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Aims: The escalating demand for medical resources to address spinal diseases as society ages is an issue that requires careful evaluation. However, few studies have examined trends in spinal surgery, especially unscheduled hospitalizations or surgeries performed after hours, through large databases. Our study aimed to determine national trends in the number of spine surgeries in Japan. We also aimed to identify trends in after-hours surgeries and unscheduled hospitalizations and their impact on complications and costs. Methods: We retrospectively investigated data extracted from the Diagnosis Procedure Combination database, a representative inpatient database in Japan. The data from April 2010 to March 2020 were used for this study. We included all patients who had undergone any combination of laminectomy, laminoplasty, discectomy, and/or spinal arthrodesis. Results: This investigation included 739,474 spinal surgeries and 739,215 hospitalizations in Japan. There was an average annual increase of 4.6% in the number of spinal surgeries. Scheduled hospitalizations increased by 3.7% per year while unscheduled hospitalizations increased by 11.8% per year. In-hours surgeries increased by 4.5% per year while after-hours surgeries increased by 9.9% per year. Complication rates and costs increased for both after-hours surgery and unscheduled hospitalizations, in comparison to their respective counterparts of in-hours surgery and scheduled hospitalizations. Conclusion: This study provides important insights for those interested in improving spine care in an ageing society. The swift surge in after-hours spinal surgeries and unscheduled hospitalizations highlights that the medical needs of an increasing number of patients due to an ageing society are outpacing the capacity of existing medical resources. Cite this article: Bone Jt Open 2024;5(8):662–670.

Abstract Biochar application can alleviate the adverse effects of saline-alkali stress on crops. However, the long-term effects of one-off biochar application on soil physicochemical properties, salt concentration, nutrient availability, soil enzyme activities, and rice yield under highly saline-alkali paddy soils remain unclear. Here, a 6-year paddy field study was conducted in a saline-alkali paddy field using two nitrogen application levels (0 and 225 kg ha−1) and four biochar application rates [0 (T0), 1.5% (T1.5), 3.0% (T3.0), and 4.5% (T4.5) biochar, w/w]. The results showed that compared with T0, the bulk density (BD) under T1.5, T3.0, and T4.5 treatments significantly decreased by 11.21%, 16.33%, and 25.57%, while total porosity (Tp) and saturated hydraulic conductivity (Ks) increased by 19.15–27.34% and 3217.78–5539.83%, respectively. Biochar consistently improved soil macro-aggregates, mean weight diameter (MWD), and the percentage of water-stable aggregates (PWSA) over the years. Additionally, one-off application of biochar continuously reduced the soil Na+ concentration, Na+/K+ ratio, Na+/Ca2+ ratio, saturated paste extract (ECe), exchangeable sodium percentage (ESP), and sodium adsorption ratio (SARe). However, it reduced the pH in 2021 and 2022 only. It enhanced the concentration of K+, Ca2+, Mg2+, and cation exchange capacity (CEC) over the 6-year study, indicating its longer-term positive impact. Furthermore, the one-off biochar application, especially under high application rate treatments (T3.0 and T4.5), significantly and continuously improved nutrient availability and soil enzyme activities. However, alkali-hydrolysable nitrogen (AN) decreased in the initial year of biochar application. The grain yield of T1.5, T3.0, and T4.5 surpassed that of T0 by 116.38%, 141.24%, and 145.20%, respectively. Notably, the rice yield reached its peak with the treatment of 3.0% (w/w) in all 6 years of study period. These findings offered new perspectives on repairing and improving soil quality and production ability of highly saline-alkali paddy soils. Graphical Abstract

Herat has a long and rich history of architecture and culture that has been shaped by many different historical and imperial periods. Since 2002, the city’s urban landscape has changed significantly due to a rapid rise in the city’s population and modern building processes. This has had a significant impact on the historical image and identity of Herat, as modern architecture has introduced identities that are not in harmony with the city’s environment, climate, and culture. This study conducts a comprehensive analysis of architectural identity characteristics to explore the role of traditional and modern architectural elements in forming Herat’s architectural identity. This research is based on primary and secondary sources including literature reviews, historical documents, case studies, and interviews with local architects and residents. The results indicate that Herat’s architectural identity is shaped by a multitude of factors, including its historical and cultural importance, the utilization of construction materials, the surrounding environmental conditions, architectural guidelines and expertise, political dynamics, and the preferences of both the architect and client. This study provides vital insights for architects, policy makers, and government agencies seeking to promote sustainable and culturally sensitive development in Herat’s dynamic architectural landscapes.

