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Electrochemiluminescence (ECL) is a powerful transduction technique with a leading role in the biosensing field due to its high sensitivity and low background signal. Although the intrinsic analytical strength of ECL depends critically on the overall efficiency of the mechanisms of its generation, studies aimed at enhancing the ECL signal have mostly focused on the investigation of materials, either luminophores or coreactants, while fundamental mechanistic studies are relatively scarce. Here, we discover an unexpected but highly efficient mechanistic path for ECL generation close to the electrode surface (signal enhancement, 128%) using an innovative combination of ECL imaging techniques and electrochemical mapping of radical generation. Our findings, which are also supported by quantum chemical calculations and spin trapping methods, led to the identification of a family of alternative branched amine coreactants, which raises the analytical strength of ECL well beyond that of present state-of-the-art immunoassays, thus creating potential ECL applications in ultrasensitive bioanalysis. Electrochemiluminescence (ECL) is a leading technique in biosensing. Here the authors identify an ECL generation mechanism near the electrode surface, which they exploit in combination with the use of branched amine coreactants to improve the ECL signal beyond the state-of-the-art immunoassays.

Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.

This study investigated the therapeutic effects of dry-preserved multi-layered fibroblast cell sheets (dry sheets) on cutaneous ulcers. Dry sheets were prepared by air-drying multi-layered fibroblast cell sheets (living sheets) to cease their life activities. Before in vivo application, we tested the release of growth factors into the medium to examine the mechanisms of dry sheets in wound healing. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were released from both dry and living sheets, while high levels of fibroblast growth factor-2 (FGF-2) and high mobility group box 1 (HMGB1) protein were only from dry sheets. An in vitro fibroblast proliferation assay revealed that the dry sheet eluate significantly enhanced cell proliferation and VEGF and HGF production compared with living sheet eluate. FGF-2-neutralizing antibodies significantly blocked this proliferative response. In wounds created on diabetic mice, the dry sheet-treatment groups using autologous or allogeneic cells showed significantly accelerated wound closure compared with that in the no-treatment group. The storage stability of the dry sheet was better at refrigeration temperature than at room temperature and remained stable for at least 4 weeks. Our data indicated that allogeneic dry sheets represent a promising new tool for regenerative medicine that promotes wound healing.

Background Despite the inferior patency compared to arterial grafts, a saphenous vein graft (SVG) is widely used for coronary artery bypass grafting (CABG). A lower atherosclerosis rate and higher patency have been reported for SVG obtained via the no-touch technique (NT) than via conventional preparation (CV). Although CV-mediated endothelial dysfunction is implied, the precise mechanism underlying the higher patency with NT is poorly understood. Methods Human residual SVGs during CABG and SVG sections after autopsy were analyzed. The endothelial surface was observed using scanning electron microscopy (SEM) and blindly compared between CV and NT. The endothelial integrity was also analyzed with immunohistochemistry. Results Unexpectedly, the hyperfine structure on SEM was comparable between CV and NT before grafting, and microvillus, a characteristic of endothelium, was indistinguishable between them. Von Willebrand Factor, an endothelial marker, was equally detected throughout the vascular wall in both groups from residual and postmortem sections. Conclusions The morphological integrity of the endothelium was successfully preserved in SVG with CV, even at an ultrastructural level. Although its functionality remains to be addressed, other factors than the endothelium may be involved in the high patency obtained by NT. The present findings suggest that the characteristics of NT and surgical methodology should be reconsidered.

Background: Positive emotions influence endocrinological and immunological response. This study examined the effect of laughter,as an expression of positive emotion, in terms of gene expression changes. Methods: Using a microarray technique, we analyzed the changes in expression of 18,716 genes from peripheral blood leukocytes in patients with type 2 diabetes, which were induced by laughter. Results: Of the 18,716 genes, 23 genes showed significantly different expression changes after listening to the comic story compared to the lecture. Eight were relatively upregulated and 15 were downregulated 1.5 h after the laughing episode. However, these genes did not include genes that are directly involved in blood glucose metabolism. Among the 23 genes discriminated, all 4 genes encoding proteins involved in the immune response and all 4 signal transduction genes were downregulated. Moreover, it is noteworthy that 5 of the 8 relatively upregulated genes were related to the cell cycle, apoptosis, and cell adhesion. Conclusions: We demonstrated that laughter, which is an expression of positive emotion, is linked to gene expression. However, the finding of this study does not allow reasonable interpretation for the regulation of gene expression by laughter. A more focused study is needed that may identify the candidate genes for the association between physical condition and positive emotion.

