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We present the requirements, design, and evaluation of the cryogenic continuously rotating half-wave plate (CHWP) for the Simons Observatory (SO). SO is a cosmic microwave background polarization experiment at Parque Astronómico de Atacama in northern Chile that covers a wide range of angular scales using both small (⌀0.42 m) and large (⌀6 m) aperture telescopes. In particular, the small aperture telescopes (SATs) focus on large angular scales for primordial B-mode polarization. To this end, the SATs employ a CHWP to modulate the polarization of the incident light at 8 Hz, suppressing atmospheric 1/f noise and mitigating systematic uncertainties that would otherwise arise due to the differential response of detectors sensitive to orthogonal polarizations. The CHWP consists of a 505 mm diameter achromatic sapphire HWP and a cryogenic rotation mechanism, both of which are cooled down to ∼50 K to reduce detector thermal loading. Under normal operation, the HWP is suspended by a superconducting magnetic bearing and rotates with a constant 2 Hz frequency, controlled by an electromagnetic synchronous motor. We find that the number of superconductors and the number of magnets that make up the superconducting magnetic bearing are important design parameters, especially for the rotation mechanism's vibration performance. The rotation angle is detected through an angular encoder with a noise level of 0.07 μrad s. During a cooldown process, the rotor is held in place by a grip-and-release mechanism that serves as both an alignment device and a thermal path. In this paper, we provide an overview of the SO SAT CHWP: its requirements, hardware design, and laboratory performance.

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All of author have no C.O.I., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant exhibits high transmissibility with a strong immune escape ability and causes frequent large-scale global infections by producing predominant subvariants. Here, using human upper/lower airway and intestinal cells, we examined the previously dominant BA.1-BA.5 and BA.2.75 subvariants, together with the recently emerged XBB/BQ lineages, in comparison to the former Delta variant. We observed a tendency for each virus to demonstrate higher growth capability than the previously dominant subvariants. Unlike human bronchial and intestinal cells, nasal epithelial cells accommodated the efficient entry of certain Omicron subvariants, similar to the Delta variant. In contrast to the Delta's reliance on cell-surface transmembrane protease serine 2, all tested Omicron variants depended on endosomal cathepsin L. Moreover, S1/S2 cleavage of early Omicron spikes was less efficient, whereas recent viruses exhibit improved cleavage efficacy. Our results show that the Omicron variant progressively adapts to human cells through continuous endosome-mediated host cell entry.IMPORTANCESARS-CoV-2, the causative agent of coronavirus disease 2019, has evolved into a number of variants/subvariants, which have generated multiple global waves of infection. In order to monitor/predict virological features of emerging variants and determine appropriate strategies for anti-viral development, understanding conserved or altered features of evolving SARS-CoV-2 is important. In this study, we addressed previously or recently predominant Omicron subvariants and demonstrated the gradual adaptation to human cells. The host cell entry route, which was altered from the former Delta variant, was conserved among all tested Omicron subvariants. Collectively, this study revealed both changing and maintained features of SARS-CoV-2 during the Omicron variant evolution.

Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability leading to microvascular obstruction and inflammation. While the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, where endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations of varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs leads to aberrant margination of the less-deformable RBC subpopulations towards the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (i.e., direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD., (Copyright © 2024 American Society of Hematology.)

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8 + T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44 + effector memory T cells and CD69 + early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

The tumor suppressor p53 regulates metabolic homeostasis. Recently, Tsaousidou et al. reported that selective activation of p53 via downregulation of Tudor interacting repair regulator (TIRR) confers protection against cancer despite obesity and insulin resistance, providing new insights into the role of p53 at the intersection of oncogenesis and systemic metabolism., Competing Interests: Declaration of interests The authors have no conflicts of interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure., Methods: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes., Results: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload., Conclusions: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure., Competing Interests: The Department of Health Development and Medicine in Osaka University (H.H, H.N) is an endowed department supported by Anges, Daicel, and FunPep. The other authors report no conflicts.

Aim: Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR., Methods: This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed., Results: High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels., Conclusions: High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication., (© 2024 Japan Society of Hepatology.)

Introduction: This study evaluated the performance of the albumin-lymphocyte-globulin-C-reactive protein (CRP) (ALGC) index as a novel prognostic biomarker for hepatocellular carcinoma (HCC) after hepatectomy., Methods: Patients (n = 178) who underwent hepatectomy for HCC (July 2010-December 2021) were analyzed. The ALGC index was calculated as ([albumin × lymphocyte]/[CRP × globulin × 104]). Patients were divided into a low ALGC group (<1.82; n = 81) and a high ALGC group (≥1.82; n = 97). The association of the ALGC index with survival was assessed by univariate and multivariate analyses., Results: The median overall survival (OS) was 100 (range: 1-149) months with 1-, 3-, and 5-year OS rates of 91.6%, 81.2%, and 64.2%, respectively. In univariate analysis, ALGC index (<1.82), alpha-fetoprotein (≥25 ng/mL), tumor size (≥3.5 cm), microvascular invasion, and multiple tumors were associated with shorter OS. ALGC index (<1.82) (hazard ratio [95% confidence interval]) (2.48 [1.407-4.513]; p = 0.001) and multiple tumors (1.92 [1.070-3.356]; p = 0.029) were independent predictors of OS in multivariate analysis., Conclusion: ALGC index is a novel prognostic biomarker for HCC after hepatectomy. It may assist in treatment stratification and better management of patients with HCC., (© 2024 S. Karger AG, Basel.)

