The Landscape of Mouse Meiotic Double-Strand Break Formation, Processing, and Repair.

Heritability and genome stability are shaped by meiotic recombination, which is initiated via hundreds of DNA double-strand breaks (DSBs). The distribution of DSBs throughout the genome is not random, but mechanisms molding this landscape remain poorly understood. Here, we exploit genome-wide maps of mouse DSBs at unprecedented nucleotide resolution to uncover previously invisible spatial features of recombination. At fine scale, we reveal a stereotyped hotspot structure-DSBs occur within narrow zones between methylated nucleosomes-and identify relationships between SPO11, chromatin, and the histone methyltransferase PRDM9. At large scale, DSB formation is suppressed on non-homologous portions of the sex chromosomes via the DSB-responsive kinase ATM, which also shapes the autosomal DSB landscape at multiple size scales. We also provide a genome-wide analysis of exonucleolytic DSB resection lengths and elucidate spatial relationships between DSBs and recombination products. Our results paint a comprehensive picture of features governing successive steps in mammalian meiotic recombination.

Molecular structures and mechanisms of DNA break processing in mouse meiosis.

Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5' → 3' exonuclease, but the DSB-responsive kinase ATM proved a key regulator of both initiation and extension of resection. In wild type, apparent intermolecular recombination intermediates clustered near to but offset from DSB positions, consistent with joint molecules with incompletely invaded 3' ends. Finally, we provide evidence for PRDM9-dependent chromatin remodeling leading to increased accessibility at recombination sites. Our findings give insight into the mechanisms of DSB processing and repair in meiotic chromatin.

Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases.

The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.

Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Triple-helix potential of the mouse genome.

Certain DNA sequences, including mirror-symmetric polypyrimidine•polypurine runs, are capable of folding into a triple-helix­containing non­B-form DNA structure called H-DNA. Such H-DNA­forming sequences occur frequently in many eukaryotic genomes, including in mammals, and multiple lines of evidence indicate that these motifs are mutagenic and can impinge on DNA replication, transcription, and other aspects of genome function. In this study, we show that the triplex-forming potential of H-DNA motifs in the mouse genome can be evaluated using S1-sequencing (S1-seq), which uses the single-stranded DNA (ssDNA)­specific nuclease S1 to generate deep-sequencing libraries that report on the position of ssDNA throughout the genome. When S1-seq was applied to genomic DNA isolated from mouse testis cells and splenic B cells, we observed prominent clusters of S1-seq reads that appeared to be independent of endogenous double-strand breaks, that coincided with H-DNA motifs, and that correlated strongly with the triplex-forming potential of the motifs. Fine-scale patterns of S1-seq reads, including a pronounced strand asymmetry in favor of centrally positioned reads on the pyrimidine-containing strand, suggested that this S1-seq signal is specific for one of the four possible isomers of H-DNA (H-y5). By leveraging the abundance and complexity of naturally occurring H-DNA motifs across the mouse genome, we further defined how polypyrimidine repeat length and the presence of repeat-interrupting substitutions modify the structure of H-DNA. This study provides an approach for studying DNA secondary structure genome-wide at high spatial resolution.

Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks.

Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double-strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called "abortive" catalysis, the resulting DSBs are repaired by tyrosyl-DNA phosphodiesterase 2 (TDP2) and non-homologous end-joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G1 phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2-DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G1 phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.

XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA.

Base excision repair (BER) removes damaged bases by generating single-strand breaks (SSBs), gap-filling by DNA polymerase ß (POLß), and resealing SSBs. A base-damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance to MMS, anti-cancer base-damaging drugs, temozolomide, carmustine, and lomustine, and to clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of BER factors to SSBs. PARP1 and XRCC1 collaboratively promote SSB resealing by recruiting POLß to SSBs, but XRCC1-/- cells are much more sensitive to MMS than PARP1-/- cells. We recently report that the PARP1 loss in XRCC1-/- cells restores their MMS tolerance and conclude that XPCC1 facilitates the release of PARP1 from SSBs by maintaining its autoPARylation. We here show that the PARP1 loss in XRCC1-/- cells also restores their tolerance to the three anti-cancer base-damaging drugs, although they and MMS induce different sets of base damage. We reveal the synthetic lethality of the XRCC1-/- mutation, but not POLß-/- , with olaparib and talazoparib, indicating that XRCC1 is a unique BER factor in suppressing toxic PARP1/SSB complex and can suppress even when PARP1 catalysis is inhibited. In conclusion, XRCC1 suppresses the PARP1/SSB complex via PARP1 catalysis-dependent and independent mechanisms.

Recent Advances in Translational Research for Heart Failure in Japan.

