2,5-Dimethyl-celecoxib induces early termination of inflammatory responses by transient macrophage accumulation and inhibits the progression of cardiac remodeling in a mouse model of cryoinjury-induced myocardial infarction.

In our previous study, we reported that 2, 5-dimethyl-celecoxib (DM-C), a derivative of celecoxib, prevents cardiac remodeling in different mouse models of heart failure, including myocardial infarction (MI). The inflammatory response after MI affects the progression of cardiac remodeling, wherein the immune cells, mainly macrophages, play crucial roles. Therefore, we evaluated the effect of DM-C on macrophages in a cryoinjury-induced myocardial infarction (CMI) mouse model. We observed that DM-C attenuated the deterioration of left ventricular ejection fraction and cardiac fibrosis 14 d after CMI. Gene expression of pro-inflammatory cytokines at the infarct site was reduced by DM-C treatment. Analysis of macrophage surface antigens revealed that DM-C induced transient accumulation of macrophages at the infarct site without affecting their polarization. In vitro experiments using peritoneal monocytes/macrophages revealed that DM-C did not directly increase the phagocytic ability of the macrophages but increased their number, thereby upregulating the clearance capacity. Moreover, DM-C rapidly excluded the cells expressing necrotic cell marker from the infarct site. These results suggested that DM-C enhanced the clearance capacity of macrophages by transiently increasing their number at the infarct site, and terminated the escape from the inflammatory phase earlier, thereby suppressing excessive cardiac remodeling and ameliorating cardiac dysfunction.

Online Personalized Preference Learning Method Based on In-Formative Query for Lane Centering Control Trajectory.

The personalization of autonomous vehicles or advanced driver assistance systems has been a widely researched topic, with many proposals aiming to achieve human-like or driver-imitating methods. However, these approaches rely on an implicit assumption that all drivers prefer the vehicle to drive like themselves, which may not hold true for all drivers. To address this issue, this study proposes an online personalized preference learning method (OPPLM) that utilizes a pairwise comparison group preference query and the Bayesian approach. The proposed OPPLM adopts a two-layer hierarchical structure model based on utility theory to represent driver preferences on the trajectory. To improve the accuracy of learning, the uncertainty of driver query answers is modeled. In addition, informative query and greedy query selection methods are used to improve learning speed. To determine when the driver's preferred trajectory has been found, a convergence criterion is proposed. To evaluate the effectiveness of the OPPLM, a user study is conducted to learn the driver's preferred trajectory in the curve of the lane centering control (LCC) system. The results show that the OPPLM can converge quickly, requiring only about 11 queries on average. Moreover, it accurately learned the driver's favorite trajectory, and the estimated utility of the driver preference model is highly consistent with the subject evaluation score.

Potential mechanism of left ventricular spherical remodeling: association of mitral valve complex-myocardium longitudinal tissue remodeling mismatch.

Since mitral valve (MV) complex (MVC) longitudinally bridges left ventricular (LV) base end and its middle, insufficient MVC longitudinal tissue length (TL) elongation relative to whole LV myocardial longitudinal TL elongation could limit LV-base-longitudinal-TL elongation, leading to predominant LV-base-transverse-TL elongation, constituting LV spherical remodeling. In 30 patients with dilated cardiomyopathy (DCM), 30 with aortic regurgitation (AR), and 30 controls, LV sphericity, LV-apex- or base-transverse- and longitudinal-TL, MVC-longitudinal-TL, and whole-LV-longitudinal-TL were measured by three-dimensional (3D) echocardiography. Ratio of each measure versus mean normal value (i.e., LV-apex-transverse-TL ratio) was considered to express the directional and regional tissue elongation. [LV-base-longitudinal-TL ratio/global-LV-TL ratio] and [MVC-longitudinal-TL ratio/whole-LV-longitudinal-TL ratio] were obtained as the degree of LV-base-longitudinal-TL or MVC-longitudinal-TL elongation relative to the whole LV elongation. LV-apex-transverse-, LV-apex-longitudinal-, and LV-base-transverse-TL ratios were significantly increased (1.27 to 1.42, P < 0.01) in both DCM and AR, while the LV-base-longitudinal-TL ratio was not increased in DCM [1.04 ± 0.19, not significant (ns)] and only modestly increased in AR (1.12 ± 0.21, P < 0.01). Whole-LV-longitudinal-TL ratio was significantly increased in both DCM and AR (1.22 ± 0.18 and 1.20 ± 0.16, P < 0.01), while MVC-longitudinal-TL ratio was not or only modestly increased in both groups (1.07 ± 0.15, ns, and 1.12 ± 0.17, P = 0.02, respectively). Multivariable analysis revealed that LV sphericity was independently related to a reduced [LV-base-longitudinal-TL ratio/global-LV-TL ratio] (standard ß = -0.42, P < 0.01), which was further related to a reduced [MVC-longitudinal-TL ratio/whole-LV-longitudinal-TL ratio] (standard ß = 0.72, P < 0.01). These are consistent with the hypothesis that relatively less MVC-longitudinal-TL elongation in the process of primary LV myocardial tissue elongation may limit LV-base-longitudinal-TL elongation, contributing to LV spherical remodeling.NEW & NOTEWORTHY Left ventricular (LV) spherical remodeling is associated with poor prognosis and less-effective cardiac performance, which commonly develops in dilated cardiomyopathy. However, its mechanism remains unclear. We hypothesized and subsequently clarified that less mitral valve complex (MVC) tissue longitudinal elongation relative to whole LV myocardial tissue longitudinal elongation is related to disproportionately less LV base longitudinal versus transverse myocardial tissue elongation, constituting spherical remodeling. This study suggests modification of MVC tissue elongation could be potential therapeutic targets.

