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General anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of γ-aminobutyric acid A (GABAA) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic-binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl−permeability of GABAAreceptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABAAreceptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABAAreceptors. The results showed large structural fluctuations in GABAAreceptors, correlations of motion between the amino-acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABAAreceptors.

Three-dimensional structures of protein-ligand complexes provide valuable insights into their interactions and are crucial for molecular biological studies and drug design. However, their high-dimensional and multimodal nature hinders end-to-end modeling, and earlier approaches depend inherently on existing protein structures. To overcome these limitations and expand the range of complexes that can be accurately modeled, it is necessary to develop efficient end-to-end methods. We introduce an equivariant diffusion-based generative model that learns the joint distribution of ligand and protein conformations conditioned on the molecular graph of a ligand and the sequence representation of a protein extracted from a pre-trained protein language model. Benchmark results show that this protein structure-free model is capable of generating diverse structures of protein-ligand complexes, including those with correct binding poses. Further analyses indicate that the proposed end-to-end approach is particularly effective when the ligand-bound protein structure is not available. The present results demonstrate the effectiveness and generative capability of our end-to-end complex structure modeling framework with diffusion-based generative models. We suppose that this framework will lead to better modeling of protein-ligand complexes, and we expect further improvements and wide applications.

Considering the importance of elucidating the heat transfer in living cells, we evaluated the thermal conductivity κ and conductance G of hydrated protein through all-atom non-equilibrium molecular dynamics simulation. Extending the computational scheme developed in earlier studies for spherical protein to cylindrical one under the periodic boundary condition, we enabled the theoretical analysis of anisotropic thermal conduction and also discussed the effects of protein size correction on the calculated results. While the present results for myoglobin and green fluorescent protein (GFP) by the spherical model were in fair agreement with previous computational and experimental results, we found that the evaluations for κ and G by the cylindrical model, in particular, those for the longitudinal direction of GFP, were enhanced substantially, but still keeping a consistency with experimental data. We also studied the influence by salt addition of physiological concentration, finding insignificant alteration of thermal conduction of protein in the present case.

The effects of buried-well potential perturbation under the buried-oxide (BOX) layer are studied in both a heavy-ion single event upset (SEU) test and a high-energy proton-SEU test of a silicon-on-insulator (SOI) dual interlocked storage cell (DICE)-based flip-flop. Their dependence on incident angle and back bias is discussed. We fabricated both DICE-based flip-flop and conventional flip-flop, which are designed as 80 000-stage shift-register chains. In a heavy-ion test, a considerable number of SEUs were observed at back bias exceeding 2.4 V, and a ten-times larger SEU-cross section was finally recorded at back bias of 3.0 V compared with the total active area of a DICE-based flip-flop cell. This marks the first case where DICE topology was found to be broken by buried-well potential perturbation on an SOI DICE-based flip-flop. In a proton test, one error was observed at back bias of 2.0 V. The SEU rate in the Van Allen belt at an altitude of 2300 km and an inclination of 90° was estimated as being once every 5 years.

Background and Aim Colonic diverticular bleeding is a common cause of acute lower gastrointestinal bleeding. Endoscopic hemostasis is generally selected as the first‐line treatment; however, a considerable number of patients experience early rebleeding after endoscopic treatment. We investigated the risk factors for early rebleeding after endoscopic treatment. Methods We retrospectively evaluated the data of 142 consecutive patients who underwent endoscopic treatment (endoscopic clipping or endoscopic band ligation) for colonic diverticular bleeding with stigmata of recent hemorrhage between April 2012 and April 2020. Multivariate logistic regression analysis was conducted to evaluate the statistical relationship between patient characteristics and the incidence of early rebleeding occurring within 30 days after endoscopic treatment. Results Of 142 patients, early rebleeding was detected in 34 (23.9%) patients. According to univariate analysis, platelet count of, Using endoscopic band ligation was associated with a decreased risk for early rebleeding compared with the use of endoscopic clipping, indicating that endoscopic band ligation was a preferable endoscopic modality to prevent early recurrent bleeding.