Despite decades of intensive research and therapeutic development, heart failure remains a leading cause of death worldwide. However, recent advances in several basic and translational research fields, such as genomic analysis and single-cell analysis, have increased the possibility of developing novel diagnostic approaches to heart failure. Most cardiovascular diseases that predispose individuals to heart failure are caused by genetic and environmental factors. It follows that genomic analysis can contribute to the diagnosis and prognostic stratification of patients with heart failure. In addition, single-cell analysis has shown great potential for unveiling the pathogenesis and/or pathophysiology and for discovering novel therapeutic targets for heart failure. Here, we summarize the recent advances in translational research on heart failure in Japan, based mainly on our studies.

Factors affecting reasonable duration of continuous electrocardiographic monitoring to detect atrial fibrillation in acute ischemic stroke.

BACKGROUND: To examine the reasonable duration of continuous electrocardiographic monitoring (CEM) to detect AF at acute ischemic stroke. MATERIALS AND METHOD: 811 consecutive patients admitted to Tsuruga Municipal Hospital by acute ischemic stroke between April 2013 and December 2021 were enrolled in this study. Excluding 78 patients, 733 patients were analyzed by cluster analysis with SurvCART algorithm, followed by Kaplan-Meier analysis. RESULTS: The analysis provided step graphs for 8 subgroups. The duration of CEM to achieve the sensitivity of 0.8, 0.9, and 0.95 in each could be calculated. The duration of CEM to achieve the sensitivity of 0.8 are 18 days in female patients with heart failure (HF) (subgroup 1), 24 days in male patients with HF (subgroup 2), 22 days in patients without HF with arterial occlusion and pulse rate (PR) more than 91 (subgroup 3), 24 days in patients without HF with occlusion with PR less than 91 (subgroup 4), 18 days in patients without HF without occlusion with lacuna (subgroup 5), 26 days in patients without HF, occlusion, and lacuna, with arterial stenosis (subgroup 6), 15 days in patients without HF, occlusion, lacuna, and stenosis with BMI more than 21%(subgroup 7), and 44 days in patients without HF, occlusion, lacuna, stenosis and with BMI less than 21% (subgroup 8). CONCLUSIONS: Duration of CEM with the sensitivity of 0.8, 0.9, and 0.95 could be determined by presence of HF, female sex, arterial occlusion, PR more than 91/minute, presence of lacuna, presence of stenosis, and BMI more than 21%. (250).

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury.

BACKGROUND: The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). METHODS: We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of ß2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. RESULTS: In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. CONCLUSIONS: The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.

Cyclodextrins with Multiple Pyrenyl Groups: An Approach to Organic Molecules Exhibiting Bright Excimer Circularly Polarized Luminescence.

We report a simple and effective approach to organic molecules exhibiting bright circularly polarized luminescence (CPL) by combining a chiral cyclic molecular scaffold and multiple excimer-enabling moieties. An α-cyclodextrin (CyD) scaffold was modified with six pyrenyl groups to obtain pyrene-cyclodextrins (PCDs) in a one-step synthesis from commercially available compounds. The PCDs exhibited high molar extinction coefficients (ϵ≈105  M-1  cm-1 ), polarized emission with a good dissymmetry factor (|glum |≈10-2 ), and quantum yield (Φf ≈0.5). Owing to the excellent photophysical properties of the PCDs, the circularly polarized luminescence brightness (BCPL ) reached 340 M-1  cm-1 . Photophysical and chiroptical studies of the PCDs with only five pyrene units and with linkers of various lengths connecting the CyD with the pyrene units revealed that the formation of a pyrene excimer in a spatially crowded environment is crucial for CPL anisotropy. This study paves the way for the development of bright CPL organic molecules.

BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes.

Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5' ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5' TOP2 adducts in G1 phase. We show here that BRCA1 promotes MRE11-mediated removal of TOP2 adducts in G1 phase. We disrupted the BRCA1 gene in 53BP1-deficient ER-positive breast cancer and B cells. The loss of BRCA1 caused marked increases of pathological TOP2ccs in G1 phase following exposure to etoposide, which generates pathological TOP2ccs. We conclude that BRCA1 promotes the removal of TOP2 adducts from DSB ends for subsequent nonhomologous end joining. BRCA1-deficient cells showed a decrease in etoposide-induced MRE11 foci in G1 phase, suggesting that BRCA1 repairs pathological TOP2ccs by promoting the recruitment of MRE11 to TOP2cc sites. BRCA1 depletion also leads to the increase of unrepaired DSBs upon estrogen treatment both in vitro in G1-arrested breast cancer cells and in vivo in epithelial cells of mouse mammary glands. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens as well as etoposide. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced pathological TOP2ccs throughout the cell cycle.

A central coupler for recombination initiation linking chromosome architecture to S phase checkpoint.

