021-01266-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076308PMC
April 2021

Lung toxicity of a vapor-grown carbon fiber in comparison with a multi-walled carbon nanotube in F344 rats.

J Toxicol Pathol 2021 Jan 20;34(1):57-71. Epub 2020 Nov 20.

Chemicals Assessment & Management Center, Responsible Care Department, Showa Denko K.K., 13-9 Shiba Daimon 1-Chome, Minato-ku, Tokyo 105-8518, Japan.

Carbon fibers have excellent physicochemical and electrical properties. Vapor-grown carbon fibers are a type of carbon fibers that have a multi-walled carbon tube structure with a high aspect ratio. The representative vapor-grown carbon fiber, VGCF-H, is extremely strong and stable and has superior thermal and electrical conductivity. Because some high-aspect-ratio multi-walled carbon nanotubes (MWCNTs) have been reported to have toxic and carcinogenic effects in the lungs of rodents, we performed a 13-week lung toxicity study using VGCF-H in comparison with one of MWCNTs, MWNT-7, in rats. Male and female F344 rats were intratracheally administered VGCF-H at doses of 0.2, 0.4, and 0.8 mg/kg bw or MWNT-7 at doses of 0.4 and 0.8 mg/kg bw once a week for 8 weeks and then up to week 13 without treatment. The lung burden was equivalent in the VGCF-H and MWNT-7 groups; however, the lung weight had increased and the inflammatory and biochemical parameters in the broncho-alveolar lavage fluid and histopathological parameters, including inflammatory cell infiltration, alveolar type II cells proliferation, alveolar fibrosis, pleural fibrosis, lung mesothelium proliferation, and diaphragm fibrosis, were milder in the VGCF-H group than in the MWNT-7 group. In addition, the proliferating cell nuclear antigen (PCNA)-positive index in the visceral and pleural mesothelium was significantly higher in the MWNT-7 group than in the controls, but not in the VGCF-H group. Thus, the results of this study indicate that the lung and pleural toxicities of VGCF-H were less than those of MWNT-7.
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http://dx.doi.org/10.1293/tox.2020-0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890169PMC
January 2021

Direct Evidence of Abortive Lytic Infection-Mediated Establishment of Epstein-Barr Virus Latency During B-Cell Infection.

Front Microbiol 2020 21;11:575255. Epub 2021 Jan 21.

Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Viral infection induces dynamic changes in transcriptional profiles. Virus-induced and antiviral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, we infected EBV-negative Akata cells with EBV-EGFP and performed transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprogramming of cell growth by EBV, and a burst of viral lytic gene expression in the early phase of infection. Experimental and mathematical investigations demonstrate that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Fate mapping using recombinant EBV provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency. Furthermore, we find that the BZLF1 protein, which is a key regulator of reactivation, was dispensable for abortive lytic infection in the pre-latent phase, suggesting the divergent regulation of viral gene expressions from a productive lytic infection.
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http://dx.doi.org/10.3389/fmicb.2020.575255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888302PMC
January 2021

Source contributions to multiple toxic potentials of atmospheric organic aerosols.

Sci Total Environ 2021 Jun 4;773:145614. Epub 2021 Feb 4.

National Institute for Environmental Studies, Tsukuba, Japan.

Fine particulate matter (PM) in the atmosphere is of high priority for air quality management efforts to address adverse health effects in human. We believe that emission control policies, which are traditionally guided by source contributions to PM mass, should also consider source contributions to PM health effects or toxicity. In this study, we estimated source contributions to the toxic potentials of organic aerosols (OA) as measured by a series of chemical and in-vitro biological assays and chemical mass balance model. We selected secondary organic aerosols (SOA), vehicles, biomass open burning, and cooking as possible important OA sources. Fine particulate matter samples from these sources and parallel atmospheric samples from diverse locations and seasons in East Asia were collected for the study. The source and atmospheric samples were analyzed for chemical compositions and toxic potentials, i.e. oxidative potential, inflammatory potential, aryl hydrocarbon receptor (AhR) agonist activity, and DNA-damage, were measured. The toxic potentials per organic carbon (OC) differed greatly among source and ambient particulate samples. The source contributions to oxidative and inflammatory potentials were dominated by naphthalene-derived SOA (NapSOA), followed by open burning and vehicle exhaust. The AhR activity was dominated by open burning, followed by vehicle exhaust and NapSOA. The DNA damage was dominated by vehicle exhaust, followed by open burning. Cooking and biogenic SOA had smaller contributions to all the toxic potentials. Regarding atmospheric OA, urban and roadside samples showed stronger toxic potentials per OC. The toxic potentials of remote samples in summer were consistently very weak, suggesting that atmospheric aging over a long time decreased the toxicity. The toxic potentials of the samples from the forest and the experimentally generated biogenic SOA were low, suggesting that toxicity of biogenic primary and secondary particles is relatively low.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145614DOI Listing
June 2021