Relations of Augmented Systolic Annular Expansion and Leaflet/Papillary Muscle Dynamics in Late-Systolic Mitral Valve Prolapse Evaluated by Echocardiography with a Speckle Tracking Analysis.

The mechanism of systolic annular expansion in mitral valve prolapse (MVP) is not clarified. Since annular expansion is systolic outward shift of MV leaflet/chorda tissue complex at superior and outer ends, annular expansion could be related to inward (superior) shift of the complex at another inferior and inner end of the papillary muscle (PM) tip and/or systolic lengthening of the tissue complex, especially MV leaflets.MV annulus systolic expansion, PMs' systolic superior shift, and MV leaflets' systolic lengthening were evaluated by echocardiography with a speckle tracking analysis in 25 normal subjects, 25 subjects with holo-systolic MVP and 20 subjects with late-systolic MVP.PMs' superior shift, MV leaflets' lengthening, MV annular area at the onset of systole and subsequent MV annulus expansion were significantly greater in late-systolic MVP than in holo-systolic MVP (4.6 ± 1.6 versus 1.5 ± 0.7 mm/m2, 2.5 ± 1.4 versus 0.6 ± 2.0 mm/m2, 6.8 ± 2.5 versus 5.7 ± 1.0 cm2/m2 and 1.6 ± 0.8 versus 0.1 ± 0.5 cm2/m2, P < 0.001, respectively). Multivariate analysis identified MV leaflets' lengthening and PMs' superior shift as independent factors associated with MV annular expansion.Conclusions: These results suggest that systolic MV annular expansion in MVP is related to abnormal MV leaflets' lengthening and PMs' superior shift.

Photochemical Characterization of a New Heliorhodopsin from the Gram-Negative Eubacterium Bellilinea caldifistulae (BcHeR) and Comparison with Heliorhodopsin-48C12.

Many microorganisms express rhodopsins, pigmented membrane proteins capable of absorbing sunlight and harnessing that energy for important biological functions such as ATP synthesis and phototaxis. Microbial rhodopsins that have been discovered to date are categorized as type-1 rhodopsins. Interestingly, researchers have very recently unveiled a new microbial rhodopsin family named the heliorhodopsins, which are phylogenetically distant from type-1 rhodopsins. Among them, only heliorhodopsin-48C12 (HeR-48C12) from a Gram-positive eubacterium has been photochemically characterized [Pushkarev, A., et al. (2018) Nature 558, 595-599]. In this study, we photochemically characterize a purple-colored heliorhodopsin from Gram-negative eubacterium Bellilinea caldifistulae (BcHeR) as a second example and identify which properties are or are not conserved between BcHeR and HeR-48C12. A series of photochemical measurements revealed several conserved properties between them, including a visible absorption spectrum with a maximum at around 550 nm, the lack of ion-transport activity, and the existence of a second-order O-like intermediate during the photocycle that may activate an unidentified biological function. In contrast, as a property that is not conserved, although HeR-48C12 shows the light adaptation state of retinal, BcHeR showed the same retinal configuration under both dark- and light-adapted conditions. These comparisons of photochemical properties between BcHeR and HeR-48C12 are an important first step toward understanding the nature and functional role of heliorhodopsins.