Higher-order chromosome structure is assumed to control various DNA-templated reactions in eukaryotes. Meiotic chromosomes implement developed structures called "axes" and "loops"; both are suggested to tether each other, activating Spo11 to catalyze meiotic DNA double-strand breaks (DSBs) at recombination hotspots. We found that the Schizosaccharomyces pombe Spo11 homolog Rec12 and its partners form two distinct subcomplexes, DSBC (Rec6-Rec12-Rec14) and SFT (Rec7-Rec15-Rec24). Mde2, whose expression is strictly regulated by the replication checkpoint, interacts with Rec15 to stabilize the SFT subcomplex and further binds Rec14 in DSBC. Rec10 provides a docking platform for SFT binding to axes and can partially interact with DSB sites located in loops depending upon Mde2, which is indicative of the formation of multiprotein-based tethered axis-loop complex. These data lead us to propose a mechanism by which Mde2 functions as a recombination initiation mediator to tether axes and loops, in liaison with the meiotic replication checkpoint.

The histone variant H2A.Z promotes initiation of meiotic recombination in fission yeast.

Meiotic recombination is initiated by programmed formation of DNA double strand breaks (DSBs), which are mainly formed at recombination hotspots. Meiotic DSBs require multiple proteins including the conserved protein Spo11 and its cofactors, and are influenced by chromatin structure. For example, local chromatin around hotspots directly impacts DSB formation. Moreover, DSB is proposed to occur in a higher-order chromatin architecture termed 'axis-loop', in which many loops protrude from cohesin-enriched axis. However, still much remains unknown about how meiotic DSBs are generated in chromatin. Here, we show that the conserved histone H2A variant H2A.Z promotes meiotic DSB formation in fission yeast. Detailed investigation revealed that H2A.Z is neither enriched around hotspots nor axis sites, and that transcript levels of DSB-promoting factors were maintained without H2A.Z. Moreover, H2A.Z appeared to be dispensable for chromatin binding of meiotic cohesin. Instead, in H2A.Z-lacking mutants, multiple proteins involved in DSB formation, such as the fission yeast Spo11 homolog and its regulators, were less associated with chromatin. Remarkably, nuclei were more compact in the absence of H2A.Z. Based on these, we propose that fission yeast H2A.Z promotes meiotic DSB formation partly through modulating chromosome architecture to enhance interaction between DSB-related proteins and cohesin-loaded chromatin.

Review of Single-Cell RNA Sequencing in the Heart.

Single-cell RNA sequencing (scRNA-seq) technology is a powerful, rapidly developing tool for characterizing individual cells and elucidating biological mechanisms at the cellular level. Cardiovascular disease is one of the major causes of death worldwide and its precise pathology remains unclear. scRNA-seq has provided many novel insights into both healthy and pathological hearts. In this review, we summarize the various scRNA-seq platforms and describe the molecular mechanisms of cardiovascular development and disease revealed by scRNA-seq analysis. We then describe the latest technological advances in scRNA-seq. Finally, we discuss how to translate basic research into clinical medicine using scRNA-seq technology.

[A Case of Putaminal Hemorrhage Caused by Underlying Tectal Glioblastoma].

We report a case of glioblastoma due to putaminal hemorrhage. Notably, the glioblastoma was located at some distance from the hematoma. A 42-year-old right-handed man presented with a sudden-onset headache, motor aphasia, and right hemiplegia. CT showed left putaminal hemorrhage and a mass lesion with a slightly high density in the midbrain away from the hematoma. Conservative treatment was initiated for the patient. Initially, we suspected a benign tumor-like cavernous malformation based on the CT findings. However, MRI showed ring enhancement of the mass lesion on contrast-enhanced MRI and hyperintensity on arterial spin labeling(ASL). A part of the wall of the putaminal hemorrhage also exhibited hyperintensity on ASL. Since we suspected a malignant brainstem tumor and a secondary intracerebral hemorrhage caused by this tumor, we performed a stereotactic brain biopsy. Histological examination revealed that the tumor was a wild-type IDH-1 glioblastoma. In the acute phase, the intracerebral hemorrhage presented as a hyperintensity on T1-weighted imaging. Therefore, it was difficult to distinguish hemorrhagic glioblastoma from an intracerebral hemorrhage. Even if an intracerebral hemorrhage is observed at common sites, it is important to consider the possibility of a malignant brain tumor and complete a prompt examination. In addition, ASL imaging may be useful in detecting hemorrhagic malignant brain tumors.

