Formations of force network and softening of amorphous elastic materials from a coarsen-grained particle model.

Amorphous materials, such as granular substances, glasses, emulsions, foams, and cells, play significant roles in various aspects of daily life, serving as building materials, plastics, food products, and agricultural items. Understanding the mechanical response of these materials to external forces is crucial for comprehending their deformation, toughness, and stiffness. Despite the recognition of the formation of force networks within amorphous materials, the mechanisms behind their formation and their impact on macroscopic physical properties remain elusive. In this study, we employ a coarse-grained particle model to investigate the mechanical response, wherein local physical properties are integrated into the softness of the particles. Our findings reveal the emergence of a chain-like force distribution, which correlates with the planar distribution of softness and heterogeneous density variations. Additionally, we observe that the amorphous material undergoes softening due to the heterogeneous distribution of softness, a phenomenon explicable through a simple theoretical framework. Moreover, we demonstrate that the ambiguity regarding the size ratio of the blob to the force network can be adjusted by the amplitude of planar fluctuations in softness, underscoring the robustness of the coarse-grained particle model.

A Rare Case of a Common Inferior Pulmonary Vein Presumed to Be a Remnant of the Common Pulmonary Vein.

A 74-year-old woman with an implanted physiological DDD pacemaker visited our department complaining of palpitations due to atrial fibrillation (AF). Catheter ablation therapy for AF was scheduled. Preoperative multidetector computed tomography showed that the inferior pulmonary vein (PV) was a common trunk, and the left and right superior PVs branched from the center of the left atrial roof. In addition, mapping of the left atrium before AF ablation revealed no potential in either the inferior PV or common trunk. We performed left and right superior PV and posterior wall isolation. After ablation, AF was not observed on pacemaker recordings.

Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis.

BACKGROUND: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. METHODS: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. RESULTS: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. CONCLUSIONS: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

Typical cutaneous small-vessel vasculitis induced by combined injection of antiphosphatidylserine/prothrombin complex antibody and anti-LAMP-2 antibody in normal rats.

We previously reported that IgA vasculitis and cutaneous arteritis could be dependently associated with the presence of the antiphosphatidylserine/prothrombin complex (anti-PS/PT) antibody and lysosomal-associated membrane protein-2 (LAMP-2). The copy number of LAMP-2 mRNA in skin tissue samples from rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after subcutaneous histone injection was significantly higher than in those without cutaneous vasculitis. We found LAMP-2 protein overexpression in neutrophils and vascular endothelial cells of the affected blood vessels in rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after cutaneous priming by histones. We found typical cutaneous small-vessel vasculitis in the skin of rats given intravenous injection of both anti-PS/PT antibody and anti-LAMP-2 antibody after cutaneous priming by histones. We suggested that the introduction of skin local histones and anti-PS/PT antibody in serum could move LAMP-2 to the cell surface of neutrophils and vascular endothelial cells, and that anti-LAMP-2 antibody could bridge these cells through antigen-specific binding in typical cutaneous small-vessel vasculitis.

A Real-Time Four-Dimensional Reconstruction Algorithm of Cine-Magnetic Resonance Imaging (Cine-MRI) Using Deep Learning.

Purpose The purpose of this study is to propose algorithms and methods for achieving high accuracy in tracking and interception irradiation technology for tumors that move by respiration using MR-linac (MRIdian®, ViewRay Inc.) and to use deep learning to predict the movement of moving tumors in real time during radiation therapy and reconstruct cine magnetic resonance imaging (cine-MRI) into four-dimensional (4D) movies. Methods In this study, we propose a reconstruction algorithm using 4DCT for treatment planning taken before irradiation as training data in consideration of the actual treatment flow. In the algorithm, two neural networks made before treatment are used to reconstruct 4D movies that predict tumor movement in real time during treatment. Cycle GAN (generative adversarial network) was used to convert MR images to CT images, and long short-term memory was used to convert cine-MRI to 4D movies and predict tumor movement. Results We succeeded in predicting the time including the imaging time of the MR images, the lag until irradiation, and the calculation time in the algorithm. In addition, the conversion and prediction results at each phase of reconstruction were generally good so that they could be clinically applied. Conclusions The reconstruction algorithm proposed in this study enables high-precision radiotherapy while predicting the volume information of the tumor and the actual tumor position, which could not be obtained during radiotherapy.

