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Chronic oxidative stress in long-distance runners adversely affects conditioning. It is important to objectively assess and monitor oxidative stress, but measuring oxidative stress can be invasive or require skill to measure. Therefore, this study aimed to verify whether skin autofluorescence (SAF), a non-invasive, rapid, and easily calculable metric for calculating advanced glycation end products (AGEs), is useful as an oxidative stress biomarker. The subjects were 50 young Japanese male long-distance runners (aged 20.2 ± 1.2 years); 35 average-sized male university students (aged 19.8 ± 1.1 years) served as controls. The interactions and relationships between SAF and plasma pentosidine and oxidative stress markers (reactive oxygen metabolite-derived compounds [d-ROMs], biological antioxidant potential [BAP], and the BAP/d-ROMs ratio) in runners were examined, and SAF in the runners and controls was compared. The results suggest that plasma pentosidine in runners is associated with oxidative stress markers and that it can assess oxidative stress. However, as SAF was not associated with oxidative stress markers, it was not validated as one. In future, clarifying the factors affecting SAF may also clarify the relationship between SAF, plasma pentosidine, and oxidative stress markers.

Dancers vividly express joy, grief, and other emotions through their body movements, which reflect the deliberate expression of certain emotions and also the unintentional emotions. Research has shown that the speed of performers' movements varies according to the emotions deliberately expressed. However, no study has examined the non-deliberate emotions. Therefore, this study examined dancers' unintentionally exposed emotions through their movements. Seventeen semi-professional dancers performed a neutral choreography to three music types—joy-inducing music, sadness-inducing music, and a metronome—and their performances were compared. Changes in the dancers' body movements were measured using a motion-capture system. Results showed that body movements were generally faster and more dynamic with emotion-inducing music compared to the metronome. While the speed of pelvic movements was more when they danced to joy-inducing music, arm movement was more apparent for sadness-inducing music. These findings help understand the unintentional emotion-expression dynamics in dance.

Abstract The phenotypes of RP1-related inherited retinal dystrophies (RP1-IRD), causing autosomal dominant (AD) and autosomal recessive (AR) diseases, vary depending on specific RP1 variants. A common nonsense mutation near the C-terminus, c.5797 C > T (p.Arg1933*), is associated with RP1-IRD, but the exact role of this mutation in genotype-phenotype correlation remains unclear. In this study, we retrospectively analyzed patients with RP1-IRD (N = 42) from a single center in Japan. AR RP1-IRD patients with the c.5797 C > T mutation (N = 14) mostly displayed macular dystrophy but rarely retinitis pigmentosa or cone-rod dystrophy. Conversely, AR RP1-IRD patients without the c.5797 C > T mutation, including those with other pathogenic RP1 variants, were mostly diagnosed with severe retinitis pigmentosa. Full-field electroretinograms were significantly better in patients homozygous or compound heterozygous for the c.5797 C > T mutation than in those without this mutation, corresponding to their milder phenotypes. Clinical tests also revealed a slower onset of age and a better mean deviation value with the static visual field in AR RP1-IRD patients with the c.5797 C > T mutation compared to those without. Therefore, the presence of c.5797 C > T may partly account for the phenotypic variety of RP1-IRD and may yield milder phenotypes. These findings may be useful for predicting the prognosis of RP1-IRD patients.

Objectives: The present study examined the incidence of incisional hernia by comparing patients from whom a specimen was extracted either through a Pfannenstiel incision (PI) with an intracorporeal anastomosis or via a midline incision (MI) with an extracorporeal anastomosis. Methods: The records of 370 consecutive patients who underwent a laparoscopic or robotically-assisted colectomy were retrospectively analyzed. Regardless of the clinical symptoms, incisional hernia was objectively diagnosed based on abdominal computed tomography findings. The surgical outcomes and incisional hernia incidence were retrospectively compared between the groups. Propensity score matching (PSM) was used to balance background differences between the groups. Results: Eighty-seven and 283 patients were in the PI group and MI group, respectively. After PSM, 71 patients were selected from each group. The median observation time was 572 and 1110 days in the PI and MI group, respectively. The PI group had no incidence of incisional hernia whereas the MI group had a 14% incidence, demonstrating that the former had significantly fewer incisional hernias (p=0.0014). The median interval from surgery to incisional hernia development was 295 days. The PI with an intracorporeal anastomosis was not associated with an increased complication rate. Conclusions: The PI was preferable for intraoperative specimen extraction owing to the low, associated incidence of incisional hernia.