Flow-injection spin-trapping electron paramagnetic resonance (FI-EPR) methods that involve the use of 5,5-dimethyl-pyrroline- N -oxide (DMPO) as a spin-trapping reagent have been developed for the kinetic study of the O 2 •- radical scavenging reactions occurring in the presence of various plant-derived and synthetic phenolic antioxidants (Aox), such as flavonoid, pyrogallol, catechol, hydroquinone, resorcinol, and phenol derivatives in aqueous media (pH 7.4 at 25 °C). The systematically estimated second-order rate constants ( k s ) of these phenolic compounds span a wide range (from 4.5 × 10 to 1.0 × 10 6 M -1 s -1 ). The semilogarithm plots presenting the relationship between k s values and oxidation peak potential ( E p ) values of phenolic Aox are divided into three groups (A1, A2, and B). The k s - E p plots of phenolic Aox bearing two or three OH moieties, such as pyrogallol, catechol, and hydroquinone derivatives, belonged to Groups A1 and A2. These molecules are potent O 2 •- radical scavengers with k s values above 3.8 × 10 4 (M -1 s -1 ). The k s - E p plots of all phenol and resorcinol derivatives, and a few catechol and hydroquinone derivatives containing carboxyl groups adjacent to the OH groups, were categorized into the group poor scavengers ( k s < 1.6 × 10 3 M -1 s -1 ). The k s values of each group correlated negatively with E p values, supporting the hypothesis that the O 2 •- radical scavenging reaction proceeds via one-electron and two-proton processes. The processes were accompanied by the production of hydrogen peroxide at pH 7.4. Furthermore, the correlation between the plots of k s and the OH proton dissociation constant (p K a • ) of the intermediate aroxyl radicals ( k s -p K a • plots) revealed that the second proton transfer process could potentially be the rate-determining step of the O 2 •- radical scavenging reaction of phenolic compounds. The k s - E p plots provide practical information to predict the O 2 •- radical scavenging activity of plant-derived phenolic compounds based on those molecular structures.

Background: Elderly living kidney donors (LKDs) are becoming increasingly important in countries with a high prevalence of living-donor kidney transplants and an aging society. This study explored the features of elderly LKDs, focusing on their subsequent outcomes., Methods: This single-center, retrospective, observational study included eligible LKDs who donated their kidneys between April 2008 and July 2022. LKDs were categorized into an elderly (≥70 years at donation) or a non-elderly group (<70 years). We examined pre-operative characteristics and post-operative outcomes, such as kidney function, complications, development of end-stage kidney disease (ESKD), and mortality., Results: Of the 188 LKDs observed for a median of 5.7 years, 31 were in the elderly group (16.5%) and 157 (83.5%) were in the non-elderly group (mean age 72.5 ± 2.7 and 58.2 ± 7.3 years, respectively). No significant differences were observed in hospital stay length or peri-operative complications between groups. Both groups experienced a similar decline in post-donation estimated glomerular filtration rate (eGFR)-approximately 37%. In the elderly group, four LKDs died, and one progressed to ESKD. In the non-elderly group, two LKDs died, and none progressed to ESKD. The cause of death was not strongly suspected to be associated with the donation., Conclusions: eGFR was maintained even in elderly LKDs post-donation. Prioritizing LKDs' safety is paramount; however, donations from elderly people would be acceptable, considering their life expectancy. This can expand the pool of living kidney donors and address the growing demand for kidney transplants., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sarcopenia accompanied by systemic inflammation is associated with poor prognosis in patients with advanced hepatocellular carcinoma (HCC). However, the effect of sarcopenia combined with systemic inflammation on the prognosis of patients with advanced HCC who underwent hepatectomy is unclear. This study aimed to evaluate the effect of sarcopenia and inflammation on the prognosis of patients with advanced HCC., Methods: This retrospective study included 151 patients recruited between July 2010 and December 2022. We defined advanced HCC as that presenting with vascular invasion or tumor size ≥2 cm or multiple tumors. Sarcopenia was assessed using the psoas muscle index. Preoperative inflammatory markers were used by calculating the prognostic nutritional index, albumin-globulin ratio (AGR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio. Cox regression analysis was performed to determine the prognostic factors for overall survival., Results: Of 151 patients, sarcopenia occurred in 84 (55.6 %). Sarcopenia was significantly associated with male sex, older age, body mass index (<25 kg/m 2 ), and a higher NLR. In the multivariate analysis, AGR <1.25 (hazard ratio [HR], 2.504; 95% confidence interval [CI]: 1.325-4.820; p < 0.05); alpha-fetoprotein levels ≥25 ng/mL (HR, 1.891; 95% CI: 1.016-3.480; p = 0.04); and sarcopenia (HR, 1.908; 95% CI: 1.009-3.776; p < 0.05) were independent predictors of overall survival. The sarcopenia and low AGR groups had significantly worse overall survival than either the non-sarcopenia and high AGR or sarcopenia and low AGR groups., Conclusion: Sarcopenia and AGR are independent prognostic factors in patients with advanced HCC. Thus, sarcopenia may achieve a better prognostic value when combined with AGR., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Objectives: This study assessed factors influencing the complete removal and recurrence of bile duct stones in patients with surgically altered anatomy (SAA) undergoing double-balloon endoscopy-assisted endoscopic retrograde cholangiography (DBERC)., Methods: A retrospective analysis of 289 patients with SAA treated for biliary stones with DBERC at Jichi Medical University Hospital (January 2007 to December 2022) was conducted. Evaluation of factors impacting complete stone removal was performed in 257 patients with successful bile duct cannulation. Logistic and Cox proportional hazards regression models were used to compute the odds ratios (ORs) and hazard ratios (HRs) at 95% confidence intervals (CIs)., Results: Of 257 patients, 139 (54.0%) and 209 (81.3%) achieved initial and complete removal, respectively. Recurrence occurred in 55 (21.4%) patients. Factors associated with initial complete stone removal included cholangitis (P < 0.01, OR 0.48, 95% CI 0.27-0.83), number of stones (P < 0.01, OR 0.31, 95% CI 0.18-0.54), and largest stone diameter (P < 0.01, OR 0.37, 95% CI 0.20-0.67). The size of the largest stone was associated with complete removal (P = 0.01, OR 0.24, 95% CI 0.13-0.76). Recurrence was associated with cholangitis (P = 0.046, HR 0.54, 95% CI 0.29-0.99), congenital biliary dilatation (P = 0.01, HR 2.65, 95% CI 1.21-5.80), and number of stones (P = 0.02, HR 1.96, 95% CI 1.12-3.41)., Conclusions: Successful complete bile stone removal in patients with SAA depends on the stone diameter and number. Stone recurrence is influenced by the number of stones and history of congenital biliary dilatation., (© 2024 Japan Gastroenterological Endoscopy Society.)

Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy., (© 2024. Japanese Society of Gastroenterology.)

Hyperleukocytosis is an emergency of acute leukemia leading to blood hyperviscosity, potentially resulting in life-threatening microvascular obstruction, or leukostasis. Due to the high number of red cells in the circulation, hematocrit/hemoglobin levels (Hct/Hgb) are major drivers of blood viscosity, but how Hct/Hgb mediates hyperviscosity in acute leukemia remains unknown. In vivo hemorheological studies are difficult to conduct and interpret due to issues related to visualizing and manipulating the microvasculature. To that end, a multi-vessel microfluidic device recapitulating the size-scale and geometry of the microvasculature was designed to investigate how Hct/Hgb interacts with acute leukemia to induce "in vitro" leukostasis. Using patient samples and cell lines, the degree of leukostasis was different among leukemia immunophenotypes with respect to white blood cell (WBC) count and Hct/Hgb. Among lymphoid immunophenotypes, severe anemia is protective against in vitro leukostasis and Hct/Hgb thresholds became apparent above which in vitro leukostasis significantly increased, to a greater extent with B-cell acute lymphoblastic leukemia (ALL) versus T-cell ALL. In vitro leukostasis in acute myeloid leukemia was primarily driven by WBC with little interaction with Hct/Hgb. This sets the stage for prospective clinical studies assessing how red cell transfusion may affect leukostasis risk in immunophenotypically different acute leukemia patients., (© 2024 Wiley Periodicals LLC.)

Purpose: To evaluate the prognostic significance of sarcopenia and systemic inflammatory markers in patients with surgically resected biliary tract cancer (BTC)., Methods: Between July 2010 and December 2022, 146 patients were recruited. Sarcopenia was assessed using the psoas muscle index. Preoperative inflammatory markers were used to calculate the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio. Cox regression analysis was performed to determine prognostic factors for overall survival (OS) and recurrence-free survival (RFS). P < 0.05 was considered statistically significant., Results: Sixty-four patients had sarcopenia. Sarcopenia was associated with body mass index (< 22 kg/m 2 ), lymph node metastasis, and low PNI (< 42). R1/R2 resection (P = 0.02), sarcopenia (P < 0.001), lymph node metastasis (P = 0.007), intrahepatic cholangiocarcinoma (P < 0.001), and low PNI (P = 0.01) were independent predictors of OS, while male sex (P = 0.04), R1/R2 resection (P < 0.001), lymph node metastasis (P = 0.005), intrahepatic cholangiocarcinoma (P < 0.001), tumor differentiation (other than well; P = 0.003), and low PNI (P = 0.03) were independent predictors of RFS. Patients were stratified into no sarcopenia and high PNI (≥ 42; A), sarcopenia or low PNI (B), and sarcopenia and low PNI (C) groups. Group C had worse OS than the other two groups (P < 0.001 and P = 0.02, respectively)., Conclusion: Sarcopenia is associated with the PNI. Sarcopenia and the PNI are independent prognostic factors among patients with resected BTC. Sarcopenia may have better prognostic value when combined with the PNI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although boron neutron capture therapy (BNCT) causes minor damage to normal cells owing to the nuclear reactions induced by neutrons with major elements of tissues such as hydrogen and nitrogen, it is useful to estimate the accurate exposure dose for radiation protection. This study aims to estimate the contribution of internal exposure in radiation exposure dose for BNCT. The study was performed by referring to clinical studies at a reactor-based BNCT facility on the basis of computational dosimetry. Five irradiation regions of head and neck were selected for the estimation. The results suggest that external exposure occurred primarily in and around the irradiation field. Furthermore, during the exposure dose estimation in BNCT, internal exposure was found to be not negligible, implying that the irradiation regions in treatment planning must be considered for avoiding damage to certain critical organs that are susceptible to internal exposure., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Diesel exhaust particles (DEPs) are very small (typically < 0.2 μm) fragments that have become major air pollutants. DEPs are comprised of a carbonaceous core surrounded by organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and nitro-PAHs. Inhaled DEPs reach the deepest sites in the respiratory system where they could induce respiratory/cardiovascular dysfunction. Additionally, a previous study has revealed that a portion of inhaled DEPs often activate immune cells and subsequently induce somatic inflammation. Moreover, DEPs are known to localize in lymph nodes. Therefore, in this study we explored the effect of DEPs on the lymphatic endothelial cells (LECs) that are a constituent of the walls of lymph nodes. DEP exposure induced cell death in a reactive oxygen species (ROS)-dependent manner. Following exposure to DEPs, next-generation sequence (NGS) analysis identified an upregulation of the integrated stress response (ISR) pathway and cell death cascades. Both the soluble and insoluble components of DEPs generated intracellular ROS. Three-dimensional Raman imaging revealed that DEPs are taken up by LECs, which suggests internalized DEP cores produce ROS, as well as soluble DEP components. However, significant cell death pathways such as apoptosis, necroptosis, ferroptosis, pyroptosis, and parthanatos seem unlikely to be involved in DEP-induced cell death in LECs. This study clarifies how DEPs invading the body might affect the lymphatic system through the induction of cell death in LECs., (© 2024. The Author(s).)