Genome-resolved viral and cellular metagenomes revealed potential key virus-host interactions in a deep freshwater lake.

Metagenomics has dramatically expanded the known virosphere, but freshwater viral diversity and their ecological interaction with hosts remain poorly understood. Here, we conducted a metagenomic exploration of planktonic dsDNA prokaryotic viruses by sequencing both virion (<0.22 µm) and cellular (0.22-5.0 µm) fractions collected spatiotemporally from a deep freshwater lake (Lake Biwa, Japan). This simultaneously reconstructed 183 complete (i.e., circular) viral genomes and 57 bacterioplankton metagenome-assembled genomes. Analysis of metagenomic read coverage revealed vertical partitioning of the viral community analogous to the vertically stratified bacterioplankton community. The hypolimnetic community was generally stable during stratification, but occasionally shifted abruptly, presumably due to lysogenic induction. Genes involved in assimilatory sulfate reduction were encoded in 20 (10.9%) viral genomes, including those of dominant viruses, and may aid viral propagation in sulfur-limited freshwater systems. Hosts were predicted for 40 (21.9%) viral genomes, encompassing 10 phyla (or classes of Proteobacteria) including ubiquitous freshwater bacterioplankton lineages (e.g., Ca. Fonsibacter and Ca. Nitrosoarchaeum). Comparison with viral genomes derived from published metagenomes revealed viral phylogeographic connectivity in geographically isolated habitats. Notably, analogous to their hosts, actinobacterial viruses were among the most diverse, ubiquitous and abundant viral groups in freshwater systems, with potential high lytic activity in surface waters.

Possible mechanism of late systolic mitral valve prolapse: systolic superior shift of leaflets secondary to annular dilatation that causes papillary muscle traction.

Progressive superior shift of the mitral valve (MV) during systole is associated with abnormal papillary muscle (PM) superior shift in late systolic MV prolapse (MVP). The causal relation of these superior shifts remains unclarified. We hypothesized that the MV superior shift is related to augmented MV superiorly pushing force by systolic left ventricular pressure due to MV annular dilatation, which can be corrected by surgical MV plasty, leading to postoperative disappearance of these superior shifts. In 35 controls, 28 patients with holosystolic MVP, and 28 patients with late systolic MVP, the MV coaptation depth from the MV annulus was measured at early and late systole by two-dimensional echocardiography. The PM tip superior shift was monitored by echocardiographic speckle tracking. MV superiorly pushing force was obtained as MV annular area × (systolic blood pressure - 10). Measurements were repeated after MV plasty in 14 patients with late systolic MVP. Compared with controls and patients with holosystolic MVP, MV and PM superior shifts and MV superiorly pushing force were greater in patients with late systolic MVP [1.3 (0.5) vs. 0.9 (0.6) vs. 3.9 (1.0) mm/m2, 1.3 (0.5) vs. 1.2 (1.0) vs. 3.3 (1.3) mm/m2, and 487 (90) vs. 606 (167) vs. 742 (177) mmHg·cm2·m-2, respectively, means (SD), P < 0.001]. MV superior shift was correlated with PM superior shift ( P < 0.001), which was further related to augmented MV superiorly pushing force ( P < 0.001). MV and PM superior shift disappeared after surgical MV plasty for late systolic MVP. These data suggest that MV annulus dilatation augmenting MV superiorly pushing force may promote secondary superior shift of the MV (equal to late systolic MVP) that causes subvalvular PM traction in patients with late systolic MVP. NEW & NOTEWORTHY Late systolic mitral valve prolapse (MVP) is associated with mitral valve (MV) and papillary muscle (PM) abnormal superior shifts during systole, but the causal relation remains unclarified. MV and PM superior shifts were correlated with augmented MV superiorly pushing force by annular dilatation and disappeared after surgical MV plasty with annulus size and MV superiorly pushing force reduction. This suggests that MV annulus dilatation may promote secondary superior shifts of the MV (late systolic MVP) that cause subvalvular PM traction.

Cooccurrence of Broad- and Narrow-Host-Range Viruses Infecting the Bloom-Forming Toxic Cyanobacterium Microcystis aeruginosa.