Abstract Aim The aim of this study was to clarify the significance of blood culture testing in the postoperative period of pancreatoduodectomy (PD), a highly invasive surgery. Methods Rates of blood culture sampling and positivity were investigated for febrile episodes (FEs) in patients who underwent PD (2016–2021). FEs were defined as body temperature of 38.0°C or higher occurring on or after the 4th postoperative day. Fever origin was diagnosed retrospectively, and FEs were classified as pancreatic fistula (PF)‐related or PF‐unrelated FEs. Factors correlated with blood culture positivity were explored. Results Among 339 patients who underwent PD, 99 experienced 202 FEs. Blood culture testing was performed on 160 FEs occurring in 89 patients. The sampling and positivity rates were 79.2% and 17.5%, respectively, per episode and 89.9% and 28.1%, respectively, per patient. Thirty‐six FEs were classified as PF‐related and 124 were classified as PF‐unrelated FEs. The blood culture positivity rate was significantly lower in PF‐related vs. PF‐unrelated FEs (1/36 vs. 27/124, respectively, p = 0.006). The blood culture positivity rate was significantly higher in patients with cholangitis, catheter‐related blood stream infection, and urinary tract infection than PF‐related FEs. Multivariate analysis showed that blood culture positivity was negatively associated with PF‐related FEs and positively associated with accompanying symptoms of shivering, Pitt Bacteremia Score, and preoperative biliary drainage. Conclusions Patients who underwent PD showed relatively high blood culture positivity rates. Based on these results, it may be possible to distinguish PF‐related and ‐unrelated FEs.

Abstract Proximity Extension Assay (PEA) and mass spectrometry (MS) methodologies were utilized for the proteomic and lipidomic characterization of plasma specimens from patients who developed Alzheimer's disease. Proteomics was performed by both PEA and Liquid Chromatography (LC)/MS in this study, but all the more because LC/MS generally tends to be biased towards proteins with high expression and high variability, generating hypotheses proved challenging. Consequently, attempt was made to interpret the results from the PEA data. There were 150 significantly variable proteins and 68 lipids among 1000 proteins and 400 lipids. Pathway analysis was performed for both total and variable proteins measured to reduce bias, and it appeared that vascular fragility was related to AD. Furthermore, a multitude of lipid-associated proteins exhibited statistical changes. In certain instances, the function of individual proteins affected the factors associated with them, whereas others demonstrated trends contrary to anticipated outcomes. These trends seem indicative of diverse feedback mechanisms that provide homeostatic equilibrium. The degree of unsaturation of fatty acids, correlated with cardiovascular risk, warrants specific attention. Certain bile acids exhibited the potential to cause vascular endothelial damage. Contemplating these discoveries in tandem with previously documented phenomena, subtle shifts in homeostatic functions seem to be linked to the fragility of vascular endothelial cells. This is evidenced by the slow and chronic evolution of Alzheimer's disease from preclinical stages to its manifestation.

Abstract The idea of utilizing unused oocytes present in the ovaries has been tested in various ways to produce offspring. However, only a limited number of studies succeeded in offspring generation. They include transplantation of ovaries into autologous or allogeneic animals, and acquisition of pups from oocytes obtained by transplanting mouse ovaries into immunodeficient rats. Here we report successful production of rat oocytes by transplanting rat ovaries under the kidney capsule of immunodeficient mice with addition of hormone administration to the mice. In addition, these oocytes were developed by in vitro fertilization, and transplanted into the oviducts of pseudopregnant rats, resulting in successful delivery of pups. The modified gene of the donor rat was confirmed to be correctly inherited to the pups. These results show that xenotransplantation of ovarian tissue makes it possible to leave offspring, beginning a new phase in developmental engineering.

Abstract For accurate mitotic cell division, replicated chromatin must be assembled into chromosomes and faithfully segregated into daughter cells. While protein factors like condensin play key roles in this process, it is unclear how chromosome assembly proceeds as molecular events of nucleosomes in living cells and how condensins act on nucleosomes to organize chromosomes. To approach these questions, we investigate nucleosome behavior during mitosis of living human cells using single-nucleosome tracking, combined with rapid-protein depletion technology and computational modeling. Our results show that local nucleosome motion becomes increasingly constrained during mitotic chromosome assembly, which is functionally distinct from condensed apoptotic chromatin. Condensins act as molecular crosslinkers, locally constraining nucleosomes to organize chromosomes. Additionally, nucleosome-nucleosome interactions via histone tails constrain and compact whole chromosomes. Our findings elucidate the physical nature of the chromosome assembly process during mitosis.