The N3O1 tetradentate ligand, TriMeOBQMOA ( N , N -bis(5,6,7-trimethoxy-2-quinolylmethyl)-2-methoxyaniline), was developed as a Cd 2+ -specific fluorescent sensor. The structure of TriMeOBQMOA is half of TriMeOBAPTQ ( N , N , N ', N '-tetrakis(5,6,7-trimethoxy-2-quinolylmethyl)-1,2-bis(2-aminophenoxy)ethane), which is a tetrakisquinoline derivative of the well-known calcium chelator BAPTA (1,2-bis(2-aminophenoxy)ethane- N , N , N ', N '-tetraacetic acid). The fluorescent Cd 2+ selectivity of TriMeOBAPTQ ( I Zn / I Cd = 5.3% in the presence of 3 equiv of metal ions in MeOH-HEPES buffer (9:1)) comes from the formation of fluorescent dinuclear cadmium (M 2 L) and nonfluorescent OH-bridged dizinc ((μ-OH)M 2 L) complexes. TriMeOBQMOA also exhibits excellent Cd 2+ specificity in fluorescence enhancement ( I Zn / I Cd = 2.3% in the presence of 5 equiv of metal ions in DMF-HEPES buffer (1:1, HEPES 50 mM, KCl 0.1 M, pH = 7.5)) via substantial formation of a highly fluorescent bis(μ-chloro)dinuclear cadmium complex ([Cd 2 (μ-Cl) 2 L 2 ] 2+ ), which is in equilibrium with the mononuclear Cd 2+ complex ([CdLCl] + ), and extremely poor stability of the TriMeOBQMOA-Zn 2+ complex. The all-nitrogen derivatives of BQMOA and BAPTQ, namely, N , N -BQDMPHEN ( N , N -bis(2-quinolylmethyl)- N ', N '-dimethyl-1,2-phenylenediamine) and BPDTQ ( N , N , N ', N '-tetrakis(2-quinolylmethyl)-2,2'-( N , N '-dimethylethylenediamino)dianiline), respectively, and their methoxy-substituted derivatives were also prepared, and the fluorescent metal ion sensing properties are discussed.