Possible implication of intermolecular epitope spreading in the production of anti-glomerular basement membrane antibody in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is sometimes complicated by anti-glomerular basement membrane (GBM) disease. Proteases, including elastase, released from neutrophils activated by ANCA are implicated in the pathogenesis of AAV. Epitopes of anti-GBM antibody exist in the α3-subunit non-collagenous (NC1) domain of collagen type IV [Col (IV)]. This region, called α3(IV)NC1, is structurally cryptic. This study aimed to determine the production mechanism of anti-GBM antibody in AAV. METHODS: We first examined whether α3(IV)NC1 could be revealed by the digestion of formalin-fixed, paraffin-embedded (FFPE) normal kidney sections and Col (IV) by proteases, including neutrophil elastase, using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Next, the reveal of α3(IV)NC1 and the infiltration of CD11c+ macrophages in the affected kidneys were evaluated by IHC and immunofluorescent staining using FFPE sections. Finally, the production of anti-GBM antibody in AAV rats was determined by ELISA. RESULTS: α3(IV)NC1 was revealed by the digestion of FFPE normal kidney sections and Col (IV) by proteases. Although the reveal of α3(IV)NC1 was observed in sclerotic glomeruli regardless of causative diseases, CD11c+ macrophages near α3(IV)NC1 were characteristics of AAV. Anti-GBM antibody was produced subsequent to ANCA in some AAV rats. IHC demonstrated the reveal of α3(IV)NC1 in affected renal tissues and the infiltration of CD11c+ macrophages around the sites. CONCLUSIONS: The collective findings suggest that, in AAV, proteases released from neutrophils activated by ANCA digest Col (IV) and result in the reveal of α3(IV)NC1, CD11c+ macrophages present GBM epitopes, and then the host's immune system produce anti-GBM antibody.

Origin of nonlinear force distributions in a composite system.

Composite materials have been actively developed in recent years because they are highly functional such as lightweight, high yield strength, and superior load response. In spite of importance of the composite materials, mechanisms of the mechanical responses of composites have been unrevealed. Here, in order to understand the mechanical responses of composites, we investigated the origin and nature of the force distribution in heterogeneous materials using a soft particle model. We arranged particles with different softness in a lamellar structure and then we applied homogeneous pressure to the top surface of the system. It is found that the density in each region differently changes and then the density difference induces a nonlinear force distribution. In addition, it is found that the attractive interaction suppresses the density difference and then the force distribution is close to the theoretical prediction. Those findings may lead material designs for functional composite materials.

Usefulness of the 2-year iodine-123 metaiodobenzylguanidine-based risk model for post-discharge risk stratification of patients with acute decompensated heart failure.

PURPOSE: A four-parameter risk model that included cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging and readily available clinical parameters was recently developed for prediction of 2-year cardiac mortality risk in patients with chronic heart failure. We sought to validate the ability of this risk model to predict post-discharge clinical outcomes in patients with acute decompensated heart failure (ADHF) and to compare its prognostic value with that of the Acute Decompensated Heart Failure National Registry (ADHERE) and Get With The Guidelines-Heart Failure (GWTG-HF) risk scores. METHODS: We studied 407 consecutive patients who were admitted for ADHF and survived to discharge, with definitive 2-year outcomes (death or survival). Cardiac MIBG imaging was performed just before discharge. The 2-year cardiac mortality risk was calculated using four parameters, namely age, left ventricular ejection fraction, New York Heart Association functional class, and cardiac MIBG heart-to-mediastinum ratio on delayed images. Patients were stratified into three groups based on the 2-year cardiac mortality risk: low- (< 4%), intermediate- (4-12%), and high-risk (> 12%) groups. The ADHERE and GWTG-HF risk scores were also calculated. RESULTS: There was a significant difference in the incidence of cardiac death among the three groups stratified using the 2-year cardiac mortality risk model (p < 0.0001). The 2-year cardiac mortality risk model had a higher C-statistic (0.732) for the prediction of cardiac mortality than the ADHERE and GWTG-HF risk scores. CONCLUSION: The 2-year MIBG-based cardiac mortality risk model is useful for predicting post-discharge clinical outcomes in patients with ADHF. TRIAL REGISTRATION NUMBER: UMIN000015246, 25 September 2014.

Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis.

We assessed the IgG and IgM prevalence of anti-phosphatidylserine/prothrombin complex (aPS/PT) antibodies (Abs) in patients with vasculitis using a novel commercial ELISA kit. To examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones in advance. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and cutaneous arteritis compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no significant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. We suggested that IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis based on these findings.

