Mapping the emergence of molecular vibrations mediating bond formation.

Fundamental studies of chemical reactions often consider the molecular dynamics along a reaction coordinate using a calculated or suggested potential energy surface1-5. But fully mapping such dynamics experimentally, by following all nuclear motions in a time-resolved manner-that is, the motions of wavepackets-is challenging and has not yet been realized even for the simple stereotypical bimolecular reaction6-8: A-B + C â†’ A + B-C. Here we track the trajectories of these vibrational wavepackets during photoinduced bond formation of the gold trimer complex [Au(CN)2-]3 in an aqueous monomer solution, using femtosecond X-ray liquidography9-12 with X-ray free-electron lasers13,14. In the complex, which forms when three monomers A, B and C cluster together through non-covalent interactions15,16, the distance between A and B is shorter than that between B and C. Tracking the wavepacket in three-dimensional nuclear coordinates reveals that within the first 60 femtoseconds after photoexcitation, a covalent bond forms between A and B to give A-B + C. The second covalent bond, between B and C, subsequently forms within 360 femtoseconds to give a linear and covalently bonded trimer complex A-B-C. The trimer exhibits harmonic vibrations that we map and unambiguously assign to specific normal modes using only the experimental data. In principle, more intense X-rays could visualize the motion not only of highly scattering atoms such as gold but also of lighter atoms such as carbon and nitrogen, which will open the door to the direct tracking of the atomic motions involved in many chemical reactions.

Antidiabetic Effect of Urolithin A in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Glucose Intolerance.

Diabetes is caused by abnormal glucose metabolism, and muscle, the largest tissue in the human body, is largely involved. Urolithin A (UroA) is a major intestinal and microbial metabolite of ellagic acid and ellagitannins and is found in fruits such as strawberry and pomegranate. In this present study, we investigated the antidiabetic effects of UroA in L6 myotubes and in KK-Ay/Ta, a mouse model of type 2 diabetes (T2D). UroA treatment elevated the glucose uptake (GU) of L6 myotubes in the absence of insulin. This elevation in GU by UroA treatment was partially inhibited by the concurrent addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K) which activates Akt (PKB: protein kinase B) or Compound C, an inhibitor of 5'-adenosine monophosphate-activated protein kinase (AMPK). Moreover, UroA was found to activate both pathways of Akt and AMPK, and then to promote translocation of glucose transporter 4 (GLUT4) from the cytosol to the plasma membrane in L6 myotubes. Based on these in vitro findings, an intraperitoneal glucose tolerance test (IPGTT) was performed after the oral administration of UroA for 3 weeks to KK-Ay/Ta mice with glucose intolerance. UroA was demonstrated to alleviate glucose intolerance. These results suggest that UroA is a biofactor with antihyperglycemic effects in the T2D state.

Mechanism of H+ dissociation-induced O-O bond formation via intramolecular coupling of vicinal hydroxo ligands on low-valent Ru(III) centers.

The understanding of O-O bond formation is of great importance for revealing the mechanism of water oxidation in photosynthesis and for developing efficient catalysts for water oxidation in artificial photosynthesis. The chemical oxidation of the RuII2(OH)(OH2) core with the vicinal OH and OH2 ligands was spectroscopically and theoretically investigated to provide a mechanistic insight into the O-O bond formation in the core. We demonstrate O-O bond formation at the low-valent RuIII2(OH) core with the vicinal OH ligands to form the RuII2(µ-OOH) core with a µ-OOH bridge. The O-O bond formation is induced by deprotonation of one of the OH ligands of RuIII2(OH)2 via intramolecular coupling of the OH and deprotonated O- ligands, conjugated with two-electron transfer from two RuIII centers to their ligands. The intersystem crossing between singlet and triple states of RuII2(µ-OOH) is easily switched by exchange of H+ between the µ-OOH bridge and the auxiliary backbone ligand.

Operando time-resolved soft x-ray absorption spectroscopy for photoexcitation processes of metal complexes in solutions.