As a novel anode material for Na-ion battery, we evaluated rutile-type TiNbO4 synthesized by a sol−gel method. It was revealed for the first time that TiNbO4 showed reversible reactions of Na+-insertion and Na+-extraction in the potential ranges of 0.005–1.0 and 0.6–1.6 V vs. Na+/Na, respectively. TiNbO4 maintained its rutile structure even after charge−discharge cycling. The size of Na+ diffusion path along its c-axis was broadened with increasing Nb amount in TiNbO4, leading to the improvement in the reversible capacity. The TiNbO4 electrode with Nb 48 at.% exhibited a high capacity of 360 mA h g−1. The long-term cyclability and rate capability were also improved by increasing Nb amount. We consider that the wider space in the diffusion path increases the degree of freedom of Na+ occupancy position, which weakens the electrostatic repulsion between Na+ and Na+ to increase Na storage capacity. These results clearly demonstrate that TiNbO4 can be applied as a promising anode material.

Introduction: Chemonucleolysis with condoliase (chondroitin sulfate ABC endolyase) has been used to treat patients with lumbar disc herniation (LDH) in Japan since 2018. In this study, we retrospectively investigated clinical outcomes in patients who received an intradiscal condoliase injection for LDH and sought to identify significant predictors of good outcome. Methods: Indications for treatment were as follows: (1) unilateral leg pain with or without back pain, (2) nerve root compression caused by LDH confirmed on magnetic resonance imaging (MRI), and (3) leg pain resistant to at least 1 month of conservative treatment, including medication, nerve root block, or physical therapy. Patients with motor weakness or a history of severe allergy were excluded, as were those with the foraminal or sequestrated type of LDH. The injection was defined as effective if the numeric rating scale score for leg pain improved by 50% at 6 months post-treatment. Results: A total of 52 patients (mean age, 45.0 years) were enrolled and classified according to whether the injection was effective (E group, n=40, 76.9%) or less effective (L group, n=9, 17.3%). Three patients (5.8%) underwent herniotomy for residual pain within 6 months of the injection. There were no severe adverse events. Reduction of herniation was seen on MRI more often in the E group than in the L group. The effectiveness in patients with transligamentous LDH was similar to that in patients with subligamentous LDH. High-intensity signal change in the area of LDH on pretreatment T2-weighted MRI was a significant predictor of successful leg pain relief. Conclusions: An intradiscal condoliase injection was a safe and effective treatment for painful radiculopathy caused by LDH. Leg pain was more likely to improve in patients with high-intensity signal change in the area of LDH before treatment.

The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.

Abstract Intracellular antibodies are valuable tools for target validation studies for clinical situations such as cancer. Recently we have shown that antibodies can be used for drug discovery in screening for chemical compounds surrogates by showing that compounds could be developed to the so-called undruggable RAS protein family. This method, called Antibody-derived compound (Abd) technology, employed intracellular antibodies binding to RAS in a competitive surface plasmon resonance chemical library screen. Success with this method requires a high affinity interaction between the antibody and the target. We now show that reduction in the affinity (dematuration) of the anti-active RAS antibody facilitates the screening of a chemical library using an in vitro AlphaScreen method. This identified active RAS specific-binding Abd compounds that inhibit the RAS-antibody interaction. One compound is shown to be a pan-RAS binder to KRAS, HRAS and NRAS-GTP proteins with a Kd of average 37 mM, offering the possibility of a new chemical series that interacts with RAS in the switch region where the intracellular antibody binds. This simple approach shows the druggability of RAS and is generally applicable to antibody-derived chemical library screening by affording flexibility through simple antibody affinity variation. This approach can be applied to find Abd compounds as surrogates of antibody-combining sites for novel drug development in a range of human diseases.

The dopamine D2 receptor (D2R) is a GPCR and an important drug target for schizophrenia treatment. Here, the authors present the crystal structure of human D2R in complex with the antipsychotic drug spiperone, which is of interest for designing antipsychotics with improved receptor selectivity.

Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.

Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme.