RNase in the saliva can affect the detection of severe acute respiratory syndrome coronavirus 2 by real-time one-step polymerase chain reaction using saliva samples.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019, which spread worldwide immediately after the first patient infected with this virus was discovered in Wuhan, China, in December 2019. Currently, polymerase chain reaction (PCR) specimens for the detection of SARS-CoV-2 include saliva, nasopharyngeal swabs, and lower respiratory tract-derived materials such as sputum. Initially, nasopharyngeal swab specimens were applied mainly to the PCR detection of SARS-CoV-2. There was a risk of infection to healthcare workers due to coughing or sneezing by the subjects at the time of sample collection. In contrast, saliva specimens have a low risk of droplet infection and are easy to collect, and their application to PCR testing has been promoted. In this study, we have determined the detection limit of SARS-CoV-2 in saliva samples and examined the effects of storage temperature and storage time of saliva samples on the PCR detection results. As a result, 5 × 103 copies of SARS-CoV-2 could be detected in 1 mL phosphate-buffered saline, whereas 5 × 104 copies of SARS-CoV-2 were needed in 1 mL saliva to detect the virus by real-time one-step PCR. Interestingly, SARS-CoV-2 (5 × 103 copies/mL) could be detected in saliva supplemented with an RNase inhibitor. Concerning the saliva samples supplemented with an RNase inhibitor, the optimal temperature for sample storage was -20 °C, and PCR detection was maintained within 48 h without problems under these conditions. These finding suggest that RNase in the saliva can affect the detection of SARS-CoV-2 by PCR using saliva samples.

Quantitative Understanding of the Decision-Making Process for Farm Biosecurity Among Japanese Livestock Farmers Using the KAP-Capacity Framework.

In a globalized world, the frequency of transboundary livestock infectious diseases is increasing, and strengthening of farm biosecurity is vital to stabilize food production. The aim of this study was to understand the decision-making process for farm biosecurity among Japanese livestock farmers. Postal surveys using structured questionnaires were conducted on beef, dairy, pig, and layer farms in Hokkaido and Saitama Prefectures, which represent the principal production area and peri-urban Tokyo, respectively, as well as randomly selected broiler farms across Japan. The question items included the attributes of farms and owners, disease experiences, related associations and sources of hygiene information, attitude toward hygiene management, and compliance with the Standards of Rearing Hygiene Management (SRHM). The compliance rates were compared between livestock sectors. Univariable analyses were conducted using combined data from both prefectures, with the compliance rate as the outcome variable and the questionnaire items as explanatory variables, in generalized linear models. Exploratory factor analyses were conducted using the variables with p < 0.2 in the univariable analyses. The factors identified were classified into knowledge, attitude, capacity, practice, and structural equation modeling (SEM) was performed. The questionnaires were completed and returned by 97 and 66 beef cattle, 86 and 136 dairy, 67 and 45 pig, 20 and 39 layer farmers in Hokkaido and Saitama Prefectures, respectively, and 95 broiler farms. The compliance rate was significantly higher among broiler farms (88.9%) compared with the other sectors, followed by pig (77.1%), layer (67.2%), dairy (63.8%), and beef (59.1%) farms in Hokkaido Prefecture, and layer (64.9%), pig (60.0%), dairy (58.5%), and beef (57.6%) farms in Saitama Prefecture. Based on SEM, the decision-making process from greater knowledge to higher attitude, and from higher attitude to greater compliance with the SRHM were significant (p < 0.01) in all sectors. Higher capacity was significantly associated with higher knowledge in dairy, pig,break and layer farms (p < 0.01), and with higher compliance in beef, pig, and layer farms (p < 0.05). These results suggest that the provision of targeted hygiene knowledge to livestock farmers and the support to smallholder farms would improve biosecurity through elevated attitudes and self-efficacy.

Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction.

AIMS: Acute decompensated heart failure (ADHF) is generally treated by decongestion using diuretic therapy. However, the use of loop diuretics is associated with increased cardiac sympathetic nerve activity (CSNA). We aimed to evaluate the effect of adjunctive tolvaptan therapy on CSNA in ADHF patients with preserved left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We enrolled 51 consecutive ADHF patients with LVEF ≥45%. Patients were randomly assigned to receive either tolvaptan add-on (n = 25) or conventional diuretic therapy (n = 26). Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed after stabilisation of heart failure symptoms, and the cardiac MIBG heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated. There were no significant differences in the body weight change and total urine volume during 2 days after randomisation or in the HMR on delayed image (HMR(d)) and WR between the tolvaptan and conventional groups. After stratification based on the median change in body weight, the patients with higher weight reduction had a significantly lower HMR(d) (P = 0.0128) and tended to have a higher WR (P = 0.0786) in the conventional group, whereas the cardiac MIBG imaging results were not influenced by body weight reduction in the tolvaptan group. CONCLUSIONS: Adjunctive tolvaptan therapy may provide rapid decongestion without a harmful effect on CSNA in ADHF patients with preserved LVEF.

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.

OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.

Improvement in interlayer structure of p-i-n-type organic solar cells with the use of fullerene-linked tetrabenzoporphyrin as additive.