Operando time-resolved soft x-ray absorption spectroscopy (TR-SXAS) is an effective method to reveal the photochemical processes of metal complexes in solutions. In this study, we have developed the TR-SXAS measurement system for observing various photochemical reactions in solutions by the combination of laser pump pulses with soft x-ray probe pulses from the synchrotron radiation. For the evaluation of the developed TR-SXAS system, we have measured nitrogen K-edge x-ray absorption spectroscopy (XAS) spectra of aqueous iron phenanthroline solutions during a photoinduced spin transition process. The decay process of the high spin state to the low spin state in the iron complex has been obtained from the ligand side by N K-edge XAS, and the time constant is close to that obtained from the central metal side by time-resolved Fe K-edge XAS in the previous studies.

Analysis of the risk factors for osteoporosis and its prevalence after gastrectomy for gastric cancer in older patients: a prospective study.

PURPOSE: Osteoporosis leads to fragility fractures and is a major public health problem. We conducted this study to analyze the prevalence of and risk factors for osteoporosis after gastrectomy in older patients. METHODS: This multicenter prospective trial comprised older patients without recurrence of gastric cancer for > 3 years after curative surgery. The prevalence of osteoporosis was identified using the World Health Organization bone mineral density (BMD)-based definition. Univariate and multivariate analyses were performed to identify the risk factors for osteoporosis. RESULTS: BMD values were measured in 267 of the 271 enrolled patients. The prevalence of osteoporosis was 38.2% (men 24.0%; women 60%). Analysis using FRAX® revealed that 51.7% of patients were candidates for pharmacologic therapy. Female sex (odds ratio [OR] 5.16, 95% confidence interval [CI] 2.61-10.2), age (OR 1.06, 95% CI 1.00-1.12), low body mass index (< 19.0 kg/m2) after gastrectomy (OR 5.31, 95% CI 2.79-10.13), and history of fracture (OR 2.06, 95% CI 1.06-4.02) were independently associated with osteoporosis. CONCLUSIONS: The prevalence of osteoporosis in older patients after gastrectomy was 38.2%. Moreover, female sex, age, low body mass index after gastrectomy, and a history of fracture were risk factors significantly associated with osteoporosis. Thus, older patients undergoing gastrectomy should have proactive surveillance and receive treatment for osteoporosis.

[A Case of Primary Liver Cancer and Gastric Glomus Tumor Diagnosed Preoperatively and Treated with Liver Segmentectomy and Local Gastrectomy].

A man in his 70s was concurrently suspected of having a submucosal tumor(SMT)of the stomach and a liver tumor during a medical examination. Abdominal contrast-enhanced CT scan revealed S8 hepatocellular carcinoma(HCC)and an SMT of the stomach, which was strongly enhanced from the early to the later phase. Upper gastrointestinal endoscopy revealed a 20 mm SMT in the antrum of the stomach. Endoscopic ultrasonography showed a hyperechoic tumor in the fourth layer of the gastric wall. T2-weighted MRI showed a 25 mm SMT in the antrum of the stomach with a faint high signal intensity compared with that of the gastric wall. The patient was diagnosed with HCC and gastric glomus tumor, and a liver segmentectomy and a local gastrectomy were performed. Immunohistochemistry of the SMT revealed the expression of α-SMA but no expression of desmin, c-kit, CD34, or S-100. Therefore, a diagnosis of a Glomus tumor of the stomach was made. Gastric Glomus tumors are very rare; therefore, we have reviewed some citations and would like to discuss our case.

[A Case of Small Thymic Carcinoma with Pleural Dissemination Preoperatively Suspected as Pulmonary Metastasis from Rectal Cancer].

A case was 73-year-old man, who had history of laparoscopic high anterior resection surgery for rectal cancer, followed by adjuvant chemotherapy 2 years ago. Preoperative diagnosis was anterior mediastinal tumor, with multiple intrapulmonary nodules noted, though no increasing tendency. During adjuvant chemotherapy for colorectal cancer, the anterior mediastinal tumor showed some shrinkage, while that and 3 intrapulmonary nodules slowly increased in size after completion, thus rectal cancer pulmonary and mediastinal metastasis were suspected. Complete resection of the intrapulmonary nodules and anterior mediastinal tumor was considered feasible. Thoracoscopic observation revealed multiple small pleural seeding lesions and all speculated to be intrapulmonary metastases before surgery were also pleural lesions. Intraoperative rapid diagnostic findings of a biopsy section revealed possible colorectal cancer metastasis, though histological type was not revealed. Final histopathological diagnosis was pleural dissemination of thymic carcinoma. Lenvatinib was introduced 2 months later for thymic carcinoma with pleural dissemination. Two years after surgery, the anterior mediastinum primary tumor had slightly decreased and the pleural nodules also showed a shrinking tendency. In such cases of small tumor with increasing tendency and irregular margins, thymic carcinoma should be considered when planning treatment.

