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Background Bacteria release a wide variety of small molecules including cell - to - cell signaling compounds. Gram-negative bacteria use a variety of self-produced autoinducers such as acylated homoserine lactones (acyl - HSLs) as signal compounds for quorum sensing (QS) within and between bacterial species. QS plays a significant role in the pathogenesis of infectious diseases and in beneficial symbiosis by responding to acyl - HSLs in Pseudomonas aeruginosa . It is considered that the selection of bacterial languages is necessary to regulate gene expression and thus it leads to the regulation of virulence and provides a growth advantage in several environments. In this study, we hypothesized that RND-type efflux pump system MexAB - OprM of P. aeruginosa might function in the selection of acyl - HSLs, and we provide evidence to support this hypothesis. Results Loss of MexAB - OprM due to deletion of mexB caused increases in QS responses, as shown by the expression of gfp located downstream of the lasB promoter and LasB elastase activity, which is regulated by a LasR - 3 - oxo - C12 - HSL complex. Either complementation with a plasmid containing wild - type mexB or the addition of a LasR - specific inhibitor, patulin, repressed these high responses to 3 - oxo - acyl - HSLs. Furthermore, it was shown that the acyl - HSLs - dependent response of P. aeruginosa was affected by the inhibition of MexB transport activity and the mexB mutant. The P. aeruginosa MexAB - OprM deletion mutant showed a strong QS response to 3 - oxo - C10 - HSL produced by Vibrio anguillarum in a bacterial cross - talk experiment. Conclusion This work demonstrated that MexAB - OprM does not control the binding of LasR to 3-oxo-Cn-HSLs but rather accessibility of non-cognate acyl-HSLs to LasR in P. aeruginosa . MexAB - OprM not only influences multidrug resistance, but also selects acyl - HSLs and regulates QS in P. aeruginosa . The results demonstrate a new QS regulation mechanism via the efflux system MexAB - OprM in P. aeruginosa .

Stent placement for treating superficial femoral artery (SFA) lesions has been approved. The Zilver PTX stent, a drug-eluting stent (DES) for treating SFA lesions, has been available in Japan since 2012. However, the penetration rate of this DES has not yet been reported. This prospective multicenter registry study enrolled 314 patients (354 limbs) to be treated by stent placement in 2014 (UMIN000011551). The primary endpoint was the measurement of the penetration rate of the DES. The secondary endpoints were measuring the freedom from restenosis, freedom from target lesion revascularization (TLR), freedom from major adverse limb event (MALE), and the survival rate at 12 months postoperatively. Female patients comprised 28% participants. The mean age was 73.1 ± 9.2 years. A total of 56% patients had diabetes mellitus (DM), 36% patients were receiving hemodialysis, and 30% used cilostazol at baseline. The mean lesion length was 156 ± 101 mm, and the percentage of TASC II C/D lesions was 58%. Critical limb ischemia (CLI) was observed in 32% limbs. The penetration rates of the Zilver PTX stent were only 8%. The primary patency rate was similar between DES and bare-metal stents (BMS) at 12 months postoperatively (77 vs. 84%, p  = 0.52). In this study, the rates of freedom from restenosis, freedom from TLR, freedom from MALE, and the survival rate at 12 months postoperatively were 83, 86, 85, and 89%, respectively. The penetration rate of a first-generation DES placement for treating SFA lesions is low in Japan. On the other hand, BMS is well utilized and its primary patency is acceptable.

To specify critical factors responsible for Pseudomonas aeruginosa penetration through the Caco-2 cell epithelial barrier, we analyzed transposon insertion mutants that demonstrated a dramatic reduction in penetration activity relative to P. aeruginosa PAO1 strain. From these strains, mutations could be grouped into five classes, specifically flagellin-associated genes, pili-associated genes, heat-shock protein genes, genes related to the glycolytic pathway, and biosynthesis-related genes. Of these mutants, we here focused on the serA mutant, as the association between this gene and penetration activity is yet unknown. Inactivation of the serA gene caused significant repression of bacterial penetration through Caco-2 cell monolayers with decreased swimming and swarming motilities, bacterial adherence, and fly mortality rate, as well as repression of ExoS secretion; however, twitching motility was not affected. Furthermore, L-serine, which is known to inhibit the D-3-phosphoglycerate dehydrogenase activity of the SerA protein, caused significant reductions in penetration through Caco-2 cell monolayers, swarming and swimming motilities, bacterial adherence to Caco-2 cells, and virulence in flies in the wild-type P. aeruginosa PAO1 strain. Together, these results suggest that serA is associated with bacterial motility and adherence, which are mediated by flagella that play a key role in the penetration of P. aeruginosa through Caco-2 cell monolayers. Oral administration of L-serine to compromised hosts might have the potential to interfere with bacterial translocation and prevent septicemia caused by P. aeruginosa through inhibition of serA function.