Comparison of Converse Ω Anastomosis and Extracorporeal Anastomosis After Laparoscopic Distal Gastrectomy for Gastric Cancer.

Surg Laparosc Endosc Percutan Tech 2021 Feb 3. Epub 2021 Feb 3.

Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center Departments of Gastroenterological Surgery Biostatistics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa Prefecture, Japan.

Background: Converse Ω anastomosis is a recently developed technique of delta-shaped anastomosis for intracorporeal gastroduodenostomy to simplify the anastomotic procedures and reduce their potential risks. This study aimed to evaluate the safety and effectiveness of converse Ω anastomosis, comparing it with conventional extracorporeal Billroth-I anastomosis after laparoscopic distal gastrectomy (LDG) for gastric cancer.

Patients And Methods: Among 169 gastric cancer patients who underwent LDG with Billroth-I anastomosis anastomosis between April 2013 and March 2018, we selected 100 patients by propensity score matching (50 in the converse Ω anastomosis group and 50 in the extracorporeal anastomosis group). Patients' characteristics, intraoperative outcomes, postoperative complications, and survival time were compared between the 2 groups.

Results: Median anastomosis time was significantly longer in the converse Ω group than in the extracorporeal group (40.0 vs. 30.5 min, P=0.005). However, the total procedure time did not differ significantly between the groups. Intraoperative blood loss volume was significantly lower in the converse Ω group than in the extracorporeal anastomosis group (40 vs. 120 mL, P<0.001). There were no significant differences in the number of dissected lymph nodes, postoperative morbidity, mortality, or length of hospital stay. The postoperative body mass index and the prognostic nutritional index did not differ between the groups 1 year after surgery. There were no significant differences in overall survival and relapse-free survival between the 2 groups.

Conclusions: Converse Ω anastomosis is feasible and safe. This novel technique can be adopted as a treatment option for reconstruction after LDG in patients with early-stage gastric cancer. Therefore, the risks and benefits of converse Ω anastomosis after LDG should be confirmed in larger cohorts.
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http://dx.doi.org/10.1097/SLE.0000000000000906DOI Listing
February 2021

The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present.

Viruses 2021 Jan 17;13(1). Epub 2021 Jan 17.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan.

The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian genes and viruses.
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http://dx.doi.org/10.3390/v13010124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830460PMC
January 2021

HIV-1 tracing method of systemic viremia in vivo using an artificially mutated virus pool.

Microbiol Immunol 2021 Jan 7;65(1):17-27. Epub 2021 Jan 7.

Department of Infectious Disease Control, Division of Systems Virology, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

The appearance of human immunodeficiency virus type 1 (HIV-1) plasma viremia is associated with progression to symptomatic disease and CD4 T cell depletion. To locate the source of systemic viremia, this study employed a novel method to trace HIV-1 infection in vivo. We created JRCSFξnef, a pool of infectious HIV-1 (strain JR-CSF) with highly mutated nef gene regions by random mutagenesis PCR and infected this mutated virus pool into both Jurkat-CCR5 cells and hematopoietic stem cell-transplanted humanized mice. Infection resulted in systemic plasma viremia in humanized mice and viral RNA sequencing helped us to identify multiple lymphoid organs such as spleen, lymph nodes, and bone marrow but not peripheral blood cells as the source of systemic viremia. Our data suggest that this method could be useful for the tracing of viral trafficking in vivo.
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http://dx.doi.org/10.1111/1348-0421.12862DOI Listing
January 2021

Comparative Analysis of PM-Bound Polycyclic Aromatic Hydrocarbons (PAHs), Nitro-PAHs (NPAHs), and Water-Soluble Inorganic Ions (WSIIs) at Two Background Sites in Japan.

Int J Environ Res Public Health 2020 11 6;17(21). Epub 2020 Nov 6.

Institute of Nature and Environmental Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Daily PM (particulate matter with aerodynamic diameter ≤2.5 μm) samples were simultaneously collected at two background sites (Wajima Air Monitoring Station (WAMS) and Fukue-Jima Atmosphere and Aerosol Monitoring Station (FAMS)) in Japan in the East Asian winter and summer monsoon periods of 2017 and 2019, to compare the characteristics of air pollutants among different regions and to determine the possible variation during the long-range transport process. Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), and water-soluble inorganic ions (WSIIs) were analyzed. Despite the PM concentrations at FAMS (8.90-78.5 µg/m) being higher than those at WAMS (2.33-21.2 µg/m) in the winter monsoon period, the average concentrations of ∑PAHs, ∑NPAHs, and ∑WSIIs were similar between the two sites. Diagnostic ratios indicated PAHs mainly originated from traffic emissions and mostly aged, whereas NPAHs were mostly secondarily formed during long-range transport. WSIIs at WAMS were mainly formed via the combustion process and secondary reactions, whereas those at FAMS mainly originated from sea salt and dust. Backward trajectories revealed the air masses could not only come from Asian continental coastal regions but also distant landlocked areas in the winter monsoon period, whereas most came from the ocean in the summer monsoon period. These findings can provide basic data for the establishment of prediction models of transboundary air pollutants in East Asia.
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http://dx.doi.org/10.3390/ijerph17218224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664402PMC
November 2020

Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells.

Nat Commun 2020 11 9;11(1):5656. Epub 2020 Nov 9.

Institute for Regenerative Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

Establishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we establish a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells differentiated from human induced pluripotent stem cells are further induced into M-prospermatogonia-like cells and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. Single cell RNA-sequencing is used to delineate the lineage trajectory leading to T1LCs, which closely resemble human T1-prospermatogonia in vivo and exhibit gene expression related to spermatogenesis and diminished proliferation, a hallmark of quiescent T1 prospermatogonia. Notably, this system enables us to visualize the dynamic and stage-specific regulation of transposable elements during human prospermatogonial specification. Together, our findings pave the way for understanding and reconstructing human male germline development in vitro.
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http://dx.doi.org/10.1038/s41467-020-19350-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653920PMC
November 2020

Exploration of Pericyte-Derived Factors Implicated in Lung Cancer Brain Metastasis Protection: A Pilot Messenger RNA Sequencing Using the Blood-Brain Barrier In Vitro Model.

Cell Mol Neurobiol 2020 Nov 2. Epub 2020 Nov 2.

Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Metastatic brain tumors have poor prognoses and pose unmet clinical problems for the patients. The blood-brain barrier (BBB) implication is supposed to play a major role in brain metastasis. However, the role of pericytes remains to be elucidated in the brain metastasis. This pilot study described the expression profile of interactions between pericytes, endothelial cells, and cancer cells. We applied an in vitro BBB model with rat primary cultured BBB-related cells (endothelial cells and pericytes), and performed the gene expression analyses of pericytes under the lung cancer cells coculture conditions. Pericytes demonstrated inhibition of the cancer cell proliferation significantly (p < 0.05). RNA was extracted from the pericytes, complementary DNA library was prepared, and RNA-seq was performed. The sequence read data were analyzed on the Management and Analysis System for Enormous Reads and Tag Count Comparison-Graphical User Interface platforms. No statistically or biologically significant differentially expressed genes (DEGs) were detected in the explanatory analyses. Lot-specific DEG detection demonstrated significant decreases in the expression of two genes (Wwtr1 and Acin1), and enrichment analyses using Metascape software revealed the inhibition of apoptotic processes in fibroblasts. Our results suggest that the expression profiles of brain pericytes are partially implicated in the prevention of lung cancer metastasis to the brain. Pericytes exerted an anti-metastatic effect in the BBB model, and their neurohumoral factors remain to be elucidated.
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http://dx.doi.org/10.1007/s10571-020-00988-yDOI Listing
November 2020

Moyamoya Disease Associated with Graves' Disease and Down Syndrome: A Case Report and Literature Review.

J Stroke Cerebrovasc Dis 2021 Jan 30;30(1):105414. Epub 2020 Oct 30.

Department of Neurosurgery, Nagasaki Prefecture Shimabara Hospital, 7895 Shimokawasiri, Shimabara, Nagasaki 855-0816, Japan.

Background: Moyamoya vessels are cerebral vasculopathies characterized by net-like collateral vessel formation at the cerebral basal area and stenosis of the terminal internal carotid artery, proximal middle cerebral artery, and anterior cerebral artery. A diagnosis of Moyamoya disease depends on the bilateral presence of Moyamoya vessels. Moyamoya disease associated with Graves' disease has rarely been reported to be a cause of ischemic events due to hyperthyroidism. However, there are extremely rare cases of Moyamoya disease with concurrent Graves' disease and Down syndrome. We aimed to report such a case, and to compare these cases' clinical features, pathogenesis, and treatment effects to those of the cases of concurrent Moyamoya disease and Graves' disease alone.

Methods: We performed an English literature search using the PubMed database and the keywords Moyamoya, quasi-Moyamoya, Graves' disease, thyrotoxicosis, Down syndrome, and trisomy 21.

Results: Only five cases of Moyamoya disease with Graves' disease and Down syndrome have been reported, including our own. Four patients were female (80%), and all underwent antithyroid therapy and experienced ischemic episodes, including transient ischemic attacks. At the time of their vascular accident, two patients were in a thyrotoxic state; only our patient was in a euthyroid state. The mean age was 15.6 years (standard deviation: 6.1), which was younger than the mean age of 31.4 years (standard deviation: 13) in patients with Moyamoya disease and Graves' disease alone. Down syndrome is commonly associated with abnormal vascular networks due to increased endostatin concentrations or immunological abnormalities such as those that occur in Graves' disease. Graves' disease accelerates the progression of Moyamoya disease and ischemic attacks due to atherosclerosis, enhances sympathetic nervous system activity and immunological changes. As compared to Moyamoya disease patients, patients with concurrent Graves' disease only and Moyamoya disease patients with concurrent Graves' disease and Down syndrome may experience accelerated disease progression or more frequent ischemic attacks.

Conclusion: Early imaging follow-ups and strict control of thyroid function are necessary in such cases; if ischemic attacks have already occurred, revascularization surgery may be effective.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105414DOI Listing
January 2021

Volatility Distribution of Organic Compounds in Sewage Incineration Emissions.

Environ Sci Technol 2020 11 27;54(22):14235-14245. Epub 2020 Oct 27.

Division of Atmospheric Sciences, Desert Research Institute, Reno, Nevada 89512, United States.

Intermediate volatility and semivolatile organic compounds (IVOC/SVOC) are important precursors of secondary organic aerosol (SOA) while SVOC is an important contributor to primary organic aerosol (POA). However, combustion emissions data for volatility classes are limited. This study reports the gas and particle emissions that were sampled with various dilution factors from a sewage sludge incinerator burning fuel oil. Volatility distributions were determined using measurements from online mass spectrometry and offline organic compound analyses. In the low volatility organic compound (LVOC) to IVOC range, volatility bins with organic saturation concentrations of 10-100 μg m were most abundant, which was due to organic acids generated from sludge burning. Organic aerosol (OA) emission factors (EF) increased 1.4 times after cooling to ambient temperatures in comparison to those of the samples from the hot stack. Upon further isothermal dilution at 25 °C, the EF decreased while organic gas phase EFs increased with increasing dilution. Phase partitioning in volatility bins with saturation concentrations of 10-100 μg m was sensitive to isothermal dilution that influenced the EFs. Therefore, gas- and particle-phase measurements alone cannot constrain EFs for these volatility classes. Low dilution factors may overestimate the particle phase and underestimate the gas phase EFs compared with real-world emission conditions.
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http://dx.doi.org/10.1021/acs.est.0c04534DOI Listing
November 2020

Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression.

Sci Adv 2020 Oct 21;6(43). Epub 2020 Oct 21.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 1088639, Japan.

Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.
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http://dx.doi.org/10.1126/sciadv.abc3020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577720PMC
October 2020

SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant.

Cell Rep 2020 09 4;32(12):108185. Epub 2020 Sep 4.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, the University of Tokyo, Tokyo 1088639, Japan. Electronic address:

One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.
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http://dx.doi.org/10.1016/j.celrep.2020.108185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473339PMC
September 2020

A role for gorilla APOBEC3G in shaping lentivirus evolution including transmission to humans.

PLoS Pathog 2020 09 10;16(9):e1008812. Epub 2020 Sep 10.

Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

The APOBEC3 deaminases are potent inhibitors of virus replication and barriers to cross-species transmission. For simian immunodeficiency virus (SIV) to transmit to a new primate host, as happened multiple times to seed the ongoing HIV-1 epidemic, the viral infectivity factor (Vif) must be capable of neutralizing the APOBEC3 enzymes of the new host. Although much is known about current interactions of HIV-1 Vif and human APOBEC3s, the evolutionary changes in SIV Vif required for transmission from chimpanzees to gorillas and ultimately to humans are poorly understood. Here, we demonstrate that gorilla APOBEC3G is a factor with the potential to hamper SIV transmission from chimpanzees to gorillas. Gain-of-function experiments using SIVcpzPtt Vif revealed that this barrier could be overcome by a single Vif acidic amino acid substitution (M16E). Moreover, degradation of gorilla APOBEC3F is induced by Vif through a mechanism that is distinct from that of human APOBEC3F. Thus, our findings identify virus adaptations in gorillas that preceded and may have facilitated transmission to humans.
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http://dx.doi.org/10.1371/journal.ppat.1008812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482973PMC
September 2020

Laparoscopic Total Gastrectomy for Gastric Cancer in Elderly Patients.

In Vivo 2020 Sep-Oct;34(5):2933-2939

Department of Surgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

Background/aim: The purpose of this study was to evaluate the safety and efficacy of laparoscopic total gastrectomy (LTG) for elderly patients.

Patients And Methods: We retrospectively analyzed 136 patients who underwent LTG. We divided the patients into elderly patients (>75 years of age) and non-elderly patients (≤75 years of age).

Results: The American Society of Anesthesiologists score, Charlson comorbidity index, Glasgow Prognostic Score and rate of comorbidities were higher in the elderly group; the rates of other clinicopathological characteristics did not differ between the two groups. Regarding the nutritional status, the body weight loss rate in the elderly group was higher in comparison to the non-elderly group (81% vs. 84%, p=0.004). The disease-specific survival (DSS) did not differ between two groups to a statistically significant extent (3-year DSS rates: 83.7 vs. 94.5%; p=0.152).

Conclusions: LTG was acceptable for elderly patients as the elderly and non-elderly groups showed comparable short-term and long-term outcomes.
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http://dx.doi.org/10.21873/invivo.12123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652532PMC
June 2021

Endogenization and excision of human herpesvirus 6 in human genomes.

PLoS Genet 2020 08 10;16(8):e1008915. Epub 2020 Aug 10.

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. 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). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. 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 solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.
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http://dx.doi.org/10.1371/journal.pgen.1008915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444522PMC
August 2020

Left atrial strain imaging differentiates cardiac amyloidosis and hypertensive heart disease.

Int J Cardiovasc Imaging 2021 Jan 29;37(1):81-90. Epub 2020 Jul 29.

Department of Cardiology, The Prince Charles Hospital, Brisbane, Australia.

Echocardiographic diagnosis of cardiac amyloidosis (CA) can be difficult to differentiate from increased left ventricular (LV) wall thickness from hypertensive heart disease. The aim of this study was to evaluate left atrial (LA) function and deformation using strain and strain rate (SR) imaging in cardiac amyloidosis. We reviewed 44 cases of CA confirmed by tissue biopsy or a combination of clinical and cardiac imaging data. Cases were classified according two subgroups: amyloid light chain (AL) or amyloid transthyretin (ATTR). These subjects underwent 2D-Speckle tracking echocardiographic derived (STE) LA strain analysis. These were compared to 25 hypertensive (HT) patients with increased LV wall thickness. The three phases of LA function were evaluated using strain and strain rate parameters. Despite a similar increase in LV wall thickness, all LA strain parameters were significantly reduced in the AL cohort compared to the HT cohort (reservoir strain/LAs: 11.0 vs. 24.8%, p < 0.05). The ATTR cohort had significantly thicker LV walls and higher atrial fibrillation burden compared to AL and HT patients but similar reduction in LA strain values compared to AL group. A reservoir strain (S-LAs) cut off value of 20% was 86.4% sensitive and 88.6% specific for detecting CA compared to HT heart disease in this cohort. LA strain parameters were able to identify LA dysfunction in all types of CA. LA function in CA is significantly worse compared with hypertensive patients despite similar increase in LV wall thickness. In combination with other clinical and imaging features, LA strain may provide incremental value in differentiating cardiac amyloidosis from increased wall thickness secondary to hypertension.
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http://dx.doi.org/10.1007/s10554-020-01948-9DOI Listing
January 2021
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