RIG-I-Like Receptor and Toll-Like Receptor Signaling Pathways Cause Aberrant Production of Inflammatory Cytokines/Chemokines in a Severe Fever with Thrombocytopenia Syndrome Virus Infection Mouse Model.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a tick-borne phlebovirus of the family Bunyaviridae, SFTS virus (SFTSV). Wild-type and type I interferon (IFN-I) receptor 1-deficient (IFNAR1-/-) mice have been established as nonlethal and lethal models of SFTSV infection, respectively. However, the mechanisms of IFN-I production in vivo and the factors causing the lethal disease are not well understood. Using bone marrow-chimeric mice, we found that IFN-I signaling in hematopoietic cells was essential for survival of lethal SFTSV infection. The disruption of IFN-I signaling in hematopoietic cells allowed an increase in viral loads in serum and produced an excess of multiple inflammatory cytokines and chemokines. The production of IFN-I and inflammatory cytokines was abolished by deletion of the signaling molecules IPS-1 and MyD88, essential for retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and Toll-like receptor (TLR) signaling, respectively. However, IPS-1-/- MyD88-/- mice exhibited resistance to lethal SFTS with a moderate viral load in serum. Taken together, these results indicate that adequate activation of RLR and TLR signaling pathways under low to moderate levels of viremia contributed to survival through the IFN-I-dependent antiviral response during SFTSV infection, whereas overactivation of these signaling pathways under high levels of viremia resulted in abnormal induction of multiple inflammatory cytokines and chemokines, causing the lethal disease.IMPORTANCE SFTSV causes a severe infectious disease in humans, with a high fatality rate of 12 to 30%. To know the pathogenesis of the virus, we need to clarify the innate immune response as a front line of defense against viral infection. Here, we report that a lethal animal model showed abnormal induction of multiple inflammatory cytokines and chemokines by an uncontrolled innate immune response, which triggered the lethal SFTS. Our findings suggest a new strategy to target inflammatory humoral factors to treat patients with severe SFTS. Furthermore, this study may help the investigation of other tick-borne viruses.

The conserved histone variant H2A.Z illuminates meiotic recombination initiation.

Meiotic recombination ensures faithful chromosome segregation and confers genetic diversity to gametes, and thus, is a key DNA-templated reaction not only for sexual reproduction, but also evolution. This recombination is initiated by programmed DNA double strand breaks (DSBs), which are mainly formed at recombination hotspots. As meiotic DSB formation requires multiple proteins, it is regulated by chromatin structure. In particular, DSB occurs in a higher-order chromatin architecture termed "axis-loop", in which many loops protrude from proteinaceous axis. Previous studies have suggested that assembly of this structure is dependent on chromatin binding of cohesin, which in turn recruits proteins implicated in DSB formation. However, roles of chromatin in meiotic DSB formation are not fully characterized. This review article summarizes our recent report showing that the conserved histone H2A variant H2A.Z promotes meiotic DSB formation in fission yeast. Through a series of experiments, we found that, in H2A.Z-lacking mutants, multiple proteins involved in DSB formation, but not cohesin subunits, are less associated with chromatin. Strikingly, nuclei were more compact in the absence of H2A.Z. These observations led us to propose that fission yeast H2A.Z promotes meiotic DSB formation partly through modulating chromosome architecture to enhance interaction between DSB-related proteins and cohesin-loaded chromatin. In addition, biological implications of our findings are discussed, and their relevance to DSB formation in other species as well as to other DNA-related events are also provided.

Axillofemoral Bypass Markedly Improved Acute Decompensated Heart Failure and Kidney Injury in a Patient with Severely Calcified Stenosis of Thoracoabdominal Aorta (Atypical Aortic Coarctation).

Atypical aortic coarctation (AAC) has been reported to occur anywhere along the aorta, except for the ascending aorta. The associated symptoms include hypotension in the lower half of the body, secondary hypertension in the upper half of the body, and heart failure. Here we present an 80-year-old Asian woman complaining of progressive exertional dyspnea. She was diagnosed with acute decompensated heart failure and kidney injury due to severely calcified stenosis of the thoracoabdominal aorta, the so called AAC. She received hemodiafiltration, and pulmonary congestion improved in part. Generally, surgical treatments are quite invasive in elderly patients. Endovascular stent graft placement is less invasive, however, fracture and rupture should be considered at severely calcified lesions like this case. Therefore, we selected extra-anatomical axillofemoral bypass. Her recovery after the surgery was remarkable. In a few days, she became free from hemodiafiltration, intravenous diuretics, and oxygen administration. We thought the contributive factors are the increase in kidney blood flow and the correction of afterload mismatch. The decrease in pulse pressure may reflect the reduction in systemic arterial compliance by axillofemoral bypass. The operative mortality of axillofemoral bypass was reported to be acceptable, although the patency of the axillofemoral bypass graft was not high enough. In conclusion, axillofemoral bypass is effective and feasible for elderly patients with acute decompensated heart failure and kidney injury due to AAC.