The GHIJKL fragment of gymnocin-B was synthesized using the oxiranyl anion strategy. The first highlight of the synthesis is the bromoketone cyclization reaction on the oxepane ring to construct the ...fused bisoxepane GH ring. The second key step is the introduction of the trans-4-hydroxy-3-methyloxepane J ring via addition of trimethylaluminum to a conjugated oxonium moiety, followed by diastereoselective epoxidation and regioselective reduction.
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IJS, KILJ, NUK, PNG, UL, UM
In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential ...antibody response, we examined spike receptor-binding domain (RBD)-specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose.
The behavioral photosensitivity of animals could be quantified via the optomotor response (OMR), for example, and the luminous efficiency function (the range of visible light) should largely rely on ...the repertoire and expression of light-absorbing proteins in the retina, i.e., the opsins. In fact, the OMR under red light was suppressed in medaka lacking the red (long-wavelength sensitive LWS) opsin.
We investigated the ultraviolet (UV)- or blue-light sensitivity of medaka lacking the violet (short-wavelength sensitive 1 SWS1) and blue (SWS2) opsins. The sws1/sws2 double or sws1/sws2/lws triple mutants were as viable as the wild type. The remaining green (rhodopsin 2 RH2) or red opsins were not upregulated. Interestingly, the OMR of the double or triple mutants was equivalent or even increased under UV or blue light (λ = 350, 365, or 450 nm), which demonstrated that the rotating stripes (i.e., changes in luminance) could fully be recognized under UV light using RH2 alone. The OMR test using dichromatic stripes projected onto an RGB display consistently showed that the presence or absence of SWS1 and SWS2 did not affect the equiluminant conditions.
RH2 and LWS, but not SWS1 and SWS2, should predominantly contribute to the postreceptoral processes leading to the OMR or, possibly, to luminance detection in general, as the medium-wavelength-sensitive and LWS cones, but not the SWS cones, are responsible for luminance detection in humans.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dynamic rearrangement of the actin cytoskeleton impacts many cellular characteristics in both the developing and adult central nervous systems (CNS), including the migration and adhesion of highly ...motile neural progenitor cells, axon guidance of immature neurons, and reconstruction of synaptic structures in the adult brain. Inka1, a known regulator of actin cytoskeleton reconstruction, is predominantly expressed by the neural crest cell lineage and regulates the migration and differentiation of these cells. In the present study, we identified a novel gene, designated as inka2, which is related to inka1. Inka2/fam212b is an evolutionarily conserved gene found in different vertebrate species and constitutes a novel gene family together with inka1. Northern blot analysis showed that inka2 mRNA was highly enriched in the nervous system. The spatiotemporal propagation cell profiles of those cells that expressed inka2 transcripts were compatible with those of Olig2-positive oligodendrocyte progenitor cells, which originate in the ventral ventricular zone during embryogenesis. Intense expression of inka2 was also noted in the proliferative neuronal progenitors in the developing cerebellum. On the other hand, immature newborn neurons in the embryonic brain showed no expression of inka2, except for the cells residing in the marginal zone of the embryonic telencephalon, which is known to contain transient cells including the non-subplate pioneer neurons and Cajal–Retzius cells. As brain development proceeds during the postnatal stage, inka2 expression emerged in some populations of immature neurons, including the neocortical pyramidal neurons, hippocampal pyramidal neurons, and granule cells migrating in the cerebellar cortex. In the adult brain, the expression of inka2 was interestingly confined in terminally differentiated neurons in the restricted forebrain regions. Taken together, as a novel regulator of actin cytoskeletons in the CNS, inka2 may be involved in multiple actin-driven processes, including cell migration and establishment of neuronal polarity.
•We identified inka2, a novel actin related protein enriched in nervous system.•Inka2 is an evolutionarily conserved gene in different vertebrate species.•Inka2 mRNA was detected in Olig2+ oligodendrocyte progenitors during embryogenesis.•Inka2 was expressed in the restricted neuronal populations in the adult forebrain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Background
The case of aortic valve stenosis complicated with lung cancer have compelled cardiovascular surgeons to make challenging. We report the first successful short-term outcomes of ...one-stage minimally invasive aortic valve replacement and video-assisted thoracoscopic surgery lobectomy through right mini-thoracotomy in a patient with synchronous bicuspid severe aortic valve stenosis which was unsuitable for transcatheter aortic valve implantation and right lung cancer.
