A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling.

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)-receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.

A 3-styrylchromone converted from trimebutine 3D pharmacophore possesses dual suppressive effects on RAGE and TLR4 signaling pathways.

Receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs) are potential therapeutic targets in the treatment of acute and chronic inflammatory diseases. We previously reported that trimebutine, a spasmolytic drug, suppresses RAGE pro-inflammatory signaling pathway in macrophages. The aim of this study was to convert trimebutine to a new small molecule using in silico 3D pharmacophore similarity search, and dissect the mechanistic anti-inflammatory basis. Of note, a unique 3-styrylchromone (3SC), 7-methoxy-3-trimethoxy-SC (7M3TMSC), converted from trimebutine 3D pharmacophore potently suppressed both high mobility group box 1-RAGE and lipopolysaccharide-TLR4 signaling pathways in macrophage-like RAW264.7 cells. More importantly, 7M3TMSC inhibited the phosphorylation of extracellular signaling-regulated kinase 1 and 2 (ERK1/2) and downregulated the production of cytokines, such as interleukin-6. Furthermore, 3D pharmacophore-activity relationship analyses revealed that the hydrogen bond acceptors of the trimethoxy groups in a 3-styryl moiety and the 7-methoxy-group in a chromone moiety in this compound are significant in the dual anti-inflammatory activity. Thus, 7M3TMSC may provide an important scaffold for the development of a new type of anti-inflammatory dual effective drugs targeting RAGE/TLR4-ERK1/2 signaling.

Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages.

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

Trimebutine attenuates high mobility group box 1-receptor for advanced glycation end-products inflammatory signaling pathways.

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.

Structural insights into the active site of poly(ADP-ribose) glycohydrolase using docking modes of 6-hydroxy-3H-xanthen-3-one derivative inhibitors.

Poly(ADP-ribose) glycohydrolase (PARG) plays an essential role in poly(ADP-ribose) (PAR) turnover, and thereby regulating DNA transactions, such as DNA repair, replication, transcription and recombination. Here, we examined the inhibitory activities of 6-hydroxy-3H-xanthene-3-one (HXO) derivatives and analyzed their binding modes in the active site of PARG by in silico docking study. Among the derivatives, Rose Bengal was found to be the most potent inhibitor of PARG and its halogen groups were revealed to cooperatively potentiate the inhibitory activity. Importantly, the binding mode of Rose Bengal occupied the active site of PARG revealed the presence of unique "Sandwich" residues of Asn869 and Tyr792, which enable the inhibitor to bind tightly with the active pocket. This sandwich interaction could stabilize the π-π interactions of HXO scaffold with Phe902 and Tyr795. In addition, to increase the binding affinity, the iodine and chlorine atoms of this inhibitor could contribute to the inducing of favorable disorders, which promote an entropy boost on the active site of PARG for structural plasticity, and making the stable configuration of HXO scaffold in the active site, respectively, as judged by the analysis of binding free energy. These results provide new insights into the active site of PARG and an additional opportunity for designing selective PARG inhibitors.

Structural Basis of Beneficial Design for Effective Nicotinamide Phosphoribosyltransferase Inhibitors.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole-piperidine (3a)- and azaindole-piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.

The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic ß-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.

Structural insight into the active site of mushroom tyrosinase using phenylbenzoic acid derivatives.

So far, many inhibitors of tyrosinase have been discovered for cosmetic and clinical agents. However, the molecular mechanisms underlying the inhibition in the active site of tyrosinase have not been well understood. To explore this problem, we examined here the inhibitory effects of 4'-hydroxylation and methoxylation of phenylbenzoic acid (PBA) isomers, which have a unique scaffold to inhibit mushroom tyrosinase. The inhibitory effect of 3-PBA, which has the most potent inhibitory activity among the isomers, was slightly decreased by 4'-hydroxylation and further decreased by 4'-methoxylation against mushroom tyrosinase. Surprisingly, 4'-hydroxylation but not methoxylation of 2-PBA appeared inhibitory activity. On the other hand, both 4'-hydroxylation and methoxylation of 4-PBA increased the inhibitory activity against mushroom tyrosinase. In silico docking analyses using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid or 4'-hydroxyl group of PBA derivatives could chelate with cupric ions in the active site of mushroom tyrosinase, and that the interactions of Asn260 and Phe264 in the active site with the adequate-angled biphenyl group are involved in the inhibitory activities of the modified PBAs, by parallel and T-shaped π-π interactions, respectively. Furthermore, Arg268 could fix the angle of the aromatic ring of Phe264, and Val248 is supposed to interact with the inhibitors as a hydrophobic manner. These results may enhance the structural insight into mushroom tyrosinase for the creation of novel tyrosinase inhibitors.

Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors.

Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, we searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50=6.97µM, monophenolase activity; IC50=36.3µM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, respectively. Analyses by in silico docking studies using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, we examined the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compound for the generation of novel tyrosinase inhibitors and provides a new insight into the molecular basis of tyrosinase catalytic mechanisms.

Structure-activity relationships of the thujaplicins for inhibition of human tyrosinase.

Tyrosinase inhibitors have become increasingly critical agents in cosmetic, agricultural, and medicinal products. Although a large number of tyrosinase inhibitors have been reported, almost all the inhibitors were unfortunately evaluated by using commercial available mushroom tyrosinase. Here, we examined the inhibitory effects of three isomers of thujaplicin (α, ß, and γ) on human tyrosinase and analyzed their binding modes using homology model and docking studies. As the results, γ-thujaplicin was found to strongly inhibit human tyrosinase with the IC50 of 1.15 µM, extremely superior to a well-known tyrosinase inhibitor kojic acid (IC50 = 571.17 µM). MM-GB/SA binding free energy decomposition analyses suggested that the potent inhibitory activity of γ-thujaplicin may be due to the interactions with His367, Ile368, and Val377 (hot spot amino acid residues) in human tyrosinase. Furthermore, the binding mode of α-thujaplicin indicated that Val377 and Ser380 may cause van der Waals clashes with the isopropyl group of α-thujaplicin. These results provide a novel structural insight into the hot spot of human tyrosinase for the specific binding of γ-thujaplicin and a way to optimize not only thujaplicins but also other lead compounds as specific inhibitors for human tyrosinase in a rational manner.

Validation of upper thermal thresholds for outdoor sports using thermal physiology modelling.

Thermal safety guidelines with upper thresholds aim to protect athletes' health, yet evidence-based sport-specific thresholds remain unestablished. Experimenting with athletes in severely hot conditions raises ethical concerns, so we used a thermo-physiological model to validate the thresholds of guidelines for outdoor sports. First, the reproducibility of the joint system thermoregulation model (JOS-3) of core temperature has been validated for 18 sports experiments (n = 213) and 11 general exercise experiments (n = 121) using the Bland - Altman analysis. Then, core temperatures were predicted using the JOS-3 in conditions corresponding to the upper thresholds, and if the 90th-99.7th percentile core temperature value (corresponding to 0.3%-10% of the participants) exceeded 40°C, the thresholds were judged as potentially hazardous. Finally, we proposed revisions for sports with potentially hazardous thresholds. As a result, the JOS-3 could simulate core temperature increases in most experiments (27/29) for six sports and general exercises with an accuracy of 0.5°C. The current upper thresholds for marathons, triathlons, and football are potentially hazardous. Suggested revisions, based on specified percentiles, include: Football: revise from wet bulb globe temperature (WBGT) 32°C to 29-31°C or not revise. Marathon: revise from WBGT 28°C to 24-27°C. Triathlon: revise from WBGT 32.2°C to 23-26°C. If conducting sports events under the revised upper thresholds proves difficult, taking measures for a possible high incidence of heat illness becomes crucial, such as placing additional medical resources, assisting heat acclimatization and cooling strategies for participants, and rule changes such as shorter match times and increased breaks.

Supplementation of Nicotinic Acid and Its Derivatives Up-Regulates Cellular NAD+ Level Rather than Nicotinamide Derivatives in Cultured Normal Human Epidermal Keratinocytes.

Nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in various physiological processes within mammalian cells, including energy metabolism, redox homeostasis, and genetic regulation. In the majority of mammalian cellular contexts, NAD+ biosynthesis primarily relies on vitamin B3, including nicotinamide (NAM) and nicotinic acid (NA). The concept of NAD+ augmentation therapy has recently emerged as a promising strategy to mitigate aging-associated phenomena, termed rejuvenation. Despite the involvement of diverse enzymatic cascades in NAD+ biosynthesis, certain cellular environments exhibit deficiencies in specific enzymes, suggesting cell type-dependent variability in optimal NAD+ precursor selection. However, the optimization of NAD+ precursors for topical formulations has received scant attention thus far. In the present investigation, we sought to delineate the most efficacious precursor for augmenting NAD+ levels in human skin keratinocytes. Remarkably, NA supplementation led to a significant 1.3-fold elevation in intracellular NAD+ levels, even in the presence of nicotinamide phosphoribosyltransferase inhibition by FK866. Additionally, NA mononucleotide demonstrated a 1.5-fold increase (but not significant) in NAD+ levels following 100 µM application. Conversely, NAM and its derivatives failed to elicit a NAD+ response in keratinocytes. Notably, NA supplementation elicited up-regulation of mitochondrial superoxide dismutase (SOD2) and sirtuin 3 (SIRT3), indicative of its beneficial impact on mitochondrial function. Furthermore, NA mitigated rotenone-induced mitochondrial reactive oxygen species (ROS) accumulation. Collectively, these findings advocate for the potential utility of NA in topical applications aimed at skin rejuvenation.

Real-World Prevalence and Tolerability of Immune-Related Adverse Events in Older Adults with Non-Small Cell Lung Cancer: A Multi-Institutional Retrospective Study.

With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective study aimed to examine irAE prevalence and tolerability in older adults. We included 436 patients with non-small lung cancer undergoing ICI therapy and dichotomized them into two age groups (< or ≥75 years). Incidence of any irAE grade, grade ≥3 irAEs, and steroid usage after irAE occurrence was similar between younger (n = 332) and older groups (n = 104). While the younger patients with irAEs showed prolonged overall survival in the 12-month landmark Kaplan-Meier analysis (Hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.38-0.89, p = 0.013), the older cohort did not (HR 0.80, 95% CI 0.36-1.78, p = 0.588). Although no differences were observed with ICI continuation or re-challenge after irAE onset, the elderly cohort had double the irAE cases that required a transition to best supportive care (BSC) (11.3% vs. 22.4%, p = 0.026). In conclusion, although irAE prevalence remains consistent regardless of age, the increased conversion to BSC post-irAE onset in older adults suggests diminished tolerability and the potential absence of favorable prognosis associated with irAEs in this population.

Protective Mechanism of Stem Cells from Human Exfoliated Deciduous Teeth in Treating Spinal Cord Injury.