Human induced pluripotent stem cells (hiPSCs) are an attractive cell source for regenerative medicine. For its widespread use as a starting material, a robust storage and distribution system in the frozen state is necessary. For this system, managing transient warming during storage and transport is essential, but how transient warming affects cells and the mechanisms involved are not yet fully understood. This study examined the influence of temperature cyclings (from −80°C to −150°C) on cryopreserved hiPSCs using a custom-made cryo Raman microscope, flow cytometry, and performance indices to assess viability. Raman spectroscopy indicated the disappearance of mitochondrial cytochrome signals after thawing. A reduction in the mitochondrial membrane potential was detected using flow cytometry. The performance indices indicated a decrease in attachment efficiency with an increase in the number of temperature cycles. This decrease was observed in the temperature cycle range above the glass transition temperature of the cryoprotectant. Raman observations captured an increase in the signal intensity of intracellular dimethyl sulfoxide (DMSO) during temperature cycles. Based on these results, we proposed a schematic illustration for cellular responses to temperature fluctuations, suggesting that temperature fluctuations above the glass-transition temperature trigger the movement of DMSO, leading to cytochrome c oxidation, mitochondrial damage, and caspase-mediated cell death. This enhances our understanding of the key events during cryopreservation and informs the development of quality control strategies for hiPSC storage and transport.

Background We previously demonstrated that the serA gene is associated with bacterial pathogenicity, including bacterial penetration through the Caco-2 cell monolayers, bacterial motility, bacterial adherence, and fly mortality. l -Serine is known to inhibit the d -3-phosphoglycerate dehydrogenase (PGDH) activity of the SerA protein, and it significantly reduced the bacterial pathogenicity as described above. We also demonstrated that in a PGDH assay using crude extracts isolated from overnight cultures of E . coli overexpressing the P . aeruginosa serA gene, l -serine inhibited the PGDH activity of the SerA protein. The basal PGDH activity of the negative control strain was high, presumably due to contamination of unknown proteins in the crude extracts. Therefore, to further confirm the direct inhibition of PGDH activity of P . aeruginosa SerA by l -serine, we purified and characterized the PGDH from P. aeruginosa and compared it with the previously characterized PGDHs from E. coli , and the human colon as controls. Results Optimum pH and ionic strength of the purified PGDHs were different depending on the three species; optimal activity of P. aeruginosa PGDH was at pH 7.5 with 50–100 mM Tris–HCl, E. coli PGDH was at pH 8.5 with 100–200 mM Tris–HCl, and human PGDH was at pH 9.0 with 100–200 mM Tris–HCl. The addition of l -serine reduced the activity of PGDH from P. aeruginosa and E. coli , but not the PGDH from human colon. The median inhibitory concentration (IC 50 ) of l -serine was 630 μM for P. aeruginosa and 250 μM for E. coli , while IC 50 of d -serine was much higher than that of l -serine; 76 mM in P. aeruginosa PGDH and 45 mM in E. coli PGDH. Conclusions These results suggest that l -serine significantly repressed P. aeruginosa pathogenicity through direct inhibition of the PGDH activity, but was not able to inhibit the human PGDH activity. Oral administration of l -serine to compromised hosts might interfere with bacterial translocation and prevent gut-derived sepsis caused by P. aeruginosa through inhibition of the function of the serA gene product.

This review summarizes the recent progress of Grubbs–Hoveyda (GH) type olefin metathesis catalysts incorporated into the robust fold of β-barrel proteins. Anchoring strategies are discussed and challenges and opportunities in this emerging field are shown from simple small-molecule transformations over ring-opening metathesis polymerizations to in vivo olefin metathesis.