A 61‐year‐old woman with hypereosinophilia and elevated interleukin (IL)‐5 level was admitted to our hospital after detection of multiple liver tumors. Liver biopsy demonstrated that the tumor consisted of scar tissue with remnants of eosinophilic infiltration, suggesting that it had formed by massive eosinophilic infiltration. The hypereosinophilia was treated mainly by prednisolone, and thereafter, the liver tumors disappeared. However, 10 months postadmission, CD4+ T‐cell lymphoma, which can produce IL‐5, was detected in the nasopharynx and oropharynx. Therefore, we believe that this is a rare case of hypereosinophilia‐related liver pseudotumor induced by presumed by IL‐5 elevation.

Abstract Although allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a curative therapy for high‐risk acute leukemia (AL), some patients still relapse. Since patients simultaneously have many prognostic factors, difficulties are associated with the construction of a patient‐based prediction algorithm of relapse. The alternating decision tree (ADTree) is a successful classification method that combines decision trees with the predictive accuracy of boosting. It is a component of machine learning (ML) and has the capacity to simultaneously analyze multiple factors. Using ADTree, we attempted to construct a prediction model of leukemia relapse within 1 year of transplantation. With the model of training data (n = 148), prediction accuracy, the AUC of ROC, and the κ‐statistic value were 78.4%, 0.746, and 0.508, respectively. The false positive rate (FPR) of the relapse prediction was as low as 0.134. In an evaluation of the model with validation data (n = 69), prediction accuracy, AUC, and FPR of the relapse prediction were similar at 71.0%, 0.667, and 0.216, respectively. These results suggest that the model is generalized and highly accurate. Furthermore, the output of ADTree may visualize the branch point of treatment. For example, the selection of donor types resulted in different relapse predictions. Therefore, clinicians may change treatment options by referring to the model, thereby improving outcomes. The present results indicate that ML, such as ADTree, will contribute to the decision‐making process in the diversified allo‐HSCT field and be useful for preventing the relapse of leukemia.

Channelrhodopsins (ChRs) are microbial light-gated ion channels utilized in optogenetics to control neural activity with light . Light absorption causes retinal chromophore isomerization and subsequent protein conformational changes visualized as optically distinguished intermediates, coupled with channel opening and closing. However, the detailed molecular events underlying channel gating remain unknown. We performed time-resolved serial femtosecond crystallographic analyses of ChR by using an X-ray free electron laser, which revealed conformational changes following photoactivation. The isomerized retinal adopts a twisted conformation and shifts toward the putative internal proton donor residues, consequently inducing an outward shift of TM3, as well as a local deformation in TM7. These early conformational changes in the pore-forming helices should be the triggers that lead to opening of the ion conducting pore.

Satellite cell proliferation is an essential step in proper skeletal muscle development and muscle regeneration. However, the mechanisms regulating satellite cell proliferation are relatively unknown compared to the knowledge associated with the differentiation of satellite cells. Moreover, it is still unclear whether overload muscle fiber hypertrophy is dependent on satellite cell proliferation. In general, cell proliferation is regulated by the activity of cell cycle regulators, such as cyclins and cyclin-dependent kinases (CDKs). Despite recent reports on the function of CDKs and CDK inhibitors in satellite cells, the physiological role of Cdk1 in satellite cell proliferation remains unknown. Herein, we demonstrate that Cdk1 regulates satellite cell proliferation, muscle regeneration, and muscle fiber hypertrophy. Cdk1 is highly expressed in myoblasts and is downregulated upon myoblast differentiation. Inhibition of CDK1 activity inhibits myoblast proliferation. Deletion of Cdk1 in satellite cells leads to inhibition of muscle recovery after muscle injury due to reduced satellite cell proliferation in vivo. Finally, we provide direct evidence that Cdk1 expression in satellite cells is essential for overload muscle fiber hypertrophy in vivo. Collectively, our results demonstrate that Cdk1 is essential for myoblast proliferation, muscle regeneration, and muscle fiber hypertrophy. These findings could help to develop treatments for refractory muscle injuries and muscle atrophy, such as sarcopenia.

Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The data reveal a twist of the D-ring, which leads to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signaling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the observed collective changes are important for the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.

Background. Heart failure is the leading cause of death in dialysis patients. Cardiac arrest due to hypotension may also occur during dialysis therapy. If cardiac arrest is elicited, manual chest compressions (MCCs) should be started as soon as possible. However, all types of dialysis chairs are not stable for MCC, because there is no steady support between the backboard of the dialysis chair and the floor. These conditions may alter the effectiveness of MCC. Methods. We investigated whether a round chair is effective in supporting the dialysis chair for MCC. Four adult males performed MCC on a mannequin placed on three dialysis chairs. MCC was performed in sets of 2 (each set was 100 times per minute) per person, with and without a round chair. A total of 4,800 compressions were performed by four executors. Results. When the chair was not used as a stabilizer, the mean values of the fluctuation range were 20.8 ± 8.1 mm, 18.7 ± 5.5 mm, and 12.8 ± 1.8 mm, respectively. When the chair was used, the mean values of the fluctuation range were 6.1 ± 1.1 mm, 7.5 ± 2.1 mm, and 1.0 ± 0 mm, decreasing by 70%, 59%, and 92%. Conclusion. MCC performed with the stool under the backrest as a stabilizer was effective in supporting the dialysis chair.

Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.

Various studies have found a high incidence of early graft dislodgement after multilevel corpectomy. Although a hybrid fusion technique was developed to resolve implant failure, the hybrid and conventional techniques have not been clearly compared in terms of perioperative complications in patients with severe ossification of the posterior longitudinal ligament (OPLL) involving three or more levels. The purpose of this study was to compare clinical and radiologic outcomes between anterior cervical corpectomy with fusion (ACCF) and anterior hybrid fusion for the treatment of multilevel cervical OPLL. We therefore retrospectively reviewed the clinical and radiologic data of 53 consecutive patients who underwent anterior fusion to treat cervical OPLL: 30 underwent ACCF and 23 underwent anterior hybrid fusion. All patients completed 2 years of follow-ups. Implant migration was defined as subsidence > 3 mm. There were no significant differences in demographics or clinical characteristics between the ACCF and hybrid groups. Early implant failure occurred significantly more frequently in the ACCF group (5 cases, 16.7%) compared with the hybrid group (0 cases, 0%). The fusion rate was 80% in the ACCF group and 100% in the hybrid group. Although both procedures can achieve satisfactory neurologic outcomes for multilevel OPLL patients, hybrid fusion likely provides better biomechanical stability than the conventional ACCF technique.

Serial femtosecond crystallography (SFX) using X-ray free-electron lasers (XFELs) holds enormous potential for the structure determination of proteins for which it is difficult to produce large and high-quality crystals. SFX has been applied to various systems, but rarely to proteins that have previously unknown structures. Consequently, the majority of previously obtained SFX structures have been solved by the molecular replacement method. To facilitate protein structure determination by SFX, it is essential to establish phasing methods that work efficiently for SFX. Here, selenomethionine derivatization and mercury soaking have been investigated for SFX experiments using the high-energy XFEL at the SPring-8 Angstrom Compact Free-Electron Laser (SACLA), Hyogo, Japan. Three successful cases are reported of single-wavelength anomalous diffraction (SAD) phasing using X-rays of less than 1 Å wavelength with reasonable numbers of diffraction patterns (13 000, 60 000 and 11 000). It is demonstrated that the combination of high-energy X-rays from an XFEL and commonly used heavy-atom incorporation techniques will enable routine de novo structural determination of biomacromolecules.

Phytochromes (PHYs) are photoreceptor proteins first discovered in plants, where they control a variety of photomorphogenesis events. PHYs as photochromic proteins can reversibly switch between two distinct states: a red light (Pr) and a far-red light (Pfr) absorbing form. The discovery of Bacteriophytochromes (BphPs) in nonphotosynthetic bacteria has opened new frontiers in our understanding of the mechanisms by which these natural photoswitches can control single cell development, although the role of BphPs in vivo remains largely unknown. BphPs are dimeric proteins that consist of a photosensory core module (PCM) and an enzymatic domain, often a histidine kinase. The PCM is composed of three domains (PAS, GAF, and PHY). It holds a covalently bound open-chain tetrapyrrole (biliverdin, BV) chromophore. Upon absorption of light, the double bond between BV rings C and D isomerizes and reversibly switches the protein between Pr and Pfr states. We report crystal structures of the wild-type and mutant (His275Thr) forms of the canonical BphP from the nonphotosynthetic myxobacterium Stigmatella aurantiaca (SaBphP2) in the Pr state. Structures were determined at 1.65 Å and 2.2 Å (respectively), the highest resolution of any PCM construct to date. We also report the room temperature wild-type structure of the same protein determined at 2.1 Å at the SPring-8 Angstrom Compact free electron LAser (SACLA), Japan. Our results not only highlight and confirm important amino acids near the chromophore that play a role in Pr-Pfr photoconversion but also describe the signal transduction into the PHY domain which moves across tens of angstroms after the light stimulus.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19902-7