Viruses play important roles in regulating the abundance and composition of bacterial populations in aquatic ecosystems. The bloom-forming toxic cyanobacterium Microcystis aeruginosa is predicted to interact with diverse cyanoviruses, resulting in Microcystis population diversification. However, current knowledge of the genomes from these viruses and their infection programs is limited to those of Microcystis virus Ma-LMM01. Here, we performed a time series sampling at a small pond in Japan during a Microcystis bloom and then investigated the genomic information and transcriptional dynamics of Microcystis-interacting viruses using metagenomic and metatranscriptomic approaches. We identified 15 viral genomic fragments classified into three groups, groups I (including Ma-LMM01), II (high abundance and transcriptional activity), and III (new lineages). According to the phylogenetic distribution of Microcystis strains possessing spacers against each viral group, the group II-original viruses interacted with all three phylogenetically distinct Microcystis population types (phylotypes), whereas the groups I and III-original viruses interacted with only one or two phylotypes, indicating the cooccurrence of broad- (group II) and narrow (groups I and III)-host-range viruses in the bloom. These viral fragments showed the highest transcriptional levels during daytime regardless of their genomic differences. Interestingly, M. aeruginosa expressed antiviral defense genes in the environment, unlike what was seen with an Ma-LMM01 infection in a previous culture experiment. Given that broad-host-range viruses often induce antiviral responses within alternative hosts, our findings suggest that such antiviral responses might inhibit viral multiplication, mainly that of broad-host-range viruses like those in group II.IMPORTANCE The bloom-forming toxic cyanobacterium Microcystis aeruginosa is thought to have diversified its population through the interactions between host and viruses in antiviral defense systems. However, current knowledge of viral genomes and infection programs is limited to those of Microcystis virus Ma-LMM01, which was a narrow host range in which it can escape from the highly abundant host defense systems. Our metagenomic approaches unveiled the cooccurrence of narrow- and broad-host-range Microcystis viruses, which included fifteen viral genomic fragments from Microcystis blooms that were classified into three groups. Interestingly, Microcystis antiviral defense genes were expressed against viral infection in the environment, unlike what was seen in a culture experiment with Ma-LMM01. Given that viruses with a broad host range often induce antiviral responses within alternative hosts, our findings suggest that antiviral responses inhibit viral reproduction, especially that of broad-range viruses like those in group II. This paper augments our understanding of the interactions between M. aeruginosa and its viruses and fills an important knowledge gap.

[A Case of Successful Surgery for Adult Partial Atrioventricular Septal Defect].

We report a case of a 55-year-old male who had been diagnosed with mitral regurgitation and atrial septal defect 5 years earlier. He was referred to our institution because of worsening of mitral regurgitation accompanied by exertional dyspnea. As an echocardiography showed atrioventricular valve regurgitation and ostium primum atrial septal defect, but without ventricular septal defect, he was diagnosed as having partial atrioventricular septal defect (pAVSD). An operation was performed through median sternotomy. The anterior atrioventricular leaflet had a cleft and thickening with calcification. Suturing the cleft could not control the regurgitation. Incomplete coaptation was seen at the edge of the anastomosis site of the cleft, where the severe calcification had been identified. A rough zone including a part of the chordae tendineae was sutured in order to compensate for the gap. The atrioventricular septal defect was closed with an autologous pericardial patch. He was discharged uneventfully on the 24th postoperative day and has been followed up without complications for 1.5 years.

Surgical Therapy for Patients with Severe Aortic Stenosis in the Era of Transcatheter Aortic Valve Replacement.

Aortic stenosis (AS) is the most common valvular heart disease and is most frequently recognized among elderly people. Surgical aortic valve replacement (SAVR) is the most effective therapy, but its indication is sometimes difficult, and is impossible for high operative risk patients. Transcatheter aortic valve replacement (TAVR) was recently approved in Japan for high risk and inoperable patients with severe AS. TAVR is a less invasive method because it does not require a cardiopulmonary bypass and is associated with excellent surgical outcomes. In Western countries, the indication of TAVR has already been extended to moderate operative risk patients with severe AS, and is going to be further extended to low risk patients. The number of patients undergoing TAVR is increasing progressively, and there are effective alternative therapies for patients with severe AS. Selection of these surgical methods will be important in the near future. In regard to low operative risk patients especially, not only operative mortality, but also long-tern mortality and morbidity and quality of life should be taken into consideration. It is considered that some comorbidities in AS patients will be revealed to have an impact on surgical outcomes at the time when these surgical methods are selected. In this review, we examine end-stage renal disease on hemodialysis, functional tricuspid regurgitation, and sigmoid septum, and give an outline of what influence SAVR and TAVR have on the surgical outcomes of severe AS patients.