Spinal cord injury (SCI) induces devastating permanent deficits. Recently, cell transplantation therapy has become a notable treatment for SCI. Although stem cells from human exfoliated deciduous teeth (SHED) are an attractive therapy, their precise mechanism of action remains to be elucidated. In this study, we explored one of the neuroprotective mechanisms of SHED treatment at the subacute stage after SCI. We used a rat clip compression SCI model. The animals were randomly divided into three groups: SCI, SCI + phosphate-buffered saline (PBS), and SCI + SHED. The SHED or PBS intramedullary injection was administered immediately after SCI. After SCI, we explored the effects of SHED on motor function, as assessed by the Basso-Beattie-Bresnahan score and the inclined plane method, the signal transduction pathway, especially the Janus kinase (JAK) and the signal transducer and activator of transcription 3 (STAT3) pathway, the apoptotic pathway, and the expression of neurocan, one of the chondroitin sulfate proteoglycans. SHED treatment significantly improved functional recovery from Day 14 relative to the controls. Western blot analysis showed that SHED significantly reduced the expression of glial fibrillary acidic protein (GFAP) and phosphorylated STAT3 (p-STAT3) at Tyr705 on Day 10 but not on Day 5. However, SHED had no effect on the expression levels of Iba-1 on Days 5 or 10. Immunohistochemistry revealed that p-STAT3 at Tyr705 was mainly expressed in GFAP-positive astrocytes on Day 10 after SCI, and its expression was reduced by administration of SHED. Moreover, SHED treatment significantly induced expression of cleaved caspase 3 in GFAP-positive astrocytes only in the epicenter lesions on Day 10 after SCI but not on Day 5. The expression of neurocan was also significantly reduced by SHED injection on Day 10 after SCI. Our results show that SHED plays an important role in reducing astrogliosis and glial scar formation between Days 5 and 10 after SCI, possibly via apoptosis of astrocytes, ultimately resulting in improvement in neurological functions thereafter. Our data revealed one of the neuroprotective mechanisms of SHED at the subacute stage after SCI, which improved functional recovery after SCI, a serious condition.

Pure rotational spectroscopy of the H2O-trans-HOCO complex.

Pure rotational spectra of the H2O-trans-HOCO complex have been observed by Fourier transform microwave (FTMW) spectroscopy and millimeter-wave FTMW double resonance spectroscopy. The complex was produced in a supersonic jet by discharging a mixture gas of CO and H2O diluted in Ar. The observed rotational lines consist of two groups of transitions with different hyperfine patterns. This is explained by considering the internal rotation of the H2O monomer in the complex. The molecular constants including the fine and hyperfine coupling constants have been determined for the two groups of lines. The hydrogen bond distance between H2O and the trans-HOCO monomer has also been determined with other structural parameters fixed to ab initio values. The hydrogen bond distance, 1.794 Å, is much shorter than that of the water dimer, and similar to those of water-acid complexes. The Fermi coupling constant of the proton of HOCO is compared with that of the trans-HOCO monomer, leading to the conclusion that there is an induced effect on the spin density on the proton of HOCO by the complex formation.

Radiographic Prediction of the Occipito-C2 Angle Variation with Changes in Distance between the Mandible and Cervical Vertebrae: A Preliminary Study.

The Occipito (O) -C2 angle reflects the correct craniocervical spine alignment; however, the poor image quality of standard intraoperative fluoroscopy at times lead to inaccurate measurements. Herein, we preliminarily investigated the relationship between the O-C2 angle and the Gonion-C2 distance, which is based on the positioning of the mandible and the cervical spine. We enrolled patients who underwent cervical spine radiography in neutral, flexion, and extension positions from January 2020 to October 2020. The difference by posture changes for each parameter was defined as the Δ value, and the Spearman's rank correlation coefficient was determined. Furthermore, we determined the cutoff value of the ΔGonion-C2 distance to predict a decrease of > 10° in the ΔO-C2 angle, which is reported to be related to dysphagia and dyspnea. Seventy-four patients were included. Spearman's rank correlations for the neutral, flexion, and extension positions were 0.630 (P < 0.001), 0.471 (P < 0.001), and 0.625 (P < 0.001), respectively, while the cutoff values of the ΔGonion-C2 distance for predicting > 10° in the ΔO-C2 angle were 9.3 mm for the neutral flexion change (sensitivity: 0.435, specificity: 0.882) and 8.3 mm for the extension-neutral change (sensitivity: 0.712, specificity: 0.909). The O-C2 angle and Gonion-C2 distances correlated; however, this correlation was weaker in the flexed position. Nevertheless, the ΔGonion-C2 distance can be used as a warning sign for postoperative complications after posterior occipital bone fusion surgery, because a decrease of > 10° in the ΔO-C2 angle can be predicted with high specificity.

