Search

The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants associated with the adaptive evolution of the virus is prolonging the global coronavirus disease 2019 (COVID-19) pandemic. The modification of neutralizing antibodies based on structural information is expected to be a useful approach to rapidly combat emerging variants. A dimerized variable domain of heavy chain of heavy chain antibody (VHH) P17 that has highly potent neutralizing activity against SARS-CoV-2 has been reported but the mode of interaction with the epitope remains unclear. Here, we report the X-ray crystal structure of the complex of monomerized P17 bound to the SARS-CoV-2 receptor binding domain (RBD) and investigated the binding activity of P17 toward various variants of concern (VOCs) using kinetics measurements. The structure revealed details of the binding interface and showed that P17 had an appropriate linker length to have an avidity effect and recognize a wide range of RBD orientations. Furthermore, we identified mutations in known VOCs that decrease the binding affinity of P17 and proposed methods for the acquisition of affinity toward the Omicron RBD because Omicron is currently the most predominant VOC. This study provides information for the rational design of effective VHHs for emerging VOCs.

We are in the midst of the historic coronavirus infectious disease 2019 (COVID-19) pandemic caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Although countless efforts to control the pandemic have been attempted—most successfully, vaccination1–3—imbalances in accessibility to vaccines, medicines, and diagnostics among countries, regions, and populations have been problematic. Camelid variable regions of heavy chain-only antibodies (VHHs or nanobodies)4 have unique modalities: they are smaller, more stable, easier to customize, and, importantly, less expensive to produce than conventional antibodies5, 6. We present the sequences of nine alpaca nanobodies that detect the spike proteins of four SARS-CoV-2 variants of concern (VOCs)—namely, the alpha, beta, gamma, and delta variants. We show that they can quantify or detect spike variants via ELISA and lateral flow, kinetic, flow cytometric, microscopy, and Western blotting assays7. The panel of nanobodies broadly neutralized viral infection by pseudotyped SARS-CoV-2 VOCs. Structural analyses showed that a P86 clone targeted epitopes that were conserved yet unclassified on the receptor-binding domain (RBD) and located inside the N-terminal domain (NTD). Human antibodies have hardly accessed both regions; consequently, the clone buries hidden crevasses of SARS-CoV-2 spike proteins undetected by conventional antibodies and maintains activity against spike proteins carrying escape mutations.

BackgroundAnastomotic leakage after intestinal resection is one of the most serious complications of surgical intervention for hollow viscus injury. Adequate vascular perfusion of the anastomotic site is essential to prevent anastomotic leakage. Near-infrared imaging using indocyanine green (NIR-ICG) is useful for the objective assessment of vascular perfusion. The aim of this study was to evaluate the association of NIR-ICG with intestinal and mesenteric injuries.MethodsThis was a retrospective, single-center study of patients undergoing surgery for intestinal and mesenteric injuries due to abdominal trauma from December 2006 to March 2021. NIR-ICG was used to evaluate vascular perfusion. Postoperative complications were assessed between NIR-ICG and non-NIR-ICG groups. ResultsThe use of NIR-ICG was associated with a lower incidence of Clavien-Dindo grade ≥ III complications with a statistical tendency (p = 0.076). No Clavien-Dindo grade ≥ II intestinal complications were observed in the NIR-ICG group. When limited to patients that underwent intestinal resection, the use of NIR-ICG was significantly associated with a lower risk of perioperative complications (p = 0.009).ConclusionsThe use of NIR-ICG tended to associate with the lower incidence of postoperative complications after intestinal and mesenteric trauma surgery. NIR-ICG was associated with a significantly lower risk of complications in patients undergoing intestinal resection. The NIR-ICG procedure is simple and quick and is expected to be useful for intestinal and mesenteric trauma.

Silicon carbide (SiC) is a next-generation semiconductor material. However, SiC is difficult to machine because it has high mechanical hardness and chemical inertness. Therefore, high-quality processing technology with high efficiency is now required. In our previous study, the authors developed UV-assisted grinding method and clarified that the critical depth of cut is expanded by UV irradiation and that the surface roughness is reduced by applying this method with a composite-abrasive wheel containing diamond abrasive grains with a mean abrasive diameter of 6 μm. On the other hand, it is important to reduce the damaged layer left by lapping or polishing process after grinding. In this study, we developed UV-assisted constant-pressure grinding method as a new alterative processing method to lapping and polishing. In this method, UV-assisted grinding is applied to the constant-pressure grinding method. To obtain a higher-quality mirror surface, we used a superabrasive wheel containing diamond abrasive grains with a mean abrasive diameter of 0.5 μm. By investigating the influence of UV irradiation on processing characteristics, we clarified that the surface roughness and removal height were reduced by UV irradiation. Finally, a high quality surface with few grinding marks was obtained by UV-assisted constant-pressure grinding.