A 75-year-old man underwent emergent endovascular aortic repair for a ruptured abdominal aortic aneurysm. Two years later, computed tomography revealed aneurysm enlargement with endoleaks. Next, late open conversion was performed. Intraoperatively, we detected a spurting type II endoleak from an artery within the aneurysmal wall, which was unconnected to any branch vessels outside the aneurysm, and surgical ligation and sacotomy was performed uneventfully. To our knowledge, this is the first report to intraoperatively identify a type II endoleak from an artery within the aneurysm wall. Even for atypical type II endoleak, such as this case, open surgical repair should be effective.

For the research and development of accelerator-driven systems (ADSs) and fundamental ADS reactor physics research using the Kyoto University Critical Assembly combined with the fixed-field alternating gradient (FFAG) accelerator, we are conducting a series of experiments on double-differential neutron yields using the FFAG accelerator at Kyoto University. This paper presents an overview of the experiments together with preliminary results.

The addition (sticking) of a negative muon to an $\alpha$ particle to form a $\mu$He$^+$ ion limits the number of chain reactions in muon-catalyzed fusion (MuCF), making scientific break-even in MuCF difficult. The reduction in the sticking probability by boosting the negative muon stripping using resonance radio-frequency (RF) acceleration of $\mu$He$^+$ ions has been examined with multi-particle tracking simulations. It was found that the stripping efficiency was largely depressed by ion–electron capture processes that have not been considered so far. Improvement of the fusion chain cycles is rather difficult with an RF electric field strength of 50 MV m$^{-1}$ even at a small deuterium/tritium (D/T) gas pressure of approximately 5 atm. However, in the scheme of using spatially localized D/T mixture gas streams, the sticking probability could be reduced almost tenfold even at a large gas density of 100 atm with a modest RF field strength of less than 50 MV m$^{-1}$.

Background Selective biliary cannulation (SBC) is the first challenge of endoscopic retrograde cholangiopancreatography (ERCP), especially for trainees, and a rotatable sphincterotome may be useful to guide the directional axis of the scope and SBC. Methods We performed a prospective randomized single-center trial, enrolling 200 patients with a native papilla who required therapeutic biliary ERCP. Patients were randomly assigned to the rotatable sphincterotome group (n = 100) or the conventional sphincterotome group (n = 100). The primary endpoint was successful SBC by the trainees within 10 minutes. Results The early and late cannulation success rates did not differ significantly between the groups (P = 0.46 and P > 0.99, respectively). For the patients in whom trainees failed to achieve SBC, the rotatable sphincterotome was used as a rescue cannulation technique in four patients from the conventional group; in no patients in the rotatable group was the conventional sphincterotome used for SBC. Post-ERCP pancreatitis (PEP) occurred in 11 patients (5.5 %; 6 mild, 5 moderate); the incidence did not differ significantly between the two groups (rotatable group 3 %, conventional group 8 %; P = 0.21). The two groups were thus combined for evaluation of the factors relating to cannulation difficulty for trainees, which revealed that orientation of the papilla was a significant factor (P Conclusions The type of sphincterotome used did not affect the success of SBC by trainees. However, orientation of the papilla was revealed to be a significant factor relating to cannulation difficulty for trainees overall.

A 1-ampere-class high-intensity deuteron linac (ImPACT2017 model) is proposed for mitigating long-lived fission products (LLFPs) by nuclear transmutation. This accelerator consists of single-cell rf cavities with magnetic focusing elements to accelerate deuterons beyond 1 A up to 200 MeV/u.