ViPTree: the viral proteomic tree server.

SUMMARY: ViPTree is a web server provided through GenomeNet to generate viral proteomic trees for classification of viruses based on genome-wide similarities. Users can upload viral genomes sequenced either by genomics or metagenomics. ViPTree generates proteomic trees for the uploaded genomes together with flexibly selected reference viral genomes. ViPTree also serves as a platform to visually investigate genomic alignments and automatically annotated gene functions for the uploaded viral genomes, thus providing virus researchers the first choice for classifying and understanding newly sequenced viral genomes. AVAILABILITY AND IMPLEMENTATION: ViPTree is freely available at: http://www.genome.jp/viptree . CONTACT: goto@kuicr.kyoto-u.ac.jp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Surgical as Opposed to Transcatheter Aortic Valve Replacement Improves Basal Interventricular Septal Hypertrophy.

BACKGROUND: Basal interventricular septum (IVS) hypertrophy (BSH) with reduced basal IVS contraction and IVS-aorta angle is frequently associated with aortic stenosis (AS). BSH shape suggests compression by the longitudinally elongated ascending aorta, causing basal IVS thickening and contractile dysfunction, further suggesting the possibility of aortic wall shortening to improve the BSH. Surgical aortic valve replacement (SAVR), as opposed to transcatheter AVR (TAVR), includes aortic wall shortening by incision and stitching on the wall and may potentially improve BSH. We hypothesized that BSH configuration and its contraction improves after SAVR in patients with AS. Methods and Results: In 32 patients with SAVR and 36 with TAVR for AS, regional wall thickness and systolic contraction (longitudinal strain) of 18 left ventricular (LV) segments, and IVS-aorta angle were measured on echocardiography. After SAVR, basal IVS/average LV wall thickness ratio, basal IVS strain, and IVS-aorta angle significantly improved (1.11±0.24 to 1.06±0.17; -6.2±5.7 to -9.1±5.2%; 115±22 to 123±14°, P<0.001, respectively). Contractile improvement in basal IVS was correlated with pre-SAVR BSH (basal IVS/average LV wall thickness ratio or IVS-aorta angle: r=0.47 and 0.49, P<0.01, respectively). In contrast, BSH indices did not improve after TAVR. CONCLUSIONS: In patients with AS, SAVR as opposed to TAVR improves associated BSH and its functional impairment.

Left Atrial Remodeling in Segmental vs. Global Mitral Valve Prolapse　- Three-Dimensional Echocardiography.

BACKGROUND: Segmental and global mitral valve prolapse (MVP) comprise 2 representative phenotypes in this syndrome. While mitral regurgitation (MR) severity is a major factor causing left atrial (LA) remodeling in MVP, prominent mitral valve (MV) annulus dilatation in global MVP may specifically cause inferiorly predominant LA remodeling. We compared MV annulus and LA geometry in patients with segmental and global MVP.Methods and Results:LA volume as well as inferior, middle, and superior LA cross-sectional areas (CSA) were measured on 3-D echocardiography in 20 controls, in 40 patients with segmental MVP, and in 18 with global MVP. On multivariate analysis, MR severity was primarily associated with LA dilatation in segmental MVP (P<0.001), while MV annular dilatation was primarily associated with LA dilatation in global MVP (P<0.001). Although there was no regional predominance in LA dilatation in segmental MVP, inferior predominance of LA dilatation was significant in global MVP (increase in inferior, middle, and superior LA-CSA relative to mean of the controls: +220±70% vs. +171±55% vs. +137±37%, P<0.001). CONCLUSIONS: LA remodeling in segmental and global MVP is considerably different regarding its association with MR volume or MV annular dilatation and its regional predominance. While MR volume may mainly contribute to LA remodeling in segmental MVP, MV annular dilatation seems to have an important role in LA remodeling in global MVP. (Circ J 2016; 80: 2533-2540).

[Mitral Valve Repair for Patients with Mitral Valve Prolapse].