Introduction The use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) in trauma patients has been controversial, but VV-ECMO plays a crucial role when the lungs are extensively damaged and when conventional management has failed. VV-ECMO provides adequate tissue oxygenation and an opportunity for lung recovery. However, VV-ECMO remains contraindicated in patients with a risk of bleeding because of systemic anticoagulation during the treatment. The most important point is controlling the bleeding from severe trauma. Case A 32-year-old male experienced blunt trauma due to a traffic accident. He presented with bilateral hemopneumothorax and bilateral flail chest. We performed emergency thoracotomy for active bleeding and established circulatory stability. After surgery, the oxygenation deteriorated under mechanical ventilation, so we decided to establish VV-ECMO. However, bleeding from the bilateral lung contusions increased after VV-ECMO was established, and the patient was switched to heparin-free ECMO. After conversion, we could control the bronchial bleeding, especially the lung hematomas, and the oxygenation recovered. The patient was discharged without significant complications. VV-ECMO and mechanical ventilation were stopped on days 10 and 11, respectively. He was discharged from the ICU on day 15. Conclusion When we consider the use of ECMO for patients with uncontrollable, severe bleeding caused by blunt trauma, it may be necessary to use a higher flow setting for heparin-free ECMO than typically used for patients without trauma to prevent thrombosis.

In the present study it was attempted to improve the performance of ultrasonic-assisted grinding using polycrystalline diamond (PCD) micropin tools processed by electrical discharge machining. The micropins acted as grinding tools because the convex parts of discharge craters can serve as cutting edges of abrasive grains in grinding wheels. The drilling conditions to prevent chippings and cracks on the hole edge were experimentally determined and then employed for the drilling of microholes less than 10 μm in diameter. As a result, microholes as small as 5.5 μm in diameter were successfully drilled in hard and brittle materials such as crown glass and monocrystalline silicon. The high wear resistance of PCD improved the tool life, making it possible to mill trenches and to mass-produce holes using a small number of tools. Moreover, the tool life was further improved by processing the tool peripheral surface at a low electrical discharge energy.

Ultra–Agile Advanced Manufacturing System (U–AMS) has been proposed for an agile prototyping system of research and development, and Super Processing Center (SPC) has been developing as a core machine tool of U–AMS. SPC has high accuracy and rigidity by double column structure based on a vertical precision machining center, hydrostatic oil guides and hydro static/dynamic hybrid oil bearing. In addition, SPC can perform various processing functions by mounting various processing units. Micro grooving by grinding has been researching for one of the SPC unit. PCD blade was developed for micro grooving using SPC. PCD blade was made from PCD disc using wire electrical discharge machining. This paper describes the fabrication method of PCD blade, and the machining characteristics of cemented carbide using PCD blade. In the fabrication method of PCD blade, it was clarified that the cross-sectional shape of PCD blade depended on the feed speed of wire electrode. Micro grooving on cemented carbide surface was performed using developed PCD blade and SPC. As a result, it was confirmed that the micro grooves can be machined using PCD blade, and the width of groove was almost same value as the width of PCD blade. The wear of PCD blade after grooving with 200 grooves was estimated by the depth of grooves. As a result, it was clarified that the wear of PCD blade is approximately 5 μm.

Background Although some predictors of COVID-19 pneumonia severity and mortality have been identified, much of the pathophysiology of this emerging infectious disease remains unclear. We hypothesized that a patient’s cholinesterase level on admission could predict COVID-19 pneumonia severity and mortality. Methods We retrospectively collected data of 26 COVID-19 pneumonia patients from February–May 2020. Outcomes were aggravation of symptoms and in-hospital mortality. We compared receiver operating curves of cholinesterase, C-reactive protein, lymphocytes, albumin, D-dimer, and PaO2/FiO2 ratio and examined prediction accuracy. Regarding the interaction between cholinesterase and other variables, each independent variable was divided into two groups using cutoff values, and interaction terms were created. Results Cholinesterase levels on admission were significantly lower in the severe group than in the mild-to-moderate group (326 vs. 218 IU/L, p = 0.006; area under the curve: 0.81; 95% confidence interval 0.61–0.94). When comparing the area under the curve, cholinesterase was comparable to C-reactive protein, albumin, lymphocytes, and PaO2/FiO2 ratio other than D-dimer in the prediction accuracy of severe cases and mortality. Cholinesterase levels on admission were significantly lower in the death group than in the survival group (274 vs. 187.5 IU/L, p = 0.028; area under the curve: 0.79; 95% interval 0.58–0.93). Regarding the interaction between cholinesterase and established predictors, the prediction accuracy of both severity and death was higher when cholinesterase was combined with each predictor than when cholinesterase was used alone. Conclusions Cholinesterase may reflect the disease state of COVID-19 pneumonia, suggesting that a patient’s cholinesterase level on admission may be useful as a predictor of severity and prognosis.