The spatial position of individuals within a social group, which provides the group members with benefits and costs, is determined by several physical and physiological factors. Lateralization (left and right asymmetry of morphology and behavior) could also be factors determining the individual's positions within a group. However, this possibility has been documented in some fish species, but never in an invertebrate species. This study investigates the association between spatial positions and lateralization in oval squid, Sepioteuthis lessoniana, which displays social behavior, such as schooling and lateralization for eye use (visual lateralization). The direction and strength of visual lateralization were determined for single squid by observing which eye was used to detect the prey, predators, and conspecifics. The spatial positions of individuals were determined by identifying whether the squids were in the left or right side from the center of the school. When the prey was presented to schooling squids, strongly lateralized squids against prey positioned themselves on the right side, whereas weakly lateralized squids positioned themselves on the left side. When the predator was presented to squids, the strongly lateralized squids against the conspecifics positioned themselves on the right side, and the weakly lateralized squids positioned themselves on the left side. When no targets were presented, the strongly lateralized squids against the predator positioned themselves on the right side, whereas the weakly lateralized squids positioned themselves on the left side. The strength of visual lateralization of oval squid could offer the defensive and offensive functions of schools with specific individual positions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In Japan, the clinical treatment of boron neutron capture therapy (BNCT) has been applied to unresectable, locally advanced, and recurrent head and neck carcinomas using an accelerator-based neutron source since June of 2020. Considering the increase in the number of patients receiving BNCT, efficiency of the treatment planning procedure is becoming increasingly important. Therefore, novel and rapid dose calculation algorithms must be developed. We developed a novel algorithm for calculating neutron flux, which comprises of a combination of a Monte Carlo (MC) method and a method based on the removal-diffusion (RD) theory (RD calculation method) for the purpose of dose calculation of BNCT., Purpose: We present the details of our novel algorithm and the verification results of the calculation accuracy based on the MC calculation result., Methods: In this study, the "MC-RD" calculation method was developed, wherein the RD calculation method was used to calculate the thermalization process of neutrons and the MC method was used to calculate the moderation process. The RD parameters were determined by MC calculations in advance. The MC-RD calculation accuracy was verified by comparing the results of the MC-RD and MC calculations with respect to the neutron flux distributions in each of the cubic and head phantoms filled with water., Results: Comparing the MC-RD calculation results with those of MC calculations, it was found that the MC-RD calculation accurately reproduced the thermal neutron flux distribution inside the phantom, with the exception of the region near the surface of the phantom., Conclusions: The MC-RD calculation method is useful for the evaluation of the neutron flux distribution for the purpose of BNCT dose calculation, except for the region near the surface., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Purpose: Boron neutron capture therapy (BNCT) is a tumor cell-selective particle-radiation therapy. In BNCT, administered p-boronophenylalanine (BPA) is selectively taken up by tumor cells, and the tumor is irradiated with thermal neutrons. High-LET α-particles and recoil 7 Li, which have a path length of 5-9 μm, are generated by the capture reaction between 10 B and thermal neutrons and selectively kill tumor cells that have uptaken 10 B. Although BNCT has prolonged the survival time of malignant glioma patients, recurrences are still to be resolved. miRNAs, that are encapsulated in small extracellular vesicles (sEVs) in body fluids and exist stably may serve critical role in recurrence. In this study, we comprehensively investigated microRNAs (miRNAs) in sEVs released from post-BNCT glioblastoma cells., Method: Glioblastoma U87 MG cells were treated with 25 ppm of BPA in the culture media and irradiated with thermal neutrons. After irradiation, they were plated into dishes and cultured for 3 days in the 5% CO 2 incubator. Then, sEVs released into the medium were collected by column chromatography, and miRNAs in sEVs were comprehensively investigated using microarrays., Result: An increase in 20 individual miRNAs (ratio > 2) and a decrease in 2 individual miRNAs (ratio < 0.5) were detected in BNCT cells compared with non-irradiated cells. Among detected miRNAs, 20 miRNAs were associated with worse prognosis of glioma in Kaplan Meier Survival Analysis of overall survival in TCGA., Conclusion: These miRNA after BNCT may proceed tumors, modulate radiation resistance, or inhibit invasion and affect the prognosis of glioma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Virus entry inhibitors are emerging as an attractive class of therapeutics for the suppression of viral transmission. Naturally occurring pradimicin A (PRM-A) has received particular attention as the first-in-class entry inhibitor that targets N-glycans present on viral surface. Despite the uniqueness of its glycan-targeted antiviral activity, there is still limited knowledge regarding how PRM-A binds to viral N-glycans. Therefore, in this study, we performed binding analysis of PRM-A with synthetic oligosaccharides that reflect the structural motifs characteristic of viral N-glycans. Binding assays and molecular modeling collectively suggest that PRM-A preferentially binds to branched oligomannose motifs of N-glycans via simultaneous recognition of two mannose residues at the non-reducing ends. We also demonstrated, for the first time, that PRM-A can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. Significantly, the anti-SARS-CoV-2 effect of PRM-A is attenuated in the presence of the synthetic branched oligomannose, suggesting that the inhibition of SARS-CoV-2 infection is due to the interaction of PRM-A with the branched oligomannose-containing N-glycans. These data provide essential information needed to understand the antiviral mechanism of PRM-A and suggest that PRM-A could serve as a candidate SARS-CoV-2 entry inhibitor targeting N-glycans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The long-term impact of permanent pacemaker (PPM) implantation on survival after cardiac surgery remains ill defined. We aimed to investigate the effect of PPM on survival and explore factors driving outcomes using meta-regression according to the type of surgery., Methods: MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched through October 2023 to identify studies reporting the long-term outcomes of PPM implantation. The primary outcome was all-cause mortality during follow-up. The secondary outcome was heart failure rehospitalization. The subgroup analysis and meta-regression analysis were performed according to the type of surgery., Results: A total of 28 studies met the inclusion criteria. 183,555 patients (n = 6298; PPM, n = 177,257; no PPM) were analyzed for all-cause mortality, with a weighted median follow-up of 79.7 months. PPM implantation was associated with increased risks of all-cause mortality during follow-up (hazard ratio, 1.22; confidence interval, 1.08-1.38, P < .01) and heart failure rehospitalization (hazard ratio, 1.24; confidence interval, 1.01-1.52, P = .04). Meta-regression demonstrated the adverse impact of PPM was less prominent in patients undergoing mitral or tricuspid valve surgery, whereas studies with a greater proportion with aortic valve replacement were associated with worse outcomes. Similarly, a greater proportion with atrioventricular block as an indication of PPM was associated with worse survival., Conclusions: PPM implantation after cardiac surgery is associated with a greater risk of long-term all-cause mortality and heart failure rehospitalization. This impact is more prominent in patients undergoing aortic valve surgery or atrioventricular block as an indication than those undergoing mitral or tricuspid valve surgery., Competing Interests: Conflict of Interest Statement Dr Kaneko has received consulting fees from Edwards Lifesciences, Medtronic, 4C Medical, CardioMech, and Cook Medical and has been a speaker for Abbott and Baylis. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE., Methods: We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded., Results: Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to -4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group., Conclusion: Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE., Trial Registration: https://clinicaltrials.gov; NCT02388737., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Objective: This meta-analysis aimed to evaluate outcomes of transcatheter aortic valve replacement (TAVR) with percutaneous coronary intervention (PCI) versus surgical aortic valve replacement (SAVR) with coronary artery bypass grafting (CABG)., Methods: The MEDLINE, EMBASE, and Cochrane Library databases were searched through November 2021 to identify studies comparing TAVR + PCI and SAVR + CABG for severe aortic stenosis with concurrent coronary artery disease. Outcomes of interest were all-cause mortality, repeat coronary intervention, rehospitalization, myocardial infarction, and stroke during follow-up, and 30-day periprocedural outcomes., Results: Two randomized controlled trials and 6 observational studies including a total of 104,220 patients (TAVR + PCI, n = 5004; SAVR + CABG, n = 99,216) were included. The weighted mean follow-up period was 30.2 months. TAVR + PCI was associated with greater all-cause mortality and coronary reintervention during follow-up period (hazard ratio, 1.35; 95% confidence interval [CI], 1.11-1.65; P = .003, hazard ratio, 4.14; 95% CI, 1.74-9.86; P = .001, respectively), 30-day permanent pacemaker implantation rate (odds ratio [OR], 3.79; 95% CI, 1.61-8.95; P = .002), and periprocedural vascular complications (OR, 6.97; 95% CI, 1.85-26.30; P = .004). In contrast, TAVR + PCI was associated with a lower rate of 30-day acute kidney injury (OR, 0.32; 95% CI, 0.20-0.50; P = .0001). Rehospitalization, myocardial infarction, stroke during follow-up, and other periprocedural outcomes including 30-day mortality were similar in both groups., Conclusions: In patients with severe aortic stenosis and coronary artery disease, TAVR + PCI was associated with greater all-cause mortality at follow-up compared with SAVR + CABG. Heart Team approach to assess TAVR candidacy remains imperative., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Gastrointestinal complications are common after solid organ transplantation. New-onset inflammatory bowel disease (IBD) after transplantation (de novo) is a major differential diagnosis of diarrhea after liver transplantation (LT) because of its high incidence in the field. However, the incidence of IBD after kidney transplantation (KT) remains unknown., Methods: This case series comprised six de novo IBD patients who had undergone KT at our hospital from April 1998 to December 2020. In this period, 232 KT recipients were identified. Participants were analyzed based on their colonoscopy diagnoses. Detailed clinical information regarding both KT- and IBD-related symptoms or outcomes was obtained, and we calculated the incidence of de novo IBD from the date of KT., Results: Of the 232 recipients in the median observation period of 6.1 (interquartile range: 2.6, 10.8) years, six recipients (one with Crohn's disease and five with ulcerative colitis) were diagnosed with de novo IBD. The incidence of de novo IBD after KT was 355.8/100,000 person-years (95% confidence interval, 159.8-791.9 per 100,000 person-years). Bloody stools and diarrhea did not always occur, with bloody stools occurring in three and diarrhea in 2 patients at the time of diagnosis. No recipient developed graft failure or extraintestinal complications (e.g., IBD-related nephritis or arthritis)., Conclusion: Despite a small sample size, this study's results indicate that the incidence of de novo IBD after KT may be similar to that after LT and higher than that in the general population. Larger studies are required to validate these preliminary findings., Competing Interests: H.Y. received lecture fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Kowa Co. Ltd., AstraZeneka K.K., Kyorin Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. outside the submitted work. Fees for consultation for H.Y. were paid to Kyoto University by Magmitt Pharmaceutical Co. and Takeda Pharmaceutical Co. Ltd. outside the submitted work. The other authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Plants emit volatile compounds when they are subjected to herbivorous, pathogenic, or artificial damages. Both the damaged plant and the neighboring intact plants induce resistance when they receive these volatiles, a phenomenon known as plant-plant communication. However, field observations of this phenomenon are limited. To understand the nature of plant-plant communication, we collected information about intra- and inter-plant signaling via volatiles in Camellia japonica and C. rusticana under natural conditions. We exposed intact branches of damaged plant (intra-plant) or neighboring plant (inter-plant) to artificially damaged plant volatiles (ADPVs). Leaf damage reduced in ADPVs-exposed branches in the neighboring plants compared to branches that were exposed to volatiles from intact leaves, thus, indicating that inter-plant signaling occur by the emission of volatiles from damaged leaves. We also conducted an air-transfer experiment wherein the headspace air of the damaged branch was transferred to the headspace of intact branches. Leaf damage reduced on the ADPVs-transferred branch compared to the control branch. The effect of volatiles on damage reduction lasted for three months. Our results indicate that ADPVs in Camellia species contain cues that induce resistance in neighboring plants. Our findings improve understanding of plant defense strategies that may be used in horticulture and agriculture., (© 2024. The Author(s).)