The aim of this study was to assess the association between the spatial location of plaque rupture and remodeling pattern of culprit lesions in acute anterior myocardial infarction (MI). Positive remodeling suggests a potential surrogate marker of plaque vulnerability, whereas plaque rupture causes thrombus formation followed by coronary occlusion and MI. Intravascular ultrasound (IVUS) can determine the precise spatial orientation of coronary plaque formation. We studied 52 consecutive patients with acute anterior MI caused by plaque rupture of the culprit lesion as assessed by preintervention IVUS. The plaques were divided into those with and without positive remodeling. We divided the plaques into three categories according to the spatial orientation of plaque rupture site: myocardial (inner curve), epicardial (outer curve), and lateral quadrants (2 intermediate quadrants). Among 52 plaque ruptures in 52 lesions, 27 ruptures were oriented toward the epicardial side (52%), 18 toward the myocardial side (35%), and 7 in the 2 lateral quadrants (13%). Among 35 plaques with positive remodeling, plaque rupture was observed in 21 (52%) on the epicardial side, 12 (34%) on the myocardial side, and 2 (6%) on the lateral side. However, among 17 plaques without positive remodeling, plaque rupture was observed in 6 (35%), 6 (35%), and 5 (30%), respectively ( p  = 0.047). Atherosclerotic plaques with positive remodeling showed more frequent plaque rupture on the epicardial side of the coronary vessel wall in anterior MI than those without positive remodeling.

In response to the heart failure (HF) pandemic, it is important to introduce appropriate pharmacological and non-pharmacological treatments for HF patients. In addition, self-management of HF, including the continuation of appropriate pharmacological treatment, is also important. There have been many reports on self-management of HF. However, the effectiveness of patient education of HF is not consistent. One of the reasons may be whether the tools used are common or not. Moreover, unified systems of HF patient education and disease management in metropolitan areas are rare. We began joint HF patient education and disease management in the Tokyo southern medical district (JONAN Heart Failure Medical Collaboration: JHFeC). Patients undergo a multidisciplinary HF education program at JHFeC member hospitals to ensure that they are able to adequately record information on the self-management sheet. After discharge, the continuity of self-management will be evaluated, and further education will be provided if necessary. HF patient education is important even in severe HF requiring a left ventricular assist device, and such patient education needs to be provided appropriately in all manner of HF patients with stage A to D.

Some experimental studies have shown that direct oral anticoagulants (DOACs) have anti-inflammatory effects. However, the interval changes in inflammatory markers in patients with non-valvular atrial fibrillation (AF) who receive DOACs remain unknown. Between July 2013 and April 2014, a total of 187 AF patients randomly assigned to receive rivaroxaban ( n  = 91) or dabigatran ( n  = 96) were assessed for eligibility. The levels of the following inflammatory markers were serially evaluated: high-sensitivity C-reactive protein, pentraxin-3, interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor-α, monocyte chemotactic protein-1, growth and differentiation factor-15, and soluble thrombomodulin (sTM). The aim in this study was to evaluate the anti-inflammatory effects of rivaroxaban and dabigatran in patients with AF, in addition to the impact of markers on bleeding events. Finally, 117 patients (rivaroxaban: n  = 55, dabigatran: n  = 62) were included in the analysis at 12 months. Although the interval changes in sTM levels tended to be greater in the dabigatran group [0.3 (0–0.7) vs. 0.5 (0–1.0) FU/ml, p  = 0.061], there were no significant differences in the interval changes in any inflammatory marker between 2 groups. There were no significant differences in bleeding events between 2 groups. The interval changes in sTM levels were significantly greater in patients with bleeding compared with those without [0.8 (0.5–1.3) vs. 0.4 (− 0.1–0.8) FU/ml, p  = 0.017]. There were no significant differences in the interval changes in any inflammatory marker between rivaroxaban and dabigatran treatments in patients with AF. The increased levels of sTM after DOACs treatment might be related to bleeding events.

Copper(I) and copper(II) complexes were covalently linked to an engineered variant of the transmembrane protein Ferric hydroxamate uptake protein component A (FhuA ΔCVF tev ). Copper(I) was incorporated using an N -heterocyclic carbene (NHC) ligand equipped with a maleimide group on the side arm at the imidazole nitrogen. Copper(II) was attached by coordination to a terpyridyl ligand. The spacer length was varied in the back of the ligand framework. These biohybrid catalysts were shown to be active in the Diels–Alder reaction of a chalcone derivative with cyclopentadiene to preferentially give the endo product.