Background Veno‐venous extracorporeal membrane oxygenation (VV‐ECMO) is one of the ultimate treatments for acute respiratory failure. However, the effectiveness of ECMO in patients with novel coronavirus disease (COVID‐19) is unknown. Case Presentation A 72‐year‐old woman who was a passenger of a cruise ship tested positive for the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) while in quarantine on board using throat swab. Three days after admission, her condition deteriorated, and she was subsequently intubated. On day 6, VV‐ECMO was introduced. Lopinavir/ritonavir was given; continuous renal replacement therapy was also introduced. On day 10, her chest radiography and lung compliance improved. She was weaned off ECMO on day 12. Conclusion Treatment of severe pneumonia in COVID‐19 by ECMO should recognize lung plasticity considering time to ECMO introduction and interstitial biomarkers. In Japan, centralization of ECMO patients has not been sufficient. Thus, we suggest nationwide centralization and further research to respond to the crisis caused by COVID‐19., ECMO is one of the treatment options in severe ARDS by SARS‐CoV‐2. It is important to recognize lung plasticity. Centralization of COVID‐19 ECMO patients may be effective in Japan.

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

Few studies have been reported on the drilling of microholes with a diameter of approximately 10 μm or less by electrochemical machining (ECM). The ECM of such holes was therefore attempted using ultrashort voltage pulses. Stainless-steel sheets were drilled using cemented tungsten carbide tool electrodes. As a result, a microhole of 4.5 μm entrance diameter and 4 μm exit diameter was successfully drilled in a 5-μm-thick sheet with a pulse width of 60 ns using a tool electrode 3 μm in diameter. This is the smallest-diameter hole drilled by ECM, to the best of our knowledge. A microhole of 5.5 μm entrance diameter and 4.5 μm exit diameter was also drilled in an 8-μm-thick sheet. Furthermore, the machining properties were investigated. The effect of the tool electrode shape, pulse width, pulse frequency, high-level and low-level voltages, and electrolyte concentration on the drilling speed and hole diameter was examined. The results suggested that a semicylindrical tool electrode, long pulse width, high pulse frequency, high low-level voltage, and high electrolyte concentration were preferable for high-speed drilling without widening the lateral gap between the tool electrode and hole.

Initial fluid resuscitation is presumed to be important for treating shock in the resuscitation phase. However, little is known how quickly and easily a physician could perform a rapid infusion with a syringe.We hypothesised that using a high-flow three-way stopcock (HTS) makes initial fluid resuscitation faster and easier than using a normal-flow three-way stopcock (NTS).This was a simulation study with a prospective, nonblinded randomised crossover design. Twenty physicians were randomly assigned into two groups. Each participant used six peripheral intravenous infusion circuits, three with the HTS and the others with the NTS, and three cannulae, 22, 20, and 18 gauge (G). The first group started with the HTS first, while the other started with the NTS first. They were asked to inject the fluid as quick as possible. We compared the time until the participants finished rapid infusions of 500 ml of 0.9% saline and the practitioner's effort.In infusion circuits attached with the 22G cannula, the mean difference using the HTS and the NTS (95% confidence interval [CI]) was 16.30 ml/min (7.65-24.94) (p 0.01). In those attached with the 20G cannula, the mean difference (95% CI) was 23.47 (12.43-34.51) (p 0.01). In those attached with the 18G cannula, the mean difference (95% CI) was 42.53 (28.68-56.38) (p 0.01).This study revealed that the push-and-pull technique using the HTS was faster, easier, and less tiresome than using the NTS, with a statistically significant difference. In the resuscitation phase, initial and faster infusion is important. If only a single physician or other staff member such as a nurse is attending or does not have accessibility to any other devices in such an environment where medical resources are scarce, performing the push-and-pull technique using the HTS could help a physician to perform fluid resuscitation faster. By setting up the HTS instead of the NTS from the beginning, we would be able to begin fluid resuscitation immediately while preparing other devices.