Trial Analysis of the Relationship between Taste and Biological Information Obtained While Eating Strawberries for Sensory Evaluation.

This paper presents a trial analysis of the relationship between taste and biological information obtained while eating strawberries (for a sensory evaluation). This study used the visual analog scale (VAS); we collected questionnaires used in previous studies and human brain activity obtained while eating strawberries. In our analysis, we assumed that brain activity is highly correlated with taste. Then, the relationships between brain activity and other data, such as VAS and questionnaires, could be analyzed through a canonical correlation analysis, which is a multivariate analysis. Through an analysis of brain activity, the potential relationship with "taste" (that is not revealed by the initial simple correlation analysis) can be discovered. This is the main contribution of this study. In the experiments, we discovered the potential relationship between cultural factors (in the questionnaires) and taste. We also found a strong relationship between taste and individual information. In particular, the analysis of cross-loading between brain activity and individual information suggests that acidity and the sugar-to-acid ratio are related to taste.

The Association of Thymidine Phosphorylase with Gastric Cancer Prognosis.

BACKGROUND: Thymidine phosphorylase(TP)plays an important role in angiogenesis and solid tumor invasion. This study aimed to investigate TP expression in gastric cancer(GC), its correlation with clinicopathological features, and its prognostic significance. METHODS: Clinical data and tumor specimens were retrospectively collected from patients with GC in Ikeda Municipal Hospital between January 2005 and December 2006. Tumor specimens were immunohistochemically analyzed for TP expression graded as 0, 1+, 2+, or 3+ and divided into low(0/1+)and high(2+/3+)TP expression groups. To determine its potential prognostic value, any correlation between TP expression and the clinicopathological features of the patients was statistically assessed. RESULTS: Among 111 patients with GC, 33 had high TP expression(29.7%)and 78 had low TP expression(70.3%). There were significant differences in tumor size, tumor depth, venous invasion, lymphatic invasion, and clinical stage between the two groups. Analysis of the Kaplan-Meier survival curves revealed that the high TP group had significantly shorter overall survival(OS; p<0.01)and progression-free survival(PFS; p<0.01)than the low TP group. Moreover, the high TP group had significantly shorter OS(p=0.040)and a trend toward a shorter PFS(p=0.064) than the low TP group in patients with stage Ⅱ, Ⅲ, and Ⅳ cancer. Multivariate analysis revealed that high TP expression was significantly associated with tumor size, tumor type, and lymphatic invasion in patients with GC. CONCLUSIONS: Our results suggest that high TP expression might predict poor prognosis in GC.

[Two Cases of Recurrent Colon Cancer with BRAF Mutation].

We report 2 cases of recurrent colon cancer with BRAF mutation. Case 1, a 75-year-old man, had rapid progress of multiple liver metastasis 5 months after curative resection, and died on 37 days after recurrence without induction of systemic therapy. Case 2, a 67-year-old man with diagnosis of peritoneal dissemination at 8 months after curative resection, received encorafenb and cetuximab (doublet-therapy) with certain effect, nevertheless advanced triplet-therapy with binimetinib was forced to pause due to severe skin disorders and he died on 123 days after recurrence. We considered that closed follow- up should be required after curatively resected colorectal cancers with BRAF mutation for early detection of recurrence, and prompt induction and evaluation of systemic treatment also should be required after unresectable recurrence including careful management with the attention to the features of doublet and triplet-therapy.

[A Case of Hypertrophic Pulmonary Osteoarthropathy Associated with Pulmonary Pleomorphic Carcinoma].