Case presentation
A 76-year-old man with severe aortic valve stenosis was diagnosed with lung cancer of the right upper lobe with stage IA2. Considering the potential risk of tumor metastasis, a one-stage surgical therapy for right lung cancer and type 0 bicuspid aortic valve stenosis was required; however, transcatheter aortic valve implantation was unsuitable due to a bicuspid aortic valve with severe calcification. Therefore, concomitant minimally invasive aortic valve replacement and lobectomy via right mini-thoracotomy were performed. The postoperative course was uneventful.
Conclusion
Concomitant aortic valve replacement and right lobectomy via right mini-thoracotomy may reduce surgical invasiveness, leading to early recovery. This surgical strategy is a useful option, particularly for patients with aortic valve stenosis complicated with right lung cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The activation mapping revealed that the earliest site of PVC (arrow in Figure 1A) was in the PA and about 10 mm above the pulmonary valve (dot lines), where a sharp potential preceded QRS onset of ...PVCs by 45 ms. The PVC excitation traveled 10 mm toward the anterior septum (Figure 1C) and then 10 mm downward (Figure 1D), propagating to the RVOT just below the pulmonary valve (Figure 1E). In this case, the high-density (HD Grid) mapping revealed the propagation of PVCs arising from the PA trunk propagated via the preferential conduction pathway and exiting from the RVOT septum beneath the pulmonary valve into ventricles. The high-density mapping can identify the origin and preferential pathway for VAs arising the PA and is useful for ablation for these VAs. Since HD Grid catheter can record potentials in two directions, it is possible to obtain information on the characteristics of minute potentials and the direction of conduction, which is useful for elucidating the mechanism of complex arrhythmias.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Myelodysplastic syndromes (MDS) have a risk of progression to acute myeloid leukemia (AML), but the deterioration mechanisms of MDS and the alteration points still remain to be elucidated. We ...previously established a myelodysplastic cell line, MDS92 from the bone marrow of an MDS patient, and after a long-term interleukin(IL)-3-containing culture of MDS92, five blastic sublines including MDS-L were isolated. From MDS-L, we obtained two sublines, MDS-L-2007 and MDS-LGF after culture in the presence and absence of IL-3, respectively. To investigate the mechanism of leukemic evolution, we applied a next-generation sequencing (NGS) to the series of cell lines for comprehensive, comparative exome analyses, and searched for the origin of mutations by ultra-deep target sequencing of the original patient bone marrow.
Whole exome sequencing and ultra-deep target sequencing demonstrated: (1) TP53 mutation was found in the patient bone marrow and this mutation was inherited by all subsequent cell lines; (2) CEBPA mutation was originally present in a small fraction of the bone marrow; (3) NRAS mutation emerged by chance during IL-3-containing culture; (4) HIST1H3C(K27M) mutation (Histone-H3-K27M) was newly detected at the generation of MDS-L from MDS92. H3-K27M mutation was detected in MDS-L-2007 but not in MDS-LGF.
We focused on H3-K27M mutation because it is frequently found in pediatric brain stem tumors and recently found in a small population of AML cases (Lehnertz et al. Blood. 2017). MDS-L cells were a mixture of H3-K27M-mutant and wild-type clones. When MDS-L was cultured in the presence of IL-3, the proportion of H3-K27M-mutant fraction gradually increased. In contrast, when MDS-L was cultured without IL-3, the proportion of H3-K27M-mutant fraction gradually decreased. To investigate the implication of H3-K27M mutation, we tried single cell cloning from MDS-L and secured four wild-type clones and seven H3-K27M-mutant clones. In all H3-K27M-mutant clones, there was a marked reduction in H3-K27me3/2. Expression of a tumor-suppressor molecule p16 was reduced in six of the seven H3-K27M-mutant clones. H3-K27M-mutant clones showed rapid growth in the presence of IL-3, but cell proliferation was suppressed without IL-3. Competitive growth experiment by co-culture of H3-K27-wild-type and H3-K27M-mutant clones in the presence or absence of IL-3 showed that H3-K27M-mutant clones were predominant in the presence of IL-3, whereas wild-type clones were sustained comparatively in the absence of IL-3. Treatment with EPZ-6438, an inhibitor of H3-K27 methyltransferase EZH2, caused growth suppression of H3-K27M-mutant clones as well as wild-type clones and involved obvious recovery of p16 expression in H3-K27M-mutant clones, which provides a possibility that p16 might be a therapeutic target for H3-K27M mutant. Although GSK-J4, an inhibitor of H3-K27 demethylase JMJD3, was reported to inhibit H3-K27M-mutated pediatric brain stem tumors, GSK-J4 exerted only non-specific growth inhibitory effect on both H3-K27M-mutant and wild-type clones.
Whole exome analyses indicated that the accumulation of oncogenic mutations seemed to have led to establishment of MDS cell lines. The finding that growth advantage of H3-K27M mutant was influenced by the presence or absence of IL-3 raised a possibility that even if neoplastic clones emerge, their expansion might be influenced not only by genetic/epigenetic status but by surrounding environmental factors including cytokines. This series of cell lines will be a useful tool as an in vitro model for leukemic evolution of MDS.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Aims
Although the delivery catheter system for pacemaker-lead implantation is a new alternative to the stylet system, no randomized controlled trial has addressed the difference in right ...ventricular (RV) lead placement accuracy to the septum between the stylet and the delivery catheter systems. This multicentre prospective randomized controlled trial aimed to prove the efficacy of the delivery catheter system for accurate delivery of RV lead to the septum.
Methods and results
In this trial, 70 patients (mean age 78 ± 11 years; 30 men) with pacemaker indications of atrioventricular block were randomized to the delivery catheter or the stylet groups. Right ventricular lead tip positions were assessed using cardiac computed tomography within 4 weeks of pacemaker implantation. Lead tip positions were classified into RV septum, anterior/posterior edge of the RV septal wall, and RV free wall. The primary endpoint was the success rate of RV lead tip placement to the RV septum.
Results
Right ventricular leads were implanted as per allocation in all patients. The delivery catheter group had higher success rate of RV lead deployment to the septum (78 vs. 50%; P = 0.024) and narrower paced QRS width (130 ± 19 vs. 142 ± 15 ms P = 0.004) than those in the stylet group. However, there was no significant difference in procedure time 91 (IQR 68–119) vs. 85 (59–118) min; P = 0.488 or the incidence of RV lead dislodgment (0 vs. 3%; P = 0.486).
Conclusion
The delivery catheter system can achieve a higher success rate of RV lead placement to the RV septum and narrower paced QRS width than the stylet system.
Trial registration number
jRCTs042200014 (https://jrct.niph.go.jp/en-latest-detail/jRCTs042200014)
Graphical Abstract
Graphical Abstract
Outcome comparison between delivery catheter and stylet systems. The delivery catheter system can achieve a higher RV lead placement on the RV septum success rate and a narrower paced QRS width than the stylet system. RV, right ventricular.
We recently investigated the contribution of the iPS-related genes SOX2, OCT4, and Nanog to de-differentiation by assaying for their mRNA levels. Given that mRNA expression does not always correlate ...with the protein levels, the aim of this study was to retrospectively determine the expression of these four iPS-related factors in human OSCC specimens by immunohistochemistry and examine their association with patient prognosis.
iPS cell-related gene expression in 89 OSCC patients by tissue microarray, and its correlation with clinicopathological factors, differentiation, metastasis, and poor prognoses were investigated.
No evidence of statistically significant relationships was found between the expression of iPS cell-related genes and clinicopathological parameters. However, our data indicated that KLF4 expression was associated with survival, and poor tumor differentiation. In addition, high expression of KLF4 was an independent poor prognostic factor (p=0.004) for OSCC patients.
In preoperative biopsies, higher KLF4 and poor differentiation may be clinically effective predictors for the prognosis of oral cancer.
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