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) for patients with traumatic torso hemorrhagic shock is available to keep a minimum level of circulatory status as a bridge to definitive therapy. However, the trajectory for placement of REBOA in the aorta has not yet been clearly defined. Methods We conducted a retrospective observational cohort study in the two tertiary critical care and emergency center from December 2014 to October 2018. A total of 28 patients who underwent focused assessment with sonography for trauma (FAST) were studied via contrast computed tomography (CT), and 27 were analyzed. Results We divided patients into two groups based on our CT findings. The REBOA deflate group included 16 patients, and the inflate group included 11 patients. The median trace value (interquartile range) of the blood vessel center line from the common femoral artery to the tip of REBOA (blood vessel length) and the length of REBOA itself from the common femoral artery to the tip of REBOA (REBOA insertion length) were 56.2 cm (54.5–57.2) and 55.2 cm (54.2–55.6), respectively (p

Recently, diamonds have been utilized gradually for sliding parts and wear-resistant parts because of their excellent properties. The shape of diamond applied to these parts is not only plane but also arc-shaped inner surface. Therefore, development of diamond polishing technology is required. In this study, ultraviolet assisted polishing was thought to develop to polish polycrystalline diamond (PCD) on arc-shaped inner surface. The authors investigated effect of ultraviolet radiation on polishing efficiency and surface roughness. As a result, the surface roughness Ra of PCD showed less than 15 nanometers. In addition, polishing efficiency was improved about 30 percent due to ultraviolet assisted polishing.

Polycrystalline diamond (PCD) has excellent properties such as high hardness, high chemical inertness, high wear resistance and a low friction coefficient. Thus, it has been expected to be applied to used in various mechanical parts such as sliding parts. However, diamond is difficult to machine owing to its high hardness and chemical inertness. Therefore, a highly efficient and high-quality machining process is required for PCD. In this study, the authors developed fixed abrasive polishing tools for the mirror-like surface finishing of PCD that contain mechanochemical abrasive grains with diamond grains. As a result of fixed abrasive polishing experiments, it was clarified that a mirror-like surface can be obtained by fixed abrasive polishing using a tool containing SiO2 and diamond abrasives. Moreover, it was found that the removal efficiency can be increased under a high-temperature condition.

There have been few reports on the drilling of microholes on rod end faces by cutting, which can be employed for fabricating micronozzles or microneedles. Such drilling was therefore attempted in the present study using a micro turn-milling machine with the tool and workpiece axes being parallel. The drilling was performed on the end faces of brass rods with cemented tungsten carbide micro-cutting tools processed by electrical discharge machining (EDM). As a result, a microhole 12‍ μm in diameter was successfully drilled using a 10-μm-diameter tool at a feed speed of 0.5‍ μm/s. The feed speed could be increased to 25 μm/s for a tool with a diameter of 20 μm and body length of 50 μm.

A turn-milling machine, which is a device having two spindles that rotate a tool and workpiece, can be used to fabricate various shapes by cutting. However, little progress has been made in microcutting using a turn-milling machine. Therefore, a micro turn-milling machine designed especially for microtools was developed and used to fabricate micropins with various cross sections. Cemented tungsten carbide microtools, which are useful both as a milling cutter and as a turning tool, were processed by electrical discharge machining and employed for microcutting. As a result, various micropins were successfully fabricated, including not only cylindrical pins but also those with cross sections having square, triangle, and cross shapes. These noncylindrical micropins have the smallest reported cross-section dimensions for pins fabricated by cutting to the best of our knowledge. Furthermore, cutting characteristics such as the machined shape and surface quality were investigated, which showed that better micropin shapes were obtained by up-cut turn-milling than by down-cut turn-milling or by turning. In contrast, turning was superior to turn-milling in terms of the surface quality.

The drilling of microholes in hard and brittle materials by ultrasonic grinding was carried out using polycrystalline diamond (PCD) micropins fabricated by electrical discharge machining. They can be employed as micro-grinding tools because the convex parts of discharge craters formed on the tool surface can serve as cutting edges of abrasive grains in grinding wheels. In the drilling of crown glass, the increase in the grinding force and the generation of cracks and chippings at hole edges were suppressed owing to the high wear resistance of PCD. Under suitable conditions, drilling was also successfully performed in silicon, which is apt to exhibit cracks and chippings at hole edges.

Whirling electrical discharge texturing (WEDT) was developed to process microstructures on the inner surface of cylindrical parts made of high hardness materials. However, the minimum processable diameter of the cylindrical parts was φ 5 mm and the equipment could not feed the new tool electrodes. Therefore, the authors devised a novel method of WEDT using a straight wire tool electrode for a cylindrical surfaces with a small diameter. It was confirmed that microstructures could be created on the inner surface of a cylinder of φ 1.1 mm diameter, and that the texture-area ratio could be controlled by the workpiece feed speed. Moreover, new EDT equipment with a feeding system for a wire tool electrode and a bending system for the tip of a wire tool electrode was developed. As a result, the equipment that can process microstructures on the inner surface of a cylinder with a small diameter and feed a wire tool electrode during texturing was successfully developed.