Prosthetic valve replacement has mainly been performed on patients with mitral regurgitation. In such cases, prosthetic valve related complications, such as thromboembolism, bleeding, prosthetic valve infection, and structural valve deterioration, are unavoidable. With valve plasty, however, not only can such complications be avoided, but patients can also have as good a quality of life as healthy people without medications. Although mitral valve plasty requires complicated techniques like chordal reconstruction and has problems of residue, recurrence, and progression of regurgitation, patients with mitral valve prolapse are considered to be good candidates for this procedure. Mitral annuloplasty with a prosthetic ring is the essential and basic procedure of this operation, usually adding to the other techniques. Resection and suture methods of quadrangular resection, triangular resection and the sliding method, by which systolic anterior movement can be avoided, are indicated for patients with posterior leaflets prolapse. The resection and suture method, chordal shortening, and chordal transposition were previously done on patients with anterior leaflets prolapse, but recently chordal reconstruction using ePTFE (expanded polytetrafluoroethylene) is performed. Superior long-term results of mitral valve plasty for patients with mitral valve prolapse compared to prosthetic valve replacement have been reported. The 10-year reoperation rate of mitral valve plasty is only 7-10% as much as valve replacement.

DiGAlign: Versatile and Interactive Visualization of Sequence Alignment for Comparative Genomics.

With the explosion of available genomic information, comparative genomics has become a central approach to understanding microbial ecology and evolution. We developed DiGAlign (https://www.genome.jp/digalign/), a web server that provides versatile functionality for comparative genomics with an intuitive interface. It allows the user to perform the highly customizable visualization of a synteny map by simply uploading nucleotide sequences of interest, ranging from a specific region to the whole genome landscape of microorganisms and viruses. DiGAlign will serve a wide range of biological researchers, particularly experimental biologists, with multifaceted features that allow the rapid characterization of genomic sequences of interest and the generation of a publication-ready figure.

Updated pathophysiological overview of functional MR (ventricular and atrial).

Basic mechanism of ventricular functional mitral regurgitation (FMR) is subvalvular tethering. Left ventricular (LV) dilatation, in association with mitral valve (MV) annular dilatation, causes outward displacement of papillary muscles (PMs), which abnormally pulls or tethers MV leaflets, resulting in MV tenting, reduction in leaflets coaptation and MR. Because surgical annuloplasty does shorten distance between anterior and posterior MV annuli to improve coaptation but does not address this subvalvular tethering, ventricular FMR frequently persists or recurs in the chronic stage after surgical annuloplasty. This high incidence of persistent/recurrent MR requires additional procedures to reduce subvalvular tethering. Although patients occasionally show marked improvements after annuloplasty with surgical tethering reduction procedures such as PM approximation, evidence to support benefits of such surgery is limited, requiring further trials. Recently, MV adaptation or MV leaflets tissue growth associated with LV dilatation attracts attention. Patients with larger MV leaflets with significant LV dilatation/dysfunction show less MV tethering and MR compared to those with smaller MV leaflets but with similar LV remodeling, suggesting the protective or beneficial role of MV leaflets tissue growth against LV remodeling. The MV leaflets tissue growth has the potential to lead to novel strategies of treatment for ventricular FMR. It is well known that atrial FMR is frequent in patients with left atrial dilatation, typically in those with isolated atrial fibrillation. The degree of atrial FMR is usually mild, even when it is present, and occasionally moderate, and severe atrial FMR is really rare. It is known that only severe regurgitation causes heart failure in primary MR, resulting in description on indications of surgery or intervention for only severe MR in current guidelines. Therefore, this atrial FMR up to moderate degree did not attract attention for a long time. However, recent studies have shown that patients with only moderate atrial FMR develop severe heart failure, suggesting more aggressive indication of MV surgery or intervention for "moderate" regurgitation in patients with atrial FMR. Therefore, atrial FMR is now recognized highly important. The unveiled malignant nature of atrial FMR arises many questions, including (1) why patients with only moderate atrial FMR develop heart failure? (2) do patients with mild atrial FMR develop heart failure or not?, and many others. Atrial FMR seems even more mysterious after the unveiling of its significance.

Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions.