Purpose Early detection of pancreatic ductal adenocarcinoma (PDAC) may improve the prognosis. We evaluated novel imaging findings that may contribute to early detection. Methods This single-center, retrospective study enrolled 37 patients with a localized main pancreatic duct (MPD) stricture and no obvious pancreatic mass. All patients underwent endoscopic retrograde cholangiopancreatography and brush sampling with cytology and serial pancreatic juice aspiration cytologic examination via endoscopic naso-pancreatic drainage. Patients with cytology-confirmed malignancy underwent surgical resection. The remaining patients were followed by contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and endoscopic retrograde cholangiopancreatography. Results Twenty patients had confirmed malignancy (cancer group) and 17 did not (non-cancer group). Age, MPD stricture location, and PDAC risk factors were similar, but the sex predominance and symptom rate differed between the two groups. In the cancer group, 17 patients were diagnosed by cytology and three by clinical symptoms. CECT, MRI, and endoscopic ultrasonography (EUS) revealed no solid tumors in either group. CECT revealed no significant differences between groups. Diffusion-weighted MRI revealed significant differences in the signal intensity between groups. EUS detected indistinct and small hypoechoic areas in 70% and 41.2% of patients in the cancer and non-cancer groups, respectively. In the cancer group, 11 were diagnosed with cancer at the first indication, and nine were diagnosed at follow-up; the prognosis did not differ between these two subgroups.ss Conclusions High signal intensity in diffusion-weighted MRI may be useful for detecting early-stage PDAC and may be an indication for surgical resection even without pathologic confirmation. Clinical trial registration The study was a registered at the University Hospital Medical Information Network (UMIN000039623). Graphic abstract

We performed metadynamics molecular dynamics simulations to reveal mechanism of antigen-dependent fluorescence response observed for site-specifically fluorescent-labeled single-chain antibody against c-Myc peptide antigen. We found that V H and V L bind with each other only when the antigen exists and that the fluorophore labeled at the N-terminus of V H interacts with Trp103 most stably. These results support the mechanism proposed from previous experiments: In the absence of antigen, Trp residues are partially exposed at the interface of V H and quench the fluorophore. In the presence of antigen, the Trp residues are buried between V H and V L , and the quenching is eliminated.

We report a case of successful endovascular repair of a dissected descending aortic aneurysm in a 70-year-old man. The patient had a history of thrombosed Stanford type A acute aortic dissection, with a dissected thoracoabdominal aorta that had increased in size to 53 mm. The celiac artery originated from the false lumen of the dissected aneurysm, and the intimal flap exhibited a reentry tear. The patient successfully underwent celiac artery coverage and false lumen embolization through the reentry tear, followed by thoracic endovascular aortic repair. Specific evaluation of the anatomical features of the aortic aneurysm enabled us to treat this patient endovascularly.

BACKGROUND AND AIM Cholecystitis is a major complication after self-expandable metallic stent (SEMS) placement for malignant biliary obstruction. Ischemia is one of the risk factors for cholecystitis, but little is known about the influence of tumor invasion to the feeding artery of the gallbladder on the onset of cholecystitis after SEMS placement. The aim of the present study was to identify risk factors for cholecystitis after SEMS placement. METHODS Incidence and nine predictive factors of cholecystitis were retrospectively evaluated in 107 patients who underwent SEMS placement for unresectable distal malignant biliary obstruction at Kyoto University Hospital and Otsu Red Cross Hospital between January 2012 and June 2016. RESULTS Cholecystitis occurred in 13 of 107 patients (12.1%) after SEMS placement during the median follow-up period of 262 days. Univariate analyses showed that tumor invasion to the feeding artery of the gallbladder and tumor involvement to the orifice of the cystic duct were significant predictors of cholecystitis (P = 0.001 and P < 0.001). Multivariate analysis confirmed that these two factors were significant and independent risks for cholecystitis with odds ratios of 22.13 (95% CI, 3.57-137.18; P = 0.001) and 25.26 (95% CI, 4.12-154.98; P < 0.001), respectively. CONCLUSIONS This study showed for the first time that tumor invasion to the feeding artery of the gallbladder as well as tumor involvement to the orifice of the cystic duct are independent risk factors for cholecystitis after SEMS placement.