Whirling Electrical Discharge Texturing (WEDT) was developed as a method of creating microstructures by a single-pulse discharge on the inner surface of a cylinder. In a previous study, a textured surface was successfully created on the inner surface of a cylinder, and it was clarified that the surface characteristics of the textured surface such as the texture-area ratio can be controlled by adjusting the texturing conditions. In this study, a new WEDT device was developed to create microstructures on the surface of a disc workpiece for the ball-on-disc or the pin-on-disc friction test. This paper describes texturing characteristics such as the texture-area ratio, crater depth and crater diameter on a disc workpiece surface and friction characteristics measured by the pin-on-disc friction test. From the results of texturing experiments, it was confirmed that the texture-area ratio can be controlled by adjusting the feed speed of the workpiece, and the diameter and depth of a crater do not depend on the feed speed. In the pin-on-disc friction test, the tip of a pin has a spherical shape with large spherical radius to prevent partial contact. As a result, the friction coefficients under the boundary lubrication condition and the mixed lubrication condition near the boundary lubrication condition were decreased by WEDT. It was confirmed that the textured surface created by WEDT is effective for reducing friction coefficient and an optimal texture-area ratio exists depending on the lubrication conditions.

Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.

Rapid Rotation Mirror-like surface Grinding (RRMG), in which combine Rapid Rotation Grinding (RRG) and Truncate Truing with Micro Dressing (TTMD) are combined, is a suitable method for mirror-like surface finishing with high efficiency. The surface roughness of a workpiece decreased with increasing work speed of RRMG, contradicting the conventional grinding principle on grinding geometry and kinematics. Furthermore, it was analyzed that a heat-affected layer and subsurface microstructure of the workpiece having a surface roughness Ra of less than 0.05 μm were obtained by RRMG. As a result, it was clarified that the thickness of the heat-affected layer was decreased and the subsurface microstructure was nanocrystallized, because the grinding temperature was suppressed with increasing peripheral work speed of RRMG.

A microstructured surface was created on a steel surface by whirling electrical discharge texturing (WEDT) since it was considered that the microstructures could act as lubricant reservoirs to assist the formation of a lubricating film, resulting in reduced friction. In this study, friction tests under engine oil were carried out over a range of loads and sliding speeds. In addition, the surface characteristics of the microstructured surface were also investigated to optimize the friction characteristics of the textured surface through pin-on-disc friction tests. It was found that under the mixed lubrication condition near the boundary condition, textured surfaces with texture-area ratio of approximately 6% and a mean crater diameter of 35 μm were considered as the optimal conditions for reducing the friction coefficient. However, a texture-area ratio of approximately 4% and a mean crater diameter of 35 μm were considered as the optimal conditions for reducing the friction coefficient under the mixed lubrication condition near the elastohydrodynamic lubrication condition. It was considered that when the normal load decreased, the lubrication region changed from the mixed lubrication condition to the hydrodynamic lubrication condition, which meant that the actual contact surface area decreased. The decrease in the actual contact surface area with decreasing texture-area ratio led to a reduction in the friction coefficient. Finally, it was clarified that the friction coefficient was reduced under the optimized conditions of the microstructured surface through a pin-on-disc friction test.

The boring of microholes has been carried out using micro-turning tools. There is a limitation, however, on machinable shapes using the tools employed therein, with the fabrication of shapes with an overhang being impossible. The fabrication of such shapes was therefore attempted in the present study using cemented tungsten carbide micro-boring tools processed by electrical discharge machining. Inner-grooving by turning was attempted in 0.15-mm-diameter holes, resulting in shapes with an overhang, such as a reverse-tapered hole. Furthermore, inner-grooving using tools moving in planetary motion was also attempted in 0.2-mm-diameter holes drilled in workpieces that were difficult to deal with by turning.

Discharge duration and pulse frequency are studied to determine the optimum conditions for creating a single crater. In addition, the relationships between pulse frequency and surface characteristics using Whirling Electrical Discharge Texturing (WEDT) are determined. It is confirmed that the texture-area ratio and the total removal volume of craters, but not crater diameter or crater depth, can be controlled by adjusting pulse frequency. Moreover, after honing, surface characteristics decrease owing to the removal of protrusions. With honing, the surface roughness of the textured surface leads to a reduced friction coefficient as expected.