BACKGROUND AND AIMS: In advanced atherosclerotic lesions, macrophage deaths result in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. Therefore, this experiment aims to clarify the role of CypD in necrotic core formation. METHODS: To clarify the specific role of CypD, encoded by Ppif in mice, apolipoprotein-E/CypD-double knockout (Apoe-/-Ppif-/-) mice were generated. These mice were fed a high-fat diet containing 0.15 % cholesterol for 24 weeks to accelerate atherosclerotic lesion development. RESULTS: Deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control Apoe-/- mice. In RAW264.7 cells, siRNA-mediated knockdown of CypD attenuated the release of cytochrome c from the mitochondria to the cytosol induced by endoplasmic reticulum stress inducer thapsigargin. In addition, necroptosis, induced by TNF-α and caspase inhibitor, was attenuated by knockdown of CypD. Ly-6Chigh inflammatory monocytes in peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-γ, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. CONCLUSIONS: These results indicate that CypD induces macrophage death and mediates necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

Double-stranded RNA sequencing reveals distinct riboviruses associated with thermoacidophilic bacteria from hot springs in Japan.

Metatranscriptome sequencing expanded the known diversity of the bacterial RNA virome, suggesting that additional riboviruses infecting bacterial hosts remain to be discovered. Here we employed double-stranded RNA sequencing to recover complete genome sequences of two ribovirus groups from acidic hot springs in Japan. One group, denoted hot spring riboviruses (HsRV), consists of viruses with distinct RNA-directed RNA polymerases (RdRPs) that seem to be intermediates between typical ribovirus RdRPs and viral reverse transcriptases. This group forms a distinct phylum, Artimaviricota, or even kingdom within the realm Riboviria. We identified viruses encoding HsRV-like RdRPs in marine water, river sediments and salt marshes, indicating that this group is widespread beyond extreme ecosystems. The second group, denoted hot spring partiti-like viruses (HsPV), forms a distinct branch within the family Partitiviridae. The genome architectures of HsRV and HsPV and their identification in bacteria-dominated habitats suggest that these viruses infect thermoacidophilic bacteria.

Draft genome sequences of three rhodopsin possessing Croceitalea sp. strains, isolated from the sea surface microlayer in Japan.

Here, we present the draft genome sequences of three Croceitalea sp. strains containing microbial rhodopsins, isolated from the Japanese coastal sea surface microlayer, which is exposed to intense sunlight. This study will contribute to the understanding of the genus Croceitalea and the diversity of microbial rhodopsins.

Potential Effects of Mild Atrial Secondary Mitral Regurgitation in Patients With Isolated Atrial Fibrillation.

BACKGROUND: Patients with only moderate atrial secondary mitral regurgitation (asMR) frequently develop heart failure (HF). Mechanisms of HF with moderate asMR and the impact of mild asMR remain unclarified. Although mild/moderate primary mitral regurgitation is compensated by left ventricular (LV) dilatation, the LV is not dilated in asMR. We hypothesized that patients with mild asMR without LV dilatation may have impaired hemodynamics and higher risks of subsequent symptomatic HF deterioration. METHODS: Stroke volume, cardiac output, and systolic pulmonary artery pressure were measured by echocardiography in 142 patients with isolated atrial fibrillation and 30 healthy controls. The prognosis of patients with isolated atrial fibrillation was followed up. RESULTS: In the 142 patients with isolated atrial fibrillation, asMR was no/trivial in 55, mild in 83, moderate in 4, while none had severe asMR. Compared with controls and patients with no/trivial asMR, LV end-diastolic volume index was not increased and hemodynamic parameters were abnormal in patients with mild asMR (LV end-diastolic volume index, 65±6 versus 58±8 versus 60±8 mL/m²; stroke volume index, 42±4 versus 35±4 versus 29±6 mL/m²; P<0.001 versus other 2 groups; cardiac output index, 2.8±0.4 versus 2.8±0.5 versus 2.3±0.6 L/min per m²; P<0.001; systolic pulmonary artery pressure, 21±3 versus 26±5 versus 37±9 mm Hg; P<0.001). Although the event-free rate of HF symptomatic deterioration or hospitalization in patients with no/trivial asMR during a median 13.9 months follow-up was 86.9% and 100%, the rate in mild asMR was 59.4% and 85.0% (P<0.001 or P=0.032), respectively. CONCLUSIONS: In the presence of isolated AF and no compensatory LV dilatation, impaired hemodynamics and higher risks of symptomatic HF deterioration were associated with mild asMR, requiring further studies of causalities.