Background Despite the inferior patency compared to arterial grafts, a saphenous vein graft (SVG) is widely used for coronary artery bypass grafting (CABG). A lower atherosclerosis rate and higher patency have been reported for SVG obtained via the no-touch technique (NT) than via conventional preparation (CV). Although CV-mediated endothelial dysfunction is implied, the precise mechanism underlying the higher patency with NT is poorly understood. Methods Human residual SVGs during CABG and SVG sections after autopsy were analyzed. The endothelial surface was observed using scanning electron microscopy (SEM) and blindly compared between CV and NT. The endothelial integrity was also analyzed with immunohistochemistry. Results Unexpectedly, the hyperfine structure on SEM was comparable between CV and NT before grafting, and microvillus, a characteristic of endothelium, was indistinguishable between them. von Willebrand Factor, an endothelial marker, was equally detected throughout the vascular wall in both groups from residual and postmortem sections. Conclusions The morphological integrity of the endothelium was successfully preserved in SVG with CV, even at an ultrastructural level. Although its functionality remains to be addressed, other factors than the endothelium may be involved in the high patency obtained by NT. The present findings suggest that the characteristics of NT and surgical methodology should be reconsidered.

The ability to characterize the binding kinetics of drug-target interactions in a biologically relevant matrix, such as serum or plasma, remains a fundamental challenge in drug discovery. We apply a novel label-based giant magnetoresistance (GMR) biosensor platform to measure protein binding kinetics and affinities of drug-target pairs in buffer and different levels of serum. Specifically, we evaluate three well-established immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab and compare the results with label-free kinetic platforms: surface plasmon resonance (SPR) and bio-layer interferometry (BLI). Labeling of analytes does not affect their association and dissociation rates (on and off rates) from GMR biosensors which enables kinetic measurements in biologically relevant matrices. Only the GMR biossensors is consistently suitable for measuring binding kinetics in up to 80% serum. The faster and different off-rates of the three immune checkpoint inhibitors in the presence of serum should be considered when modeling their pharmacological performance. Competing Interest Statement DY, HY, SJO, MLC and KC are employees of MagArray, Inc. ABK is a consultant for MagArray, Inc. and SXW has stock options in MagArray Inc, which has licensed relevant patents from Stanford University for commercialization of GMR biosensor technology. TS is an employee of Hitachi High-Tech Corp.

BackgroundLaparoscopic proximal gastrectomy (LPG) is regarded as a less invasive surgery than laparoscopic total gastrectomy (LTG) for early gastric cancer located on the proximal side of the stomach. However, whether LPG is more effective than LTG remains unclear.MethodsA systematic literature search of studies assessing short-term surgical and nutritional outcomes after LPG and LTG was conducted. A meta-analysis of surgical outcomes (operative time, intraoperative estimated blood loss, postoperative complications, and length of hospital stay) and nutritional outcomes (decrease in body weight, albumin, hemoglobin, total protein, and lymphocyte count) was then performed. All of 11 papers are a retrospective cohort study.ResultsEleven studies reported assessments of the above-mentioned outcomes in 883 patients. There was a trend towards shorter operative time and lower blood loss for LPG compared to LTG though not reaching statistical significance. Other surgical outcomes showed no significant differences. Patients who underwent LTG had a significantly lower body weight (95% confidence interval, 3.01–6.05, -¯x = 4.53, p < 0.01) and hemoglobin level (95% confidence interval, 1.88–5.87, -¯x = 3.87, p < 0.01) than patients who underwent LPG at 1 year after surgery. There were no significant differences in other nutritional outcomes.ConclusionsThese results indicate LPG had some advantages in postoperative nutrition. However, no significant differences in short-term surgical outcomes were noted between the two operations. Our analysis suggests that LPG may be more beneficial compared with LTG in terms of perioperative and nutritional outcomes for early-stage gastric cancer.

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65 years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in “true” ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.

Background Liver resection is the standard operative procedure for patients with T2 and T3 gallbladder cancers (GBC). However, the optimal extent of hepatectomy remains unclear. Methods We conducted a systematic literature search and meta-analysis to assess the safety and long-term outcomes of wedge resection (WR) vs. segment 4b + 5 resection (SR) in patients with T2 and T3 GBC. We reviewed surgical outcomes (i.e., postoperative complications and bile leak) and oncological outcomes (i.e., liver metastasis, disease-free survival (DFS), and overall survival (OS)). Results The initial search yielded 1178 records. Seven studies reported assessments of the above-mentioned outcomes in 1795 patients. WR had significantly fewer postoperative complications than SR, with an odds ratio of 0.40 (95% confidence interval, 0.26 − 0.60; p  < 0.001), although there were no significant differences in bile leak between WR and SR. There were no significant differences in oncological outcomes such as liver metastases, 5-year DFS, and OS. Conclusions For patients with both T2 and T3 GBC, WR was superior to SR in terms of surgical outcome and comparable to SR in terms of oncological outcomes. WR that achieves margin-negative resection may be a suitable procedure for patients with both T2 and T3 GBC.