Power transmission systems using gears require both large capacity and miniaturization. As a result, the gears used in power transmission need to be strong enough to withstand high loads and high engine speeds. Because surface damage and temperature are related, it is very important to know the surface temperature of gears in operation. However, measuring the surface temperature of gears in operation is difficult. As an effective means to measure the surface temperature, method of using dissimilar metals is known. The voltage proportional to surface temperature was produced by contacting dissimilar metals. This is known as Seebeck effect. The authors tried to use two simple ferrous metals. In this study, S55C (Carbon steel) and SUS316 (Stainless steel) were selected to dissimilar metals. Both dissimilar metals were heat-treated and surfaces were hardened. SUS316 was performed plasma carburizing process and S55C was performed induction hardening. As for the gear, it is known that the two or more teeth will mesh simultaneously. In order to remove the influence of the number of tooth in operation, the gear of two sheets were made into the one structure meshed by turns (combined lacked gear). When making the gear of two sheets into one structure meshed by turns. The experiments were operated on maximum condition of contact pressure 1.47GPa in a pitch point. As a result, surface temperature measured almost successfully by combined lacked gear by SUS316 plasma carburizing process and S55C induction hardening. When we compared the experimental values and the theoretical values using Blok's formula, surface temperatures on gear teeth values were largely same.

Keap1 protein acts as a cellular sensor for oxidative stresses and regulates the transcription level of antioxidant genes through the ubiquitination of a corresponding transcription factor, Nrf2. A small molecule capable of binding to the Nrf2 interaction site of Keap1 could be a useful medicine. Here, we report two crystal structures, referred to as the soaking and the cocrystallization forms, of the Kelch domain of Keap1 with a small molecule, Ligand1. In these two forms, the Ligand1 molecule occupied the binding site of Keap1 so as to mimic the ETGE motif of Nrf2, although the mode of binding differed in the two forms. Because the Ligand1 molecule mediated the crystal packing in both the forms, the influence of crystal packing on the ligand binding was examined using a molecular dynamics (MD) simulation in aqueous conditions. In the MD structures from the soaking form, the ligand remained bound to Keap1 for over 20 ns, whereas the ligand tended to dissociate in the cocrystallization form. The MD structures could be classified into a few clusters that were related to but distinct from the crystal structures, indicating that the binding modes observed in crystals might be atypical of those in solution. However, the dominant ligand recognition residues in the crystal structures were commonly used in the MD structures to anchor the ligand. Therefore, the present structural information together with the MD simulation will be a useful basis for pharmaceutical drug development.

Serial crystallography has emerged as an important tool for structural studies of integral membrane proteins. The ability to collect data from micrometre-sized weakly diffracting crystals at room temperature with minimal radiation damage has opened many new opportunities in time-resolved studies and drug discovery. However, the production of integral membrane protein microcrystals in lipidic cubic phase at the desired crystal density and quantity is challenging. This paper introduces VIALS (versatile approach to high-density microcrystals in lipidic cubic phase for serial crystallography), a simple, fast and efficient method for preparing hundreds of microlitres of high-density microcrystals suitable for serial X-ray diffraction experiments at both synchrotron and free-electron laser sources. The method is also of great benefit for rational structure-based drug design as it facilitates in situ crystal soaking and rapid determination of many cocrystal structures. Using the VIALS approach, room-temperature structures are reported of (i) the archaerhodopsin-3 protein in its dark-adapted state and 110 ns photocycle intermediate, determined to 2.2 and 1.7 Å, respectively, and (ii) the human A2A adenosine receptor in complex with two different ligands determined to a resolution of 3.5 Å. [ABSTRACT FROM AUTHOR]