The usefulness of three-dimensional fusion imaging of spinal arteriovenous malformation by a workstation connected to angiography systems.

Digital subtraction angiography (DSA) is the most useful technique for diagnosing spinal arteriovenous malformations (AVM). In recent years, with the improvement of imaging capabilities, the usefulness of three-dimensional (3D) imaging by fusing various modalities has been recognized. The use of 3D fusion imaging with a workstation connected to an angiography system has been reported in many cases of intracranial disease, but less frequently for spinal AVM. In this article, we describe two illustrative cases of spinal AVM in which 3D fusion imaging was useful for treatment. Although 3D fusion images using the system have the disadvantage that only a maximum of two images can be fused, it provides spinal surgeons with useful information for preoperative evaluation in a small amount of time.

Evaluation of Posterior Ligamentous Complex Injury in Thoracolumbar Burst Fractures: Correlation Analysis of CT and MRI Findings.

The goal of this study is to perform correlation analysis of Computed tomography (CT) and magnetic resonance imaging (MRI) results in posterior ligament complex (PLC) injury and define the morphological traits of thoracolumbar (TL) burst fractures connected to PLC injury. Forty patients with surgically repaired TL burst fractures between January 2013 and December 2020 were retrospectively analyzed. The patients were split into two groups for comparison based on MRI (Group P: patients with a confirmed or suspected PLC injury; Group N: patients with PLC injury denied). The radiographic morphological examination based on CT scans and clinical evaluation was performed and compared between two groups. The thoracolumbar injury classification and severity score (TLICS), the load sharing classification (LSC) scores, and the number of patients with neurological impairments were considerably greater in Group P. Loss of height of the fracture (loss height), local kyphosis of the fracture (local kyphosis), and supraspinous distance were significantly higher in Group P and significantly associated with PLC injuries indicating severe vertebral body destruction and traumatic kyphosis in multivariate logistic analysis [odds ratio: 1.90, 1.06, and 1.13, respectively]. Cutoff value for local kyphosis obtained from the receiver operating characteristic curve was 18.8. If local kyphosis is greater than 18.8 degrees on CT scans, we should take into account the probability of the highly damaged burst fracture associated with PLC injury. In this situation, we should carefully assess MRI to identify the spinal cord injury or spinal cord compression in addition to PLC injury because these instances likely present with neurological abnormalities.

Pure rotational spectra of the CO-trans-HOCO complex.

Pure rotational spectra of the CO-trans-HOCO complex have been observed by Fourier transform microwave (FTMW) and millimeter-wave FTMW double resonance spectroscopy. The complex was produced in a supersonic jet by discharging a mixture gas of CO and H(2)O diluted in Ar. The molecular constants including the fine and hyperfine coupling constants have been precisely determined. The inter-molecular distance between the CO and trans-HOCO monomers has been determined by fixing the structures of the trans-HOCO and CO monomers, where this complex has the OC···HO configuration with the C···HO angle almost linear. The C···H distance, 2.166 Å, is much shorter than those of the closed shell complexes, CO-CH(3)OH and CO-H(2)O. The Fermi contact constant of the proton for the complex was compared with that of the trans-HOCO monomer, leading to a conclusion that there is almost no induced effect for the spin density on the proton of HOCO by the complex formation.

Feasibility of the Olympic marathon under climatic and socioeconomic change.

There are concerns about the impact of climate change on Olympic Games, especially endurance events, such as marathons. In recent competitions, many marathon runners dropped out of their races due to extreme heat, and it is expected that more areas will be unable to host the Games due to climate change. Here, we show the feasibility of the Olympic marathon considering the variations in climate factors, socioeconomic conditions, and adaptation measures. The number of current possible host cities will decline by up to 27% worldwide by the late twenty-first century. Dozens of emerging cities, especially in Asia, will not be capable of hosting the marathon under the highest emission scenario. Moving the marathon from August to October and holding the Games in multiple cities in the country are effective measures, and they should be considered if we are to maintain the regional diversity of the Games.