Hypertrophic pulmonary osteoarthropathy(HPO)is a tumor-associated syndrome that features the triad of clubbed fingers, periosteal bone growth in long bones, and arthritis, and is often associated with an adenocarcinoma or squamous cell carcinoma. This report presents details of a case of HPO associated with pleomorphic carcinoma, which was relieved by treatment. A 47-year-old woman was presented with a complaint of generalized arthralgia. A physical examination showed swollen joints in the body and clubbed fingers. Chest CT revealed a mass shadow in the left upper lobe and ultrasound- guided biopsy findings led to a diagnosis of non-small cell lung cancer. Furthermore, bone scintigraphy indicated symmetrical accumulation in bones and joints throughout the body. A right upper lobectomy was performed along with combined chest wall resection and mediastinal lymph node dissection with an open chest, and the presence of lung cancer complicated with HPO was indicated. Pathological examination results revealed a diagnosis of pleomorphic carcinoma(pT4N0M0, Stage ⅢA). Systemic arthralgia was resolved on the first postoperative day. One year after surgery, a solitary brain metastasis developed and was removed, with no recurrence at the time of writing. Joint symptoms related to HPO can be expected to improve with treatment of pulmonary lesions, thus aggressive procedures for diagnosis and treatment are desirable.

Diarylethene-Powered Light-Induced Folding of Supramolecular Polymers.

Helical folding of randomly coiled linear polymers is an essential organization process not only for biological polypeptides but also for synthetic functional polymers. Realization of this dynamic process in supramolecular polymers (SPs) is, however, a formidable challenge because of their inherent lability of main chains upon changing an external environment that can drive the folding process (e.g., solvent, concentration, and temperature). We herein report a photoinduced reversible folding/unfolding of rosette-based SPs driven by photoisomerization of a diarylethene (DAE). Temperature-controlled supramolecular polymerization of a barbiturate-functionalized DAE (open isomer) in nonpolar solvent results in the formation of intrinsically curved, but randomly coiled, SPs due to the presence of defects. Irradiation of the randomly coiled SPs with UV light causes efficient ring-closure reaction of the DAE moieties, which induces helical folding of the randomly coiled structures into helicoidal ones, as evidenced by atomic force microscopy and small-angle X-ray scattering. The helical folding is driven by internal structure ordering of the SP fiber that repairs the defects and interloop interaction occurring only for the resulting helicoidal structure. In contrast, direct supramolecular polymerization of the ring-closed DAE monomers by temperature control affords linearly extended ribbon-like SPs lacking intrinsic curvature that are thermodynamically less stable compared to the helicoidal SPs. The finding represents an important concept applicable to other SP systems; that is, postpolymerization (photo)reaction of preorganized kinetic structures can lead to more thermodynamically stable structures that are inaccessible directly through temperature-controlled protocols.

Antidiabetic Effect of Taxifolin in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Hyperglycemia and Hyperuricemia.

Muscle is the largest tissue in our body and plays an important role in glucose homeostasis and hence diabetes. In the present study, we examined the effects of taxifolin (TXF) on glucose metabolism in cultured L6 muscle cells (myotubes) and in type 2 diabetic (T2D) model KK-Ay/Ta mice. TXF dose-dependently increased glucose uptake (GU) in L6 myotubes under the condition of insulin absence. This increase in GU was partially, but significantly canceled by TXF treatment in combination with either LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), which phosphorylates protein kinase B (Akt) or Compound C, an inhibitor of 5'-adenosine monophosphate-activated protein kinase (AMPK). Furthermore, TXF was demonstrated to activate (=phosphorylate) both Akt and AMPK, and promote glucose transporter 4 (GLUT4) translocation to the plasma membrane from cytosol of L6 myotubes via both PI3K/Akt and AMPK signaling pathways. Based on these in vitro findings, we conducted an in vivo experiment in KK-Ay/Ta mice with hyperglycemia and hyperuricemia. Fasting plasma glucose, insulin, uric acid levels and an index of insulin resistance (HOMA-IR) increased significantly in the T2D model mice compared with normal ones. Such rises in the T2D state were significantly suppressed by oral administration of TXF for four weeks. These results suggest that TXF is a potent antihyperglycemic and antihyperuricemic phytochemical in the T2D state.

Diffracted X-ray blinking measurements of interleukin 15 receptors in the inner/outer membrane of living NK cells.

Interleukin 15 receptor (IL-15R) is a transmembrane signalling protein consisting of 3 subsets: α, ß (IL-15Rß), and γ (γc). IL-2 and IL-15 share the signalling domains IL-15Rß and γc, although they bind to intrinsic α-subsets and non-signalling domains. Additionally, IL-2 and IL-15 play different roles; therefore, there have been many observations of the dynamic behaviours of IL-15R, which are linked to physiological functions. For more practical discrimination between IL-2 and IL-15, a study was designed and carried out in which α-subsets were removed and a cytoplasmic inhibitor was applied to create a simplified environment in which secondary signalling molecules were reduced. We also applied a new measurement method, diffracted X-ray blinking (DXB), to achieve higher accuracy (<0.01 Å). The dynamics of IL-2 binding (confined motion, max range = 0.71 Å) and IL-15 binding (normal motion) in live natural killer cells were different. We also confirmed. that DXB was a suitable method to quantitatively evaluate the transmembrane protein dynamics of inner/outer live cell membranes by labeling the extracellular domain since the measurements were dependent on the cytosolic environment.

Prolyl-hydroxyproline, a collagen-derived dipeptide, enhances hippocampal cell proliferation, which leads to antidepressant-like effects in mice.

Depression has been a mental health issue worldwide. We previously reported that ginger-degraded collagen hydrolysate (GDCH) suppressed depression-like behavior in mice. Furthermore, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG) were detected in the circulating blood after the oral administration of GDCH. In the present study, PO, but not OG, was detected in the cerebrospinal fluid of rats after the oral administration of GDCH, suggesting that PO is transported from blood to the brain. We then investigated the effects of PO and OG on the depression-like behavior of mice. The oral administration of PO significantly decreased depression-like behavior in the forced swim test. OG had no antidepressant-like effect. In addition, proline and hydroxyproline, components of PO, also had no antidepressant-like effect after their oral administration. PO significantly increased the gene expression of brain-derived neurotrophic factor and nerve growth factor in the hippocampus, and promoted the proliferation of neural progenitor cells in vivo and in vitro. PO also increased the dopamine concentration in the prefrontal cortex. Thus, PO-dependent regulation of neurotrophic function and neurotransmitter may be the mechanism for antidepressant-like behavior. Together, these results demonstrate that PO is an antidepressant bioactive peptide accompanying the proliferation of hippocampal neural progenitor cells.

Determining Excited-State Structures and Photophysical Properties in Phenylphosphine Rhenium(I) Diimine Biscarbonyl Complexes Using Time-Resolved Infrared and X-ray Absorption Spectroscopies.

We have explored the structural factors on the photophysical properties in two rhenium(I) diimine complexes in acetonitrile solution, cis,trans-[Re(dmb)(CO)2(PPh2Et)2]+ (Et(2,2)) and cis,trans-[Re(dmb)(CO)2(PPh3)2]+ ((3,3)) (dmb = 4,4'-dimethyl-2,2'-bipyridine, Ph = phenyl, Et = ethyl) using the combination method of time-resolved infrared spectroscopy, time-resolved extended X-ray absorption fine structure, and quantum chemical calculations. The difference between these complexes is the number of phenyl groups in the phosphine ligand, and this only indirectly affects the central Re(I). Despite this minor difference, the complexes exhibit large differences in emission wavelength and excited-state lifetime. Upon photoexcitation, the bond length of Re-P and angle of P-Re-P are significantly changed in both complexes, while the phenyl groups are largely rotated by ∼20° only in (3,3). In contrast, there is little change in charge distribution on the phenyl groups when Re to dmb charge transfer occurs upon photoexcitation. We concluded that the instability from steric effects of phenyl groups and diimine leads to a smaller Stokes shift of the lowest excited triplet state (T1) in (3,3). The large structural change between the ground and excited states causes the longer lifetime of T1 in (3,3).

Direct observation of bond formation in solution with femtosecond X-ray scattering.

The making and breaking of atomic bonds are essential processes in chemical reactions. Although the ultrafast dynamics of bond breaking have been studied intensively using time-resolved techniques, it is very difficult to study the structural dynamics of bond making, mainly because of its bimolecular nature. It is especially difficult to initiate and follow diffusion-limited bond formation in solution with ultrahigh time resolution. Here we use femtosecond time-resolved X-ray solution scattering to visualize the formation of a gold trimer complex, [Au(CN)2(-)]3 in real time without the limitation imposed by slow diffusion. This photoexcited gold trimer, which has weakly bound gold atoms in the ground state, undergoes a sequence of structural changes, and our experiments probe the dynamics of individual reaction steps, including covalent bond formation, the bent-to-linear transition, bond contraction and tetramer formation with a time resolution of ∼500 femtoseconds. We also determined the three-dimensional structures of reaction intermediates with sub-ångström spatial resolution. This work demonstrates that it is possible to track in detail and in real time the structural changes that occur during a chemical reaction in solution using X-ray free-electron lasers and advanced analysis of time-resolved solution scattering data.

Structural Dynamics of C2F4I2 in Cyclohexane Studied via Time-Resolved X-ray Liquidography.

The halogen elimination of 1,2-diiodoethane (C2H4I2) and 1,2-diiodotetrafluoroethane (C2F4I2) serves as a model reaction for investigating the influence of fluorination on reaction dynamics and solute-solvent interactions in solution-phase reactions. While the kinetics and reaction pathways of the halogen elimination reaction of C2H4I2 were reported to vary substantially depending on the solvent, the solvent effects on the photodissociation of C2F4I2 remain to be explored, as its reaction dynamics have only been studied in methanol. Here, to investigate the solvent dependence, we conducted a time-resolved X-ray liquidography (TRXL) experiment on C2F4I2 in cyclohexane. The data revealed that (ⅰ) the solvent dependence of the photoreaction of C2F4I2 is not as strong as that observed for C2H4I2, and (ⅱ) the nongeminate recombination leading to the formation of I2 is slower in cyclohexane than in methanol. We also show that the molecular structures of the relevant species determined from the structural analysis of TRXL data provide an excellent benchmark for DFT calculations, especially for investigating the relevance of exchange-correlation functionals used for the structural optimization of haloalkanes. This study demonstrates that TRXL is a powerful technique to study solvent dependence in the solution phase.

[Could Preoperative Conditions Be Preserved or Improved by the Support of Preoperative ONS Administration in Patients with Gastric Cancer?]

INTRODUCTION: In our hospital, we measure the body composition of patients undergoing gastrointestinal surgery. For patients who have a skeletal muscle mass(SMM)of less than 90% of the ideal, we provide them with guidance on having oral nutritional supplements(ONS)and self-exercise therapy. Therefore, we perform operations after taking measures on preserving/improving patient's preoperative conditions. This study was aimed to evaluate the effects on body weight, SMM, and fat mass(FM)in the patients scheduled for gastrectomy. PATIENTS AND METHODS: From January 2017 to December 2020, we retrospectively analyzed 64 gastric cancer patients whose body composition changes were measured at the time of initial diagnosis and immediately before surgery. The body composition was measured by a nutritionist using the BIA method, while the self-exercise therapy was instructed by a rehabilitation therapist. RESULTS: A total of 64 patients were divided into 2 groups: ONS group(36 patients)and Non-ONS group(28 patients). The median preoperative ONS administered to the ONS group was 15 packs. Body weight change showed a significant difference between the 2 groups(+0.73% and -0.91%[p<0.01]in the ONS group and Non-ONS group respectively). SMM change showed no significant difference between the 2 groups(+1.18% and +0.64%[p=0.19]in the ONS group and Non-ONS group respectively). Likewise, FM change showed no significant difference between the 2 groups(-1.08% and -3.50%[p=0.39]in the ONS group and Non-ONS group respectively). CONCLUSION: This study suggested that SMM and FM could be preserved, and body weight could be increased by the support of preoperative ONS administration even in patients with gastric cancer close to having sarcopenia.