Objectives: To clarify whether self-expandable metallic stent (SEMS) placement for obstructive colorectal cancer (CRC) increases perineural invasion (PNI), thereby worsening the prognosis. Methods: In total, 1022 patients with pathological T3 or T4 colon or rectosigmoid cancer who underwent resection were retrospectively reviewed. The study patients were divided into a no obstruction group (n=693), obstruction without stent group (n=251), and obstruction with stent group (n=78), and factors demonstrating an independent association with PNI, the difference in PNI incidence and severity between groups, and the association between PNI and the duration from SEMS placement to surgery were investigated. Survival analysis was performed for each group. Results: On multivariate analysis, SEMS placement (hazard ratio [HR]: 2.08) was independently associated with PNI whereas SEMS placement was not. PNI occurred in 39%, 45%, and 68% of the no obstruction, obstruction without stent, and obstruction with stent group, respectively. In the obstruction with stent group, the proportion of PNI was not associated with the duration from SEMS placement to surgery. Extramural PNI, an advanced form of PNI, demonstrated no increase with increasing interval. The five-year OS was 86.3%, 76.7%, and 73.1% in no obstruction, obstruction without stent, and obstruction with stent group, respectively. On multivariate analysis, obstruction was an independent risk factor of decreased OS (HR: 1.57) whereas SEMS placement was not. Conclusions: The prognosis was comparable between patients with SEMS placement and those with an obstruction who did not undergo SEMS placement, thus demonstrating that SEMS is a viable, therapeutic option for BTS.

Background: Washing with water is not inferior to washing with soaps and detergents in children with atopic dermatitis (AD) in remission during the fall-winter seasons. We investigated whether this finding varies during summer based on the type of cleanser (soaps and detergents). Methods: This evaluator-blinded, pragmatic, randomized, and non-inferiority study enrolled patients with AD whose eczema was controlled following regular steroid ointment application 2 days/week. For 8 ± 4 weeks, participants washed their upper and lower limbs with a cleanser on one side and with water alone on the other. Each participant chose either a weakly alkaline soap or an acidic detergent. The primary outcome was the Eczema Area and Severity Index (EASI) score at week 8 ± 4. Results: The data of 43 of the 47 registered participants were analyzed. The median patient age was 44 (23–99) months; 28 and 15 participants chose weakly alkaline and acidic cleansers, respectively. At week 8 ± 4, EASI scores of the water and cleanser sides were 0.00 (0.00–0.40) and 0.15 (0.00–0.40), respectively (p = 0.74). The difference between both sides was 0.00 (−0.07 to 0.14); the limits of the 95 % confidence interval did not reach the pre-specified non-inferiority margin. No difference was observed in the median Patient-Oriented Eczema Measure score, number of additional steroid ointment applications, and occurrences of skin infections. There were no differences between the cleanser types in any of the results. Conclusions: We demonstrated that washing with water was not inferior to that with a cleanser in patients with AD in the maintenance phase during summer, regardless of the type of cleanser.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Summary: MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

Objective: To investigate the feasibility of poststroke interventions using a motivational instructional design model with occupational therapy (OT) and swallowing therapy (ST) and the model's potential physical and mental health effects. Design: An open-label, single-arm, feasibility study on the Attention, Relevance, Confidence, and Satisfaction model. Setting: Two convalescent rehabilitation wards. Participants: Twenty-five patients with stroke (N=25) (19 men; mean age, 62.4±11.9y; 61.9±36.8d from the first stroke) were recruited. Interventions: Twelve participants received a motivational approach based on the Attention, Relevance, Confidence, and Satisfaction model during OT (OT group), and 13 received it during ST (ST group). The intervention lasted 40-60 minutes daily, 5 days weekly, for 4 weeks. Main Outcome Measures: The primary outcomes included the dropout rate, an adverse event, and the participants’ acceptability of the intervention. Paretic arm function was assessed in the OT group; swallowing ability was assessed in the ST group; and activities of daily living, depressive symptoms, and apathy were assessed in both groups. Results: No participants dropped out of the intervention or experienced an adverse event. Twenty-one participants (84%) were satisfied with the intervention, and 19 (76%) hoped to continue receiving it. The OT group showed statistically significant improvements in paretic arm function and activities of daily living (Cohen's r=0.68-0.77), whereas the ST group improved in swallowing ability, activities of daily living, and depressive symptoms (Cohen's r=0.62-0.85). Conclusions: The interventions using the motivational instructional model with OT and ST were feasible and could improve poststroke paretic arm function, swallowing ability, and activities of daily living after stroke.