Background/aim: Sarcopenia accompanied by systemic inflammation is associated with poor prognosis in patients with cancer. This study evaluated the prognostic significance of sarcopenia (myopenia and myosteatosis) and systemic inflammatory markers in older patients (aged ≥80 years) with resected biliary tract cancer., Patients and Methods: Patients who underwent resection for biliary tract cancer between July 2010 and January 2023 at the NHO Fukuyama Medical Center were retrospectively reviewed. Preoperative computed tomography measured myopenia and myosteatosis, using the psoas muscle index and modified intramuscular adipose tissue content. Associations between clinicopathological characteristics, inflammation-based prognostic scores, and overall survival were analyzed using Cox proportional hazards models., Results: Univariate analysis revealed low C-reactive protein-to-albumin ratio (<0.125), low prognostic nutritional index (<42), low modified intramuscular adipose tissue content, higher T-stage (T3-4), lymph node metastasis, and postoperative complications associated with worse overall survival in older patients (aged ≥ 80 years) with resected biliary tract cancer (n=48). Multivariate analysis identified low prognostic nutritional index (<42) (p=0.007), low modified intramuscular adipose tissue content (p=0.015), higher T-stage (T3-4) (p<0.001), lymph node metastasis (p=0.001), and postoperative complications (p=0.017) as independent predictors of overall survival., Conclusion: Preoperative myosteatosis and low prognostic nutritional index are independent prognostic factors for overall survival in older patients (aged ≥80 years) with resected biliary tract cancer. These factors may be useful for risk stratification and clinical decision-making. Early interventions, such as nutritional support and physical exercise, may improve outcomes after resection of biliary tract cancer., Competing Interests: The Authors declare that they have no competing interests., (Copyright 2024, International Institute of Anticancer Research.)

This study investigated the effects of low doses of alcohol, which are acceptable for driving a car, on inhibitory control and neural processing using the stop-signal task (SST) in 17 healthy right-handed social drinkers. The study employed simultaneous functional magnetic resonance imaging and electromyography (EMG) recordings to assess behavioral and neural responses under conditions of low-dose alcohol (breath-alcohol concentration of 0.15 mg/L) and placebo. The results demonstrated that even a small amount of alcohol consumption prolonged Go reaction times in the SST and modified stopping behavior, as evidenced by a decrease in the frequency and magnitude of partial response EMG that did not result in button pressing during successful inhibitory control. Furthermore, alcohol intake enhanced neural activity during failed inhibitory responses in the right inferior frontal cortex, suggesting its potential role in behavioral adaptation following stop-signal failure. These findings suggest that even low levels of alcohol consumption within legal driving limits can greatly impact both the cognitive performance and brain activity involved in inhibiting responses. This research provides important evidence on the neurobehavioral effects of low-dose alcohol consumption, with implications for understanding the biological basis of impaired motor control and decision-making and potentially informing legal guidelines on alcohol consumption., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Learning is classified into two types: "classical conditioning," which modifies simple reflexes, and "operant conditioning," which modifies complex voluntary behaviors. The neural circuits underlying these two types differ significantly. During the learning process of operant conditioning tasks, various changes in firing rate and firing synchrony of neurons can be observed across multiple brain regions. Additionally, neuronal firing rate and synchrony in several brain regions can be voluntarily controlled through operant conditioning. Consequently, it is evident that neurons in widespread brain regions have the potential for plastic changes to facilitate learning. It may be suggested that the learning of complex voluntary behaviors is underlined by widespread dynamic changes in neural activity and is not restricted to only a few brain regions.

Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In TG mice, suppressed proliferation of β-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in β-cells play an important role in regulating glucose homeostasis and β-cell mass., (© 2024 by the American Diabetes Association.)

We developed a broadband two-layer anti-reflection (AR) coating for use on a sapphire half-wave plate (HWP) and an alumina infrared (IR) filter for the cosmic microwave background (CMB) polarimetry. Measuring the faint CMB B-mode signals requires maximizing the number of photons reaching the detectors and minimizing spurious polarization due to reflection with an off-axis incident angle. Sapphire and alumina have high refractive indices of 3.1 and are highly reflective without an AR coating. This paper presents the design, fabrication, quality control, and measured performance of an AR coating using thermally sprayed mullite and Duroid 5880LZ. This technology enables large optical elements with diameters of 600 mm. We also present a thermography-based nondestructive quality control technique, which is key to assuring good adhesion and preventing delamination when thermal cycling. We demonstrate the average reflectance of about 2.6% (0.9%) for two observing bands centered at 90/150 (220/280) GHz. At room temperature, the average transmittance of a 105 mm square test sample at 220/280 GHz is 83%, and it will increase to 90% at 100 K, attributed to reduced absorption losses. Therefore, our developed layering technique has proved effective for 220/280 GHz applications, particularly in addressing dielectric loss concerns. This AR coating technology has been deployed in the cryogenic HWP and IR filters of the Simons Array and the Simons observatory experiments and applies to future experiments such as CMB-S4.

A 73-year-old woman with posterior cortical atrophy (PCA) presented with progressive apperceptive visual agnosia, alexia, agraphia, ventral simultanagnosia, prosopagnosia, and allocentric (stimulus-centered) left-sided hemispatial neglect. All of these symptoms were attributed to damage to the bilateral occipito-temporal cortices, consistent with ventral variant PCA. While the Pittsburgh compound B uptake was extensively distributed throughout the occipito-parietal (dorsal) and occipito-temporal (ventral) areas, the THK5351 (ligand binding to tau aggregates/astrocyte gliosis) accumulation was limited to the ventral area. These findings suggest that local accumulation of tau proteins and/or astrocyte gliosis over the occipito-temporal cortices can result in ventral variant PCA.

REV7 is a multifunctional protein implicated in various biological processes, including DNA damage response. REV7 expression in human cancer cells affects their sensitivity to DNA-damaging agents. In the present study, we investigated the significance of REV7 in pancreatic ductal adenocarcinoma (PDAC). REV7 expression was immunohistochemically examined in 92 resected PDAC specimens and 60 endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens of unresectable PDAC treated with platinum-based chemotherapy, and its association with clinicopathologic features was analyzed. Although REV7 expression was not significantly associated with the progression of primary tumors (T-factor and Stage) in either resected or unresectable PDAC, decreased levels of REV7 expression in EUS-FNAB specimens of unresectable PDAC were significantly associated with better outcomes of platinum-based chemotherapy and a favorable prognosis. REV7-deficient PDAC cell lines showed suppressed cell growth and enhanced sensitivity to cisplatin in vitro. Tumor-bearing mice generated using REV7-deficient PDAC cell lines also showed enhanced sensitivity to cisplatin in vivo. RNA sequencing analysis using WT and REV7-deficient PDAC cell lines revealed that REV7 inactivation promoted the downregulation of genes involved in the DNA repair and the upregulation of genes involved in apoptosis. Our results indicate that decreased expression of REV7 is associated with better outcomes of platinum-based chemotherapy in PDAC by suppressing the DNA damage response. It is also suggested that REV7 is a useful biomarker for predicting the outcome of platinum-based chemotherapy and the prognosis of unresectable PDAC and is a potential target for PDAC treatment., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Thrombosis is the major cause of death in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the pathology of vascular endothelial cells (ECs) has received much attention. Although there is evidence of the infection of ECs in human autopsy tissues, their detailed pathophysiology remains unclear due to the lack of animal model to study it. We used a mouse-adapted SARS-CoV-2 virus strain in young and mid-aged mice. Only mid-aged mice developed fatal pneumonia with thrombosis. Pulmonary ECs were isolated from these infected mice and RNA-Seq was performed. The pulmonary EC transcriptome revealed that significantly higher levels of viral genes were detected in ECs from mid-aged mice with upregulation of viral response genes such as DDX58 and IRF7. In addition, the thrombogenesis-related genes encoding PLAT, PF4, F3 PAI-1, and P-selectin were upregulated. In addition, the inflammation-related molecules such as CXCL2 and CXCL10 were upregulated in the mid-aged ECs upon viral infection. Our mouse model demonstrated that SARS-CoV-2 virus entry into aged vascular ECs upregulated thrombogenesis and inflammation-related genes and led to fatal pneumonia with thrombosis. Current results of EC transcriptome showed that EC uptake virus and become thrombogenic by activating neutrophils and platelets in the aged mice, suggesting age-associated EC response as a novel finding in human severe COVID-19., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Although heterotopic pancreas usually occurs in the stomach and rarely presents as a submucosal tumor, an accurate preoperative diagnosis is often difficult because of the variety of clinical symptoms and findings depending on the size and location of the lesion. We experienced a case of gastric type III heterotopic pancreas presenting as a gastric adenomyoma in the antrum of the stomach. A 62-year-old woman visited a local hospital for epigastric discomfort. An esophagogastroduodenoscopy study indicated a submucosal tumor in the greater curvature of the gastric antrum. The patient underwent surgical resection of the tumor because it was enlarged. The histological sections of the resected specimen showed that the tumor was composed of ductular structures lined by tall columnar epithelia and a prominent smooth muscle stroma with no atypical cells. The tumor was compatible with Heinrich's type III heterotopic pancreas, which presented as an adenomyoma of the stomach. These findings provide useful histological features and some insight into a better understanding of the embryonic origin and development of adenomyoma and heterotopic pancreas in the antrum of the stomach., (© 2023. Japanese Society of Gastroenterology.)

We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.

In the process of developing carbon-supported metal catalysts, determining the catalyst particle-size distribution is an essential step, because this parameter is directly related to the catalytic activities. The particle-size distribution is most effectively determined by small-angle X-ray scattering (SAXS). When metal catalysts are supported by high-performance mesoporous carbon materials, however, their mesopores may lead to erroneous particle-size estimation if the sizes of the catalysts and mesopores are comparable. Here we propose a novel approach to particle-size determination by introducing contrast variation-SAXS (CV-SAXS). In CV-SAXS, a multi-component sample is immersed in an inert solvent with a density equal to that of one of the components, thereby rendering that particular component invisible to X-rays. We used a mixture of tetrabromoethane and dimethyl sulfoxide as a contrast-matching solvent for carbon. As a test sample, we prepared a mixture of a small amount of platinum (Pt) catalyst and a bulk of mesoporous carbon, and subjected it to SAXS measurement in the absence and presence of the solvent. In the absence of the solvent, the estimated Pt particle size was affected by the mesopores, but in the presence of the solvent, the Pt particle size was correctly estimated in spite of the low Pt content. The results demonstrate that the CV-SAXS technique is useful for correctly determining the particle-size distribution for low-Pt-content catalysts, for which demands are increasing to reduce the use of expensive Pt., (© 2024. The Author(s).)