Generalized-ensemble algorithms are powerful techniques for investigating biomolecules such as protein, DNA, lipid membrane, and glycan. The generalized-ensemble algorithms were originally developed in the canonical ensemble. On the other hand, not only temperature but also pressure is controlled in experiments. Additionally, pressure is used as perturbation to study relationship between function and structure of biomolecules. For this reason, it is important to perform efficient conformation sampling based on the isothermal-isobaric ensemble. In this article, we review a series of the generalized-ensemble algorithms in the isothermal-isobaric ensemble: multibaric-multithermal, pressure- and temperature-simulated tempering, replica-exchange, and replica-permutation methods. These methods achieve more efficient simulation than the conventional isothermal-isobaric simulation. Furthermore, the isothermal-isobaric generalized-ensemble simulation samples conformations of biomolecules from wider range of temperature and pressure. Thus, we can estimate physical quantities more accurately at any temperature and pressure values. The applications to the biomolecular system are also presented.

We designed a coil-dominated magnet wound with coated conductors for a spiral sector fixed-field alternating-gradient (FFAG) accelerator for carbon cancer therapy. The magnet consisted of deformed pancake coils with negative bends. Coils were arranged similar to a ladder to generate the required radial profile of magnetic field. The positions and the number of turns of the coils were iteratively adjusted to reduce the magnetic field error. We carried out numerical electromagnetic field analyses of the designed magnet to evaluate the influence of coated-conductor magnetization (screening or shielding current) on its field quality.

Transmutation using intense negative muon beams is useful to mitigate long-lived fission products from nuclear plants. To produce high intensity negative muon beams, the MERIT (multiplex energy recovery internal target) scheme was suggested. To prove the MERIT scheme, a proof-of-principle experiment was performed at KURNS (Institute of Radiation and Nuclear Science at Kyoto University). This paper presents the results of the experiment.

We report the progress of an R&D project of fundamental technologies for cryocooler-cooled accelerator magnets using coated conductors funded by the Japan Science and Technology Agency under its S-Innovation Program. Its target applications include carbon cancer therapy and accelerator-driven subcritical reactor. We have been carrying out design studies of HTS magnets for spiral sector fixed-field alternating gradient accelerators to show their feasibility for the target applications and to clarify the requirements of winding technologies. A three-dimensional winding machine has been developed to fabricate a model magnet in which winding technologies required for the designed magnet are implemented. With respect to the large magnetization of coated conductors, which is one of the big concerns on their uses in accelerator magnets, the magnetic field measurements using rotating pick-up coils have been made to clarify its influence on the multipole components of the magnetic field. A method for numerical electromagnetic field analyses of coils with three-dimensional shapes has been developed to predict the influence of magnetization on the field quality of magnets.

A new muon beam line, the muon science innovative channel, was set up at the Research Center for Nuclear Physics, Osaka University, in Osaka, Japan, using the 392 MeV proton beam impinging on a target. The production of an intense muon beam relies on the efficient capture of pions, which subsequently decay to muons, using a novel superconducting solenoid magnet system. After the pion-capture solenoid, the first 36° of the curved muon transport line was commissioned and the muon flux was measured. In order to detect muons, a target of either copper or magnesium was placed to stop muons at the end of the muon beam line. Two stations of plastic scintillators located upstream and downstream from the muon target were used to reconstruct the decay spectrum of muons. In a complementary method to detect negatively charged muons, the x-ray spectrum yielded by muonic atoms in the target was measured in a germanium detector. Measurements, at a proton beam current of 6 pA, yielded ( 10.4 ± 2.7 ) × 1 0 5 muons per watt of proton beam power ( μ + and μ − ), far in excess of other facilities. At full beam power (400 W), this implies a rate of muons of ( 4.2 ± 1.1 ) × 1 0 8 muons s − 1 , among the highest in the world. The number of μ − measured was about a factor of 10 lower, again by far the most efficient muon beam produced. The setup is a prototype for future experiments requiring a high-intensity muon beam, such as a muon collider or neutrino factory, or the search for rare muon decays which would be a signature for phenomena beyond the Standard Model of particle physics. Such a muon beam can also be used in other branches of physics, nuclear and condensed matter, as well as other areas of scientific research.