The additive effect on small-molecule-based p-i-n-type devices has been little investigated so far. We focus on the improvement of the miscibility of tetrabenzoporphyrin (BP) and [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) blend film by addition of fullerene-linked tetrabenzoporphyrin (BP-C60) as an additive to the interlayer (i-layer). BP is one of the most promising p-type organic semiconductors, and BP films can be prepared readily by heating as-cast films of the precursor (a bicyclo[2.2.2]octadiene-fused porphyrin; CP), that results in changes from amorphous CP films to polycrystalline BP films. Because of the high crystallinity of BP, large BP grains on the scale of tens to hundreds of nanometers are generated in blend films of BP and PC61BM during film fabrication. We found that the addition of BP-C60 as an additive (3, 5, 7, and 10 wt%) to the i-layer composed of BP and PC61BM improves the miscibility of BP and PC61BM. The power conversion efficiency of p-i-n-type organic solar cells consisting of a blend film of BP and PC61BM (i-layer) sandwiched by BP (p-layer) and PC61BM (n-layer) improved by up to 50% as compared to that of a control device after the addition of BP-C60 to the i-layer. The film morphology was investigated using atomic force microscopy, fluorescence microspectroscopy, two-dimensional grazing-incident wide-angle X-ray diffraction measurements, and scanning electron microscopy. Interacting with both BP and PC61BM, the addition of BP-C60 led to changes in the grain size as well as an increase in the size of the BP/PC61BM interface and hence effective charge separation in the p-i-n device. This morphological improvement is attributable to the ability of BP-C60, which exhibits the characteristics of both BP and C60, to promote the compatibility of BP and PC61BM. This study is a significant step towards the development of high-performance p-i-n-type solar cells and should pave the way for the fabrication of high-performance bulk-heterojunction layers in solution-processed organic photovoltaic devices.

Probing Charge Carrier Dynamics in Porphyrin-Based Organic Semiconductor Thin Films by Time-Resolved THz Spectroscopy.

To improve the power conversion efficiency of solar cells, it is important to understand the underlying relaxation mechanisms of photogenerated charge carriers in organic semiconductors. In this work, we studied the charge carrier dynamics of diketopyrrolopyrrole-linked tetrabenzoporphyrin thin films where the diketopyrrolopyrrole unit has two n-butyl groups, abbreviated as C4-DPP-BP. We used time-resolved terahertz (THz) spectroscopy to track charge carrier dynamics with excitations at 800 and 400 nm. Compared with tetrabenzoporphyrin (BP), the extension of π-electron delocalization to the diketopyrrolopyrrole peripherals leads to an increase in absorption in the near-infrared region. Following the excitation at 800 nm, we found that the transient THz signals in C4-DPP-BP thin films decay with time constants of 0.5 and 9.1 ps, with small residual components. With excitation at 400 nm, we found that the transient THz signals decay with time constants of 0.4 and 7.5 ps. On the basis of the similarity of the decay profiles of the transient THz signals obtained with excitations at 400 and 800 nm, we considered that the decaying components are due to charge carrier recombination and/or trapping at defect sites, which do not depend on the excess energy of the photoexcitation. In contrast to BP, even without an electron acceptor, we observed the finite offset of the transient THz signals at 100 ps, demonstrating the existence of long-lived charge carriers. We also measured the photoconductivity spectra of C4-DPP-BP thin films with the excitation at both 800 and 400 nm. It was found that the spectra can be fitted by the Drude-Smith model. From these results, it was determined that the charge carriers are localized right after photoexcitation. At 0.4 ps, the product of the quantum yield of charge generation and mobility of charge carriers at 400 nm is approximately twice that obtained at 800 nm. We discuss the implications of the excess excitation energy in organic semiconductor-based devices.

Conversion of 3,3,3-Trisubstituted Prop-1-ynes with tert-Butylhydrazine into 3,3,3-Trisubstituted Propionitriles Catalyzed by TpRh(C2H4)2/P(2-furyl)3.

The combination of TpRh(C2H4)2 (Tp = tris(pyrazol-1-yl)borate) and P(2-furyl)3 catalyzes the reaction of tertiary alkyl-substituted alkynes with tert-butylhydrazine, leading to the formation of 3,3,3-trisubstituted propionitrile derivatives. This reaction system is applicable to 1,1-disubstituted propargyl alcohols and amines to afford the corresponding ß-cyanohydrins and ß-amino nitriles, respectively. The catalytic cycle involves the formation of a vinylidenerhodium complex as a key intermediate.

Direct comparison of a covalently-linked dyad and a 1:1 mixture of tetrabenzoporphyrin and fullerene as organic photovoltaic materials.

A p-i-n organic photovoltaic cell with tetrabenzoporphyrin (BP), a BP-C60 dyad and PCBM for the p-, i- and n-layers, respectively, gave a better fill factor and power conversion efficiency than the corresponding p-i-n cell having a 1:1 blend film of BP and PCBM as the i-layer.