Vulvar intestinal adenocarcinoma is a rare malignancy. The most significant predictor of advanced vulvar cancer is achieving complete resection, although determining the optimal treatment for this rare histologic type remains uncertain. We report the case of a 63-year-old woman with a primary vulvar tumor suspected of having rectal invasion and inguinal lymph node metastases based on preoperative magnetic resonance imaging and computed tomography scans. To achieve complete resection of stage IIIC intestinal-type vulvar adenocarcinoma, we performed a laparoscopic posterior pelvic exenteration (PPE) and radical vulvectomy, along with bilateral inguinal lymph node dissection. This case report highlights the use of a novel hybrid procedure that combines laparoscopic PPE with radical vulvectomy and bilateral inguinal lymph node dissection for vulvar adenocarcinoma of the intestinal type. Laparoscopic PPE can be considered a minimally invasive approach for vulvar tumor when complete resection is achievable with an appropriate safety margin.

Abstract Detached plasma formation is a way to reduce the heat load on the wall in magnetic fusion devices. This study proposes a novel analysis technique consisting of the conditional averaging, sliding window, and tomography to reveal the spatiotemporal behavior of the rotating radial ejection event of detached plasma, which further contributes to local heat load reduction. The used equipment is a high-speed camera and an electrostatic probe located at the periphery of the linear plasma device NAGDIS-II. By applying this method, four-dimensional (4D) behavior of the emission structure along time (1D) and space perpendicular and parallel to the magnetic field (3D) was clarified; a rotating distorted structure appears as a precursor, which is then scraped and transported radially and axially. The proposed method is widely applicable to short-term rigid-body rotating structures, especially in linear plasmas.

Abstract A chemical proteomics approach using Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor–immobilized sepharose (TIM-063-Kinobeads) identified main targets such as CaMKKα/1 and β/2, and potential off-target kinases, including AP2-associated protein kinase 1 (AAK1), as TIM-063 interactants. Because TIM-063 interacted with the AAK1 catalytic domain and inhibited its enzymatic activity moderately (IC50 = 8.51 µM), we attempted to identify potential AAK1 inhibitors from TIM-063-derivatives and found a novel AAK1 inhibitor, TIM-098a (11-amino-2-hydroxy-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one) which is more potent (IC50 = 0.24 µM) than TIM-063 without any inhibitory activity against CaMKK isoforms and a relative AAK1-selectivity among the Numb-associated kinases family. TIM-098a could inhibit AAK1 activity in transfected cultured cells (IC50 = 0.87 µM), indicating cell-membrane permeability of the compound. Overexpression of AAK1 in HeLa cells significantly reduced the number of early endosomes, which was blocked by treatment with 10 µM TIM-098a. These results indicate TIM-063-Kinobeads-based chemical proteomics is efficient for identifying off-target kinases and re-evaluating the kinase inhibitor (TIM-063), leading to the successful development of a novel inhibitory compound (TIM-098a) for AAK1, which could be a molecular probe for AAK1. TIM-098a may be a promising lead compound for a more potent, selective and therapeutically useful AAK1 inhibitor.

Our body movements often reflect our inner states. Dance is one of the remarkable movements closely related to the emotional state. Previous studies suggest that the velocity of dance movements changes when dancers are instructed to express joyful or sad feelings through neutral gestures. However, whether a dancer’s emotions can emerge in dance movements remains unclear. We examined changes in dance movements when dancers’ emotions were naturally induced by music. In the experiment, semi-professional dancers were asked to perform the same choreography while listening to joyful or sad music or a metronome. The results revealed that joyful music increased the dancers’ heart rates, pelvic velocity, and range of motion compared to sad music and the metronome. This outcome suggests that naturally induced joyful emotions promote fast, bouncing dance movements. The dance performance could implicitly express the dancers’ inner states, which an audience might feel.

Summary: To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2LRR1-driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for “backup” mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes.