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Abstract This retrospective study evaluated the use of laminin γ2 monomer (LG2m) as a predictive biomarker for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Serum LG2m levels were measured in two cohorts of patients: cohort 1 comprised 56 patients with chronic liver disease for assessing LG2m stability, whereas cohort 2 included 89 patients with chronic HBV infection who did not have HCC for evaluating the usefulness of LG2m measurement in HCC prediction. LG2m was highly stable in cryopreserved serum, and an increased LG2m level was significantly associated with a higher risk of HCC in chronically HBV-infected patients (P = 0.012). Multivariable Cox regression analysis revealed that high LG2m was an independent significant risk factor for HCC (hazard ratio, 7.16; 95% confidence interval, 1.31–39.2; P = 0.023). These findings suggest that LG2m may serve as a useful biomarker for the prediction of future HCC in patients with chronic HBV infection.

Abstract Selective perturbation of protein interactions with chemical compounds enables dissection and control of developmental processes. Differentiation of stomata, cellular valves vital for plant growth and survival, is specified by the basic-helix-loop-helix (bHLH) heterodimers. Harnessing a new amination reaction, we here report a synthesis, derivatization, target identification, and mode of action of an atypical doubly-sulfonylated imidazolone, Stomidazolone, which triggers stomatal stem cell arrest. Our forward chemical genetics followed by biophysical analyses elucidates that Stomidazolone directly binds to the C-terminal ACT-Like (ACTL) domain of MUTE, a master regulator of stomatal differentiation, and perturbs its heterodimerization with a partner bHLH, SCREAM in vitro and in plant cells. On the other hand, Stomidazolone analogs that are biologically inactive do not bind to MUTE or disrupt the SCREAM-MUTE heterodimers. Guided by structural docking modeling, we rationally design MUTE with reduced Stomidazolone binding. These engineered MUTE proteins are fully functional and confer Stomidazolone resistance in vivo. Our study identifies doubly-sulfonylated imidazolone as a direct inhibitor of the stomatal master regulator, further expanding the chemical space for perturbing bHLH-ACTL proteins to manipulate plant development.

Abstract Background Posterior synechiae of the iris rarely cause secondary angle-closure glaucoma after pars plana vitrectomy, mainly reported in cases with high postoperative inflammation. The face-down position with gas tamponade can cause acute angle-closure glaucoma in phakic eyes owing to relative pupillary block. This report presents a rare case of pseudophakic eye with secondary acute angle-closure glaucoma after 25-gauge pars plana vitrectomy and long-term vitreous gas tamponade for a macular hole. Case presentation A 61-year-old Japanese female patient presented with a chief complaint of right-sided visual impairment that had persisted for several months. Slit-lamp examination revealed deep anterior chamber and moderate nuclear sclerotic cataracts in both eyes. The axial length of the eye was 23.53 mm right eye and 24.05 mm left eye, and the fundus examination revealed a full-thickness macular hole (stage 3) in the right eye. The patient underwent simultaneous cataract surgery and pars plana vitrectomy with 7-mm diameter 3-piece monofocal intraocular lens implantation, internal limiting membrane peeling, and air tamponade. There were no complications during surgery. Due to non-closure of the macular hole, a second pars plana vitrectomy with internal limiting membrane inverted flap and SF6 gas tamponade was performed 13 days later. The patient maintained face-down position after both surgeries, and 6 days after the second surgery, intraocular pressure was elevated to 53 mmHg, and acute angle-closure glaucoma with iris bombe was diagnosed in the right eye. A laser peripheral iridotomy was performed, resulting in a deepened anterior chamber, normalized intraocular pressure, and a closed macular hole. Conclusions This case presents a rare occurrence of secondary acute angle-closure glaucoma in a pseudophakic eye after 25-gauge minimally invasive pars plana vitrectomy and SF6 gas tamponade for macular hole. The cause was presumed to be posterior synechiae of the iris or relative pupillary block due to forward pushing of the intracapsular intraocular lens by vitreous gas. In cases where surgery is repeated without achieving macular hole closure, necessitating long-term face-down position, where vitreous gas is retained for an extended period, or when a large-diameter intraocular lens is implanted, secondary acute angle-closure glaucoma should be considered. This applies even when the 25-gauge pars plana vitrectomy is performed not for a highly invasive proliferative diabetic retinopathy but for macular hole repair, especially if the patient has a pseudophakic eye.

Abstract Background Pregnancy in women with chronic kidney disease (CKD) is associated with an increased risk of adverse maternal and fetal outcomes, including worsening renal function, hypertension, proteinuria, preeclampsia, preterm delivery, stillbirth, and intrauterine growth restriction. Some pregnant women with CKD may require dialysis after conception. Clinical guidelines provide recommendations for optimal hemodialysis prescription in pregnant women undergoing maintenance hemodialysis for end-stage kidney disease. However, the timing of initiation and optimal doses of hemodialysis for pregnant women with non-dialysis advanced CKD remain uncertain. Case presentation We describe the case of a 29-year-old woman with a history of CKD for at least 2 years. She was referred to our department with a serum creatinine level of 2.48 mg/dL and an estimated glomerular filtration rate of 20 mL/min/1.73 m2. Because she was found to be pregnant at the initial visit, she was referred to the Department of Obstetrics. At 23 weeks’ gestation, she was admitted due to threatened premature delivery and urinary tract infection, which were managed with ritodrine hydrochloride and antibiotics. Owing to maternal weight loss and asymmetrical fetal growth restriction, daily protein intake was increased from 40 g/day to 60–80 g/day. Additionally, supportive hemodialysis (three times per week) was initiated at 26 weeks’ gestation, and the pre-dialysis blood urea nitrogen (BUN) level was consistently maintained

Objectives: The prognosis of patients with colorectal diverticular perforations requiring surgery is poor, and the efficacy of polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) in these patients has not yet been established. In the present study, we evaluated the prognostic factors and the efficacy of PMX-DHP in surgically treated patients with perforated colorectal diverticula. Methods: Of the 116 patients with colorectal perforations who underwent emergency surgery at our hospital between April 2018 and May 2023, we retrospectively reviewed 46 patients with perforated colorectal diverticula. Preoperative, surgical, and postoperative factors were compared between the survival and mortality groups. Subgroup analysis was performed to evaluate the efficacy of PMX-DHP in severe cases. Results: The postoperative mortality group included 7 patients (15.2%), and PMX-DHP was performed in 14 (30.4%). PMX-DHP was performed significantly more often in the mortality group (P

Abstract It is essential to elucidate the molecular mechanisms underlying liver transplant tolerance and rejection. In cases of mouse liver transplantation between inbred strains, immunological rejection of the allograft is reduced with spontaneous apoptosis without immunosuppressive drugs, which differs from the actual clinical result. This may be because inbred strains are genetically homogeneous and less heterogeneous than others. We exploited outbred CD1 mice, which show highly heterogeneous genotypes among individuals, to search for biomarkers related to immune responses and to construct a model for predicting the outcome of liver allografting. Of the 36 mice examined, 18 died within 3 weeks after transplantation, while the others survived for more than 6 weeks. Whole-exome sequencing of the 36 donors revealed more than 9 million variants relative to the C57BL/6 J reference. We selected 6517 single-nucleotide and indel variants and performed machine learning to determine whether or not we could predict the prognosis of each genotype. Models were built by both deep learning with a one-dimensional convolutional neural network and linear classification and evaluated by leave-one-out cross-validation. Given that one short-lived mouse died early in an accident, the models perfectly predicted the outcome of all individuals, suggesting the importance of genotype collection. In addition, linear classification models provided a list of loci potentially responsible for these responses. The present methods as well as results is likely to be applicable to liver transplantation in humans.

Abstract Urgent haploidentical haematopoietic cell transplantation may be considered in cases of severe aplastic anaemia (SAA) without a human leukocyte antigen‐matched donor and suffering from severe infection. However, deciding on allogeneic transplantation in the setting of active systemic infection is challenging due to poor outcomes. This report presents a case of disseminated Magnusiomyces capitatus infection in a 5‐year‐old male who underwent immunosuppressive therapy for hepatitis‐associated SAA. To address the critical situation, granulocyte transfusion was promptly administered from the patient's mother, followed by unmanipulated haploidentical peripheral blood stem cell transplantation from the patient's father with posttransplant cyclophosphamide, ultimately resulting in successful rescue.

Abstract Background Nuts consumption is related to cardioprotective effects on primary cardiovascular prevention, but studies conducted in secondary prevention are small, scarce and controversial. The objective of this trial was to evaluate the effects of a regional and sustainable cardioprotective diet added or not with an affordable mixed nuts on cardiometabolic features in patients with previous myocardial infarction. Methods DICA-NUTS study is a national, multi-center, and superiority-parallel randomized clinical trial. Males and females over 40 years old diagnosed with previous myocardial infarction in the last 2 to 6 months were included. Patients were allocated into two groups: the Brazilian Cardioprotective diet (DICA Br) supplemented with 30 g/day of mixed nuts (10 g of peanuts; 10 g of cashew; 10 g of Brazil nuts) (intervention group, n = 193); or only DICA Br prescription (control group, n = 195). The primary outcome was low-density lipoprotein cholesterol means (in mg/dL) after 16 weeks. Secondary outcomes were other lipid biomarkers, glycemic and anthropometric data and diet quality. Results After adjustment for baseline values, participating study site, time since myocardial infarction and statin treatment regimen (high potency, moderate and low potency/no statins), no significant difference was found between the groups in low-density lipoprotein cholesterol concentrations (intervention-control difference: 3.48 mg/dL [-3.45 to 10.41], P = 0.32). Both groups improved their overall diet quality at the end of the study without differences between them after 16 weeks (intervention-control difference: 1.05 (-0.9 to 2.99); P = 0.29). Other lipids, glycemic profile and anthropometrics were also not different between study groups at the end of the study. Conclusion Adding 30 g/day of mixed nuts to the DICA Br for 16 weeks did not change lipid, glycemic and anthropometric features in the post-myocardial infarction setting. Trial registration This study is registered on ClinicalTrials.gov website under number NCT03728127 and its World Health Organization Universal Trial Number (WHO-UTN) is U1111-1259–8105.

Abstract Aims Congestive heart failure (HF) is a common complication in patients with acute myocardial infarction (AMI). The estimated plasma volume status [ePVS = (100 − haematocrit)/haemoglobin] is used as the blood plasma volume index to determine the presence of congestion in patients with HF. However, the clinical impact of ePVS at discharge in patients with AMI remains unclear. This study aimed to investigate whether ePVS at discharge could determine the long‐term prognosis in patients with AMI. Methods and results We retrospectively identified patients with AMI with ePVS measured at discharge between January 2012 and December 2020. The primary endpoint was post‐discharge all‐cause death. The patients were divided into two groups according to an ePVS cut‐off value of 5.5%, which is commonly used in HF. In total, 1012 patients with AMI were included. The median age was 70 years (range, 61–78 years), and 76.4% of the patients were male. The ePVS > 5.5% (high‐ePVS) group included 365 patients (36.1%), and the all‐cause mortality rate in the total cohort was 17.7%. The log‐rank test revealed that the high‐ePVS group had a significantly higher rate of all‐cause death than the ePVS ≤ 5.5% (low‐ePVS) group (P

Soil crust is of high concern in soybean cultivation due to its adverse impact on seedling emergence. Despite the necessity of soybean varieties with stable seedling emergence against soil surface crust, genotypic variation of this trait has not been well understood because there have been no general protocols widely applicable to a set of accessions. The major constraint in conducting such experiments is the difficulty in reproducing soil crust with uniform hardness for each set of experiments. In this study, a simple method that can evaluate the seedling emergence under the conditions of uniform hardness of soil crust using gypsum mixed soil was developed and tested for 82 soybean accessions. Among the tested accessions, five genotypes with high seedling emergence under soil crust conditions were identified.

Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine‐ and cisplatin‐resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine‐resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia‐inducible factor1α (HIF1α) expression, stimulating aerobic glycolysis. In gemcitabine‐resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain‐containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1α expression. PHGDH downregulation or inhibition in gemcitabine‐resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin‐resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl‐CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1α expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in vitro and in vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed.

Abstract Establishing a decision-making scheme for multiple land use types in a shrinking society is an urgent and persistent task. In particular, residents and governments face the complexity of cross-sectoral visions over concerned landscapes. This study examined the preference of residents for future visions and the effects of group deliberation in a Japanese rural community to enhance the current understanding of decision and learning processes on cross-sectoral land use types (i.e., agricultural land, forest land, and boundary areas) across ages and groups. This study posed the following questions: (i) what types of interactions do residents find among options on cross-sectoral land uses? and (ii) how do group deliberation influence the individual preferences of residents for land use? In the survey, the residents disclosed their preferences for the prepared visions over three land use types. The survey also enabled the comparison of choices before and after group deliberation. Regarding question (i), the residents’ choice prior to the deliberation demonstrated thematic coherence through land use categories. Smart technology and potential productivity improvement were selected across agriculture and forests. However, regarding question (ii), thematic coherence decreased after the group deliberation. The residents could communicate disagreements during group deliberation and consider the issues relatively independently over land use types, which separately views agriculture lands and forests. The choice after group discussions became increasingly embedded and influenced by residential areas and land ownership of residents. These findings provide unique insights into the group discussion on how individual decisions are affected. In summary, the preferences of cross-sectoral land use types did not converge but tended to diverge.

Abstract We investigate a composite model of spontaneous CP violation based on a new supersymmetric QCD as a solution to the strong CP problem. The scalar components of the meson chiral superfields obtain complex vacuum expectation values to break CP symmetry spontaneously. Then, wavefunction renormalization for the quark kinetic terms provides the Cabibbo-Kobayashi-Maskawa (CKM) phase, while the strong CP phase θ ¯ $$ \overline{\theta} $$ is protected by nonrenormalization of the superpotential and hermiticity of the wavefunction renormalization factor. In our model, the right-handed down-type quark multiplets are given by composite states, enhancing their couplings to CP breaking fields, which is essential to realize the observed CKM phase. The non-perturbative dynamics generates the scale of spontaneous CP violation hierarchically lower than the Planck scale. We discuss potential corrections to θ ¯ $$ \overline{\theta} $$ and find a viable parameter space of the model to solve the strong CP problem without fine-tuning.

Abstract Clostridioides difficile, a cause of healthcare-associated infections, poses a significant global health threat. This multi-institutional retrospective study focuses on epidemic dynamics, emphasizing minor and toxin-negative clinical isolates through high-resolution genotyping. The genotype of the C. difficile clinical isolates during 2005 to 2022 was gathered from 14 hospitals across Japan (N = 982). The total number of unique genotypes was 294. Some genotypes were identified in every hospital (cross-regional genotypes), while others were unique to a specific hospital or those in close geographic proximity (region-specific genotypes). Notably, a hospital located in a sparsely populated prefecture exhibited the highest prevalence of region-specific genotypes. The isolation rate of cross-regional genotypes positively correlated with the human mobility flow. A 6-month interval analysis at a university hospital from 2019 to 2021 revealed a temporal transition of the genotype dominance. The frequent isolation of identical genotypes over a brief timeframe did not always align with the current criteria for defining nosocomial outbreaks. This study highlights the presence of diverse indigenous C. difficile strains in regional environments. The cross-regional strains may have a higher competency to spread in the human community. The longitudinal analysis underscores the need for further investigation into potential nosocomial spread.

Abstract Automation and quality control (QC) are critical in manufacturing safe and effective cell and gene therapy products. However, current QC methods, reliant on molecular staining, pose difficulty in in-line testing and can increase manufacturing costs. Here we demonstrate the potential of using label-free ghost cytometry (LF-GC), a machine learning-driven, multidimensional, high-content, and high-throughput flow cytometry approach, in various stages of the cell therapy manufacturing processes. LF-GC accurately quantified cell count and viability of human peripheral blood mononuclear cells (PBMCs) and identified non-apoptotic live cells and early apoptotic/dead cells in PBMCs (ROC-AUC: area under receiver operating characteristic curve = 0.975), T cells and non-T cells in white blood cells (ROC-AUC = 0.969), activated T cells and quiescent T cells in PBMCs (ROC-AUC = 0.990), and particulate impurities in PBMCs (ROC-AUC ≧ 0.998). The results support that LF-GC is a non-destructive label-free cell analytical method that can be used to monitor cell numbers, assess viability, identify specific cell subsets or phenotypic states, and remove impurities during cell therapy manufacturing. Thus, LF-GC holds the potential to enable full automation in the manufacturing of cell therapy products with reduced cost and increased efficiency.

Introduction: Erythema nodosum (EN) is the most common form of panniculitis. EN can be idiopathic or secondary to an underlying systemic disease, infection, drug use, or tumor. CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a relapsed and refractory lymphoma, and further understanding of its pathology is required. We report a case of newly diagnosed CD5+ DLBCL with concomitant EN. Within the scope of our search, there were no reports of CD5+ DLBCL complicated with EN. Case Presentation: A 79-year-old woman experienced swelling, warmth, redness, and pain in both legs and a mass lesion on the right side of the back at almost the same time. The respective lesions were diagnosed as EN and CD5+ DLBCL by biopsy. With chemotherapy, the lymphoma and EN improved in parallel courses. The patient has completed scheduled chemotherapy, and there has been no recurrence of swelling in the legs or mass on the right side of the back. Discussion: The lymphoma and EN developed simultaneously and followed a parallel clinical course after chemotherapy, suggesting that EN was a paraneoplastic symptom of CD5+ DLBCL. Recognizing and treating underlying malignancies in patients presenting with EN is crucial.

Abstract Background Since the 1920s, motor development has been a strong research theme, focusing on infants' acquisition of motor skills, such as turning over and crawling. In the 1980s, a dynamic systems approach began emphasizing children's own motivation, which helped explain individual differences in the emergence of motor skills. However, few studies have examined factors contributing to individual differences in early motor development. In response, we investigated directional associations between temperament and motor development in children aged 6 months to 3 years. Method The Japan Environment and Children’s Study (JECS-A) recruited mothers between January 2011 and March 2014. 2,639 mothers were sent a questionnaire at 6 months, and responses were received from 1,657 of them, with full data for children aged 6 months, 2 years, and 3 years, including from three mothers of twins, were analyzed through structural equation modeling. Question items regarding fine and gross motor activities at each age were selected by pediatric neurologists specializing in developmental disorders. The Japanese version of the Little Developmental Coordination Disorder Questionnaire was administered at 42 months. Temperament was assessed through the parent-reported Behavior Questionnaire (short version) for infants, toddlers, and children. In all three measures, Surgency and Negative Affectivity were extracted, and Effortful Control, a major form of self-regulation, was found from toddlerhood onward, as in previous studies. Results A path diagram reveals that at 6 months, Surgency and Orienting/Regulation interacted positively with the motor function (respectively, r = .57; r = 40, ps

Abstract During the development of multicellular organisms and cell differentiation, the chromatin structure in the cell nucleus undergoes extensive changes, and the nucleosome structure is formed by a combination of various histone variants. Histone variants with diverse posttranslational modifications are known to play crucial roles in different regulatory functions. We have previously reported that H3t, a testis-specific histone variant, is essential for spermatogenesis. To elucidate the function of this chromatin molecule in vivo, we generated knock-in mice with a FLAG tag attached to the carboxyl terminus of H3t. In the present study, we evaluated the utility of the generated knock-in mice and comprehensively analyzed posttranslational modifications of canonical H3 and H3t using mass spectrometry. Herein, we found that H3t-FLAG was incorporated into spermatogonia and meiotic cells in the testes, as evidenced by immunostaining of testicular tissue. According to the mass spectrometry analysis, the overall pattern of H3t-FLAG posttranslational modification was comparable to that of the control H3, while the relative abundances of certain specific modifications differed between H3t-FLAG and the control bulk H3. The generated knock-in mice could be valuable for analyzing the function of histone variants in vivo.

Understanding orbital-scale changes in East Asian summer monsoon (EASM) precipitation is a fundamental issue in paleoclimate research as it helps assess the response of the East Asian monsoon to different climatic forcings, such as insolation, ice volume, and greenhouse gases. However, due to inconsistencies between different proxies, the fundamental driving force for EASM variability remains controversial. The present study simulated the global climate under given insolation changes over the past 450 kyr using a climate model, version 2.3 of the Meteorological Research Institute's Coupled General Circulation Model (MRI-CGCM2.3). Changes in summer insolation over East Asia resulted in distinct climatic responses in China and Japan: an increase in summer insolation led to increased summer precipitation in China and decreased summer precipitation in Japan. Composite analyses of simulated climate under strong boreal-summer insolation suggest that warming of the Indian Ocean occurs under intense insolation, resulting in the intensification of the North Pacific subtropical high (sub-high). The northern shift in the monsoon front, associated with the intensified sub-high, leads to an increase in rainfall in the coastal area of China. In contrast, the intensity of the EASM around Japan is affected by the strength of the North Pacific High. Under strong insolation, the increase in thermal contrast between the North American continent and the North Pacific Ocean intensifies the North Pacific High, decreasing summer precipitation around Japan. Thus, strong regional differences in the effects of solar-insolation variability on summer precipitation in East Asia exist due to interactions with different ocean basins.

Abstract The objective of this study was to assess radiolucent lines (RLLs) and to determine their effect on clinical outcomes of the newly introduced cementless mobile-bearing total knee arthroplasty (TKA) system. This was prospective, multicentre study. Seventy-eight patients with knee osteoarthritis who underwent primary TKA were enrolled. Patient-reported outcome measures (PROMs) and radiographic assessments were evaluated at preoperative baseline and at 6 weeks, 1 year, and 2 years after surgery. KOOS, PKIP, 2011KSS, EQ-5D-3L and SKO improved from preoperative baseline to all postoperative timepoints, with no loosening of components. No RLLs were detected at 6 weeks after surgery. However, RLLs ≥ 1 mm developed in 2.8% of the patients for the femur and 9.7% for the tibia at 1 year after surgery, and values were 5.7% and 10.9%, respectively, at 2 years after surgery. RLL incidence was not correlated with PROMs. Age, sex, body mass index, range of motion knee flexion, posterior cruciate ligament treatment and β angle did not impact the occurrence of RLLs. There were no intraoperative complications, revisions or reoperations. This TKA system improved PROMs and showed less incidence of RLLs compared to the previous reported TKA without implant-related complications.

Abstract High-intensity, short-pulse lasers are crucial for generating energetic electrons that produce high-energy-density (HED) states in matter, offering potential applications in igniting dense fusion fuels for fast ignition laser fusion. High-density targets heated by these electrons exhibit spatially non-uniform and highly transient conditions, which have been challenging to characterize due to limitations in diagnostics that provide simultaneous high spatial and temporal resolution. Here, we employ an X-ray Free Electron Laser (XFEL) to achieve spatiotemporally resolved measurements at sub-micron and femtosecond scales on a solid-density copper foil heated by laser-driven fast electrons. Our X-ray transmission imaging reveals the formation of a solid-density hot plasma localized to the laser spot size, surrounded by Fermi degenerate, warm dense matter within a picosecond, and the energy relaxation occurring within the hot plasma over tens of picoseconds. These results validate 2D particle-in-cell simulations incorporating atomic processes and provide insights into the energy transfer mechanisms beyond current simulation capabilities. This work significantly advances our understanding of rapid fast electron heating and energy relaxation in solid-density matter, serving as a key stepping stone towards efficient high-density plasma heating and furthering the fields of HED science and inertial fusion energy research using intense, short-pulse lasers.

Abstract Background Atheroma is a serious atherosclerotic lesion related to plaque rupture, thrombosis, and ischemic disease. To clarify the pathogenesis of human atheroma, particularly the formation of the liponecrotic tissue in the necrotic core, the distribution of connective tissue fibers, such as collagen and elastic fibers, and related substances was investigated in this study. Methods Atherosclerotic lesions in human coronary arteries were classified into three categories: pathologic intimal thickening (PIT), atheroma with lipid core (ALC), and atheroma with necrotic core (ANC). PIT and ALC consisted of the lipid pool and the lipid core, respectively. The necrotic core of ANC was composed of a lipid core-like region and liponecrotic tissue containing amorphous materials and lacking cells and connective tissue fibers. The distribution of collagen type I, elastin, C-terminal crosslinked telopeptide of collagen type I (CTX-I), and cathepsin K (CatK) was investigated through immunohistochemistry. CTX-I is a fragmented peptide consisting of the C-terminal region of collagen type I that is generated by CatK. The distribution of denatured and unfolded collagen chains was also investigated through collagen hybridizing peptide staining. Results Collagen type I, denatured and unfolded collagen chains, and elastin were positively stained in the PIT, ALC, and lipid core-like region of ANC. However, they were negatively stained in the liponecrotic tissue of ANC. CTX-I and CatK were positively stained in all four regions, and their grade of staining appeared to show a positive relationship. Both CTX-I and CatK demonstrated higher staining grades in the liponecrotic tissue. These findings suggested that pre-existing collagen type I was severely degraded by CatK, resulting in the production of CTX-I in the liponecrotic tissue, and that pre-existing elastin was also degraded in this region. CatK was mainly found in macrophage foam cells, many of which were localized within and around the liponecrotic tissue. Conclusions This study suggests that the liponecrotic tissue in the necrotic core of human atheroma is formed by severe degradation of pre-existing connective tissue fibers and consequent collapse of tissue structure. This degradation is likely caused by proteolytic enzymes, such as CatK, secreted by macrophage foam cells.

Introduction Although uterine perforation is a rare but serious complication, intrauterine devices are globally popular and effective contraceptive methods. Case presentation A 76‐year‐old female patient manifesting symptoms of vaginal leakage and lower abdominal discomfort was admitted to our hospital. Diagnostic imaging identified a vesicovaginal fistula and bladder calculi attributable to perforation of the bladder by an intrauterine device that had been inserted over four decades ago. The patient underwent open surgery for cystolith removal and vesicovaginal fistula repair. Conclusions If a patient with an intrauterine device complains of bladder stones or ongoing lower urinary tract symptoms, bladder perforation caused by the device should be considered in the differential diagnosis.

Abstract Aims Interleukin‐16 (IL‐16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL‐16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF. Methods and results We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL‐16 levels after stabilization were available (53% female, median age 81 [interquartile range 75–85] years). We divided this sub‐cohort into four phenogroups using our established clustering algorithm. The study endpoint was all‐cause death. Patients were subclassified into phenogroup 1 (‘rhythm trouble’ [n = 69]), phenogroup 2 (‘ventricular‐arterial uncoupling’ [n = 49]), phenogroup 3 (‘low output and systemic congestion’ [n = 41]), and phenogroup 4 (‘systemic failure’ [n = 52]). After a median follow‐up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL‐16 level. The IL‐16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL‐16 level had a significant predictive value for all‐cause death only in phenogroup 2 (C‐statistic 0.750, 95% confidence interval 0.606–0.863, P = 0.017), while there was no association between the IL‐16 level and the endpoint in the other phenogroups. Conclusions Our results indicated that the serum IL‐16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

Abstract Aims Low‐density lipoprotein cholesterol (LDL‐C), anaemia and low platelets have been associated with worse clinical outcomes in heart failure patients. We investigated the relationship between the combination of these three components and clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We examined the data of 1021 patients with HFpEF hospitalized with acute decompensated heart failure (HF) from the PURSUIT‐HFpEF registry, a prospective, multicenter observational study. The enrolled patients were classified into four groups by an LEP (LDL‐C, Erythrocyte, and Platelet) score of 0 to 3 points, with 1 point each for LDL‐C, erythrocyte and platelet values less than the cut‐off values as calculated by receiver operating characteristic curve analysis. The endpoint, a composite of all‐cause death and HF readmission, was evaluated among the four groups. Median follow‐up duration was 579 [300, 978] days. Risk of the composite endpoint significantly differed among the four groups (P

Este artigo discute as manifestações antidespejos ocorridas no bairro Lavapiés, em Madri, com o intuito de compreender a correlação entre dois aspectos: a caracterização desses eventos como ciberacontecimentos, pelos quais irrompem novas formas de atuação da cidadania, e a emersão de uma nova esfera de aparecimento por meio das visualidades da precariedade. Tais ações buscam denunciar a gentrificação presente no local, a qual visa impor um campo de aparecimento que instaura a condição de precariedade das pessoas consideradas inadequadas. Com isso, busca-se explicitar de que maneira o ciberacontecimento agencia a constituição de visualidades urbanas da condição precária, de modo que existir e ter direitos implica, antes de tudo, aparecer.

Correction to: Molecular Psychiatry, published online 2 May 2023 In this article Honami Arai, Irene Bollettini, Rosa Calvo Escalona, Ana Coelho, Federica Colombo, Leila Darwich, Martine Fontaine, Toshikazu Ikuta, Jonathan C. Ipser, Asier Juaneda-Seguí, Hitomi Kitagawa, Gerd Kvale, Mafalda Machado-Sousa, Astrid Morer, Takashi Nakamae, Jin Narumoto, Joseph O’Neill, Sho Okawa, Eva Real, Veit Roessner, Joao R. Sato, Cinto Segalàs, Roseli G. Shavitt, Dick J. Veltman, Kei Yamada were missing from the author list indexed under the ENIGMA-OCD Working Group. Additionally, there was an error regarding Tokiko Yoshida’s name, where the first name and last name were written in the wrong order. The original article has been corrected.

Fracture injection/shut-in tests are commonly used to measure the state of stress in the subsurface. Injection creates a hydraulic fracture (or in some cases, opens a preexisting fracture), and then the pressure after shut-in is monitored to identify fracture closure. Different interpretation procedures have been proposed for estimating closure, and the procedures sometimes yield significantly different results. In this study, direct, in-situ strain measurements are used to observe fracture reopening and closure. The tests were performed as part of the EGS Collab project, a mesoscale project performed at 1.25 and 1.5 km depth at the Sanford Underground Research Facility. The tests were instrumented with the SIMFIP tool, a double-packer probe with a high-resolution three-dimensional borehole displacement sensor. The measurements provide a direct observation of the fracture closure signature, enabling a high-fidelity estimate of the fracture closure stress (ie, the normal stress on the fracture). In two of the four tests, injection created an opening mode fracture, and so the closure stress can be interpreted as the minimum principal stress. In the other two tests, injection probably opened preexisting natural fractures, and so the closure stress can be interpreted as the normal stress on the fractures. The strain measurements are compared against different proposed methods for estimating closure stress from pressure transients. The shut-in transients are analyzed with two techniques that are widely used in the field of petroleum engineering – the ‘tangent’ method and the ‘compliance’ method. In three of the four tests, the tangent method significantly underestimates the closure stress. The compliance method is reasonably accurate in all four tests. Closure stress is also interpreted using two other commonly-used methods – ‘first deviation from linearity’ and the method of (Hayashi and Haimson, 1991). In comparison with the SIMFIP data, these methods tend to overestimate the closure stress, evidently because they identify closure from early-time transient effects, such as near-wellbore tortuosity. In two of the tests, microseismic imaging provides an independent estimate of the size of the fracture created by injection. When combined with a simple mass balance calculation, the SIMFIP stress measurements yield predictions of fracture size that are reasonably consistent with the estimates from microseismic. The calculations imply an apparent fracture toughness 2-3x higher than typical laboratory-derived values.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohens d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohens d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single-cell RNA sequencing, we uncovered both direct and indirect paths by which resident SG progenitors ordinarily differentiate into sebocytes, including transit through a Krt5+PPARγ+ transitional basal cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair-follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR2 signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.

Introduction: Mesenchymal stem cells (MSCs) are increasingly used for intra-articular injections in the treatment of knee osteoarthritis. The aim of this study was to use scanning electron microscopy (SEM) to compare the morphological characteristics of synovial and adipose MSCs. Methods: Synovium and adipose tissues were concurrently harvested from eight patients with knee osteoarthritis. Suspensions of both synovial and adipose MSCs were examined to identify the presence of microspikes. In addition to this study, the MSC suspensions in four patients were applied to abraded porcine cartilage discs and observed 10 s, 10 min, and 1 h later. Results: The median percentage of cells exhibiting microspikes was 14% for synovial MSC suspensions and 13% for adipose MSC suspensions; this difference was not statistically significant (n = 8). No notable differences were detected in the number of adherent cells or in the proportion of cells displaying microspikes or pseudopodia. Strong correlations were found between the proportion of cells with pseudopodia and the number of attached cells for both synovial (r = 0.92, n = 12) and adipose (r = 0.86, n = 12) MSCs, with no significant difference in the correlation coefficients between the two groups. Conclusion: SEM analysis revealed no obvious differences in morphological characteristics during MSC adhesion to cartilage for either synovial or adipose MSCs.

AbstractHypoxia may promote tumor progression, and hypoxically altered noncoding RNA (ncRNA) expression may play a role in metastasis. Canine oral melanoma (COM) frequently metastasizes, and ncRNA expression under hypoxia may be clinically significant. We aimed to elucidate ncRNA fragments whose expression is altered by hypoxia in COM-derived primary KMeC and metastatic LMeC cell lines using next-generation sequencing to validate these results in qRT-PCR, and then compare expression between metastatic and non-metastatic COM. The NGS analysis and subsequent qRT-PCR validation were performed using hypoxic and normoxic KMeC and LMeC cells, and clinical samples [tumor tissue, plasma, and plasma-derived extracellular vesicles] obtained from dogs with metastatic or non-metastatic melanoma were analyzed with qRT-PCR. Y RNA was significantly decreased in metastatic LMeC cells versus primary KMeC cells in hypoxic and normoxic conditions. The expression of Y RNA was decreased in dogs with metastatic melanoma versus those with non-metastatic melanoma for all clinical sample types, reflecting the pattern found with hypoxia. Receiver operating characteristic analysis demonstrated that Y RNA level is a promising biomarker for discriminating metastatic from non-metastatic melanoma in plasma [area under the curve (AUC) = 0.993, p