Endogenous chondroitin extends the lifespan and healthspan in C. elegans.

Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17.

Malonate induces the browning of white adipose tissue in high-fat diet induced obesity model.

Obesity increases the risk of various diseases, and many studies have examined prevention and treatment strategies. Browning of white adipocytes promotes triglyceride (TG) metabolism and is the new focus for treating obesity. This study investigated the role of malonate-a modulator of mitochondrial function-in adipocyte browning, and its potential as a therapeutic agent in obesity. Our findings revealed that malonate increased oxygen consumption without inhibiting ATP synthesis. Malonate induced expression of PRDM16-an important transcription factor for browning-and uncoupling protein 1 (beige adipocyte marker), suggesting that malonate induces browning in white adipocytes. In an obesity mouse model induced by a high-fat diet, malonate significantly reduced body weight and white adipose tissue weight, as well as improved insulin resistance. Importantly, malonate stimulated browning in white adipose tissue and maintained the mass of brown adipose tissue in the high-fat diet-induced obesity mouse model. We propose that manipulation of mitochondrial function by malonate is a promising therapeutic approach for obesity.

A synthetic synaptic organizer protein restores glutamatergic neuronal circuits.

Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory-inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.

A micro channel-cut crystal X-ray monochromator for a self-seeded hard X-ray free-electron laser.

A channel-cut Si(111) crystal with a channel width of 90 µm was developed for achieving reflection self-seeding in hard X-ray free-electron lasers (XFELs). With the crystal a monochromatic seed pulse is produced from a broadband XFEL pulse generated in the first undulator section with an optical delay of 119 fs at 10 keV. The small optical delay allows a temporal overlap between the seed optical pulse and the electron bunch by using a small magnetic chicane for the electron beam placed between two undulator sections. Peak reflectivity reached 67%, which is reasonable compared with the theoretical value of 81%. By using this monochromator, a monochromatic seed pulse without broadband background in the spectrum was obtained at SACLA with a conversion efficiency from a broadband XFEL pulse of 2 × 10-2, which is ∼10 times higher than the theoretical efficiency of transmission self-seeding using a thin diamond (400) monochromator.

X-ray optics for advanced ultrafast pump-probe X-ray experiments at SACLA.

X-ray optics were implemented for advanced ultrafast X-ray experiments with different techniques at the hard X-ray beamline BL3 of SPring-8 Ångstrom Compact free-electron LAser. A double channel-cut crystal monochromator (DCCM) and compound refractive lenses (CRLs) were installed to tailor the beam conditions. These X-ray optics can work simultaneously with an arrival-timing monitor that compensates for timing jitter and drift. Inner-walls of channel-cut crystals (CCs) in the DCCM were processed by plasma chemical vaporization machining to remove crystallographic damage. Four-bounced reflection profiles of the CCs were investigated and excellent diffraction qualities were achieved. The use of CRLs enabled two-dimensional X-ray focusing with a spot size of ∼1.5 µm × 1.5 µm full width at half-maximum, while keeping reasonable throughputs for a wide photon energy range of 5-15 keV.

Craniofacial abnormality with skeletal dysplasia in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-1.

Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and plays an important part in organogenesis. To elucidate the roles of CS for craniofacial development, we analyzed the craniofacial morphology in CS N-acetylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. T1KO mice showed the impaired intramembranous ossification in the skull, and the final skull shape of adult mice included a shorter face, higher and broader calvaria. Some of T1KO mice exhibited severe facial developmental defect, such as eye defects and cleft lip and palate, causing embryonic lethality. At the postnatal stages, T1KO mice with severely reduced CS amounts showed malocclusion, general skeletal dysplasia and skin hyperextension, closely resembling Ehlers-Danlos syndrome-like connective tissue disorders. The production of collagen type 1 was significantly downregulated in T1KO mice, and the deposition of CS-binding molecules, Wnt3a, was decreased with CS in extracellular matrices. The collagen fibers were irregular and aggregated, and connective tissues were dysorganized in the skin and calvaria of T1KO mice. These results suggest that CS regulates the shape of the craniofacial skeleton by modulating connective tissue organization and that the remarkable reduction of CS induces hypoplasia of intramembranous ossification and cartilage anomaly, resulting in skeletal dysplasia.

Performance of a hard X-ray split-and-delay optical system with a wavefront division.

The performance of a hard X-ray split-and-delay optical (SDO) system with a wavefront division scheme was investigated at the hard X-ray free-electron laser facility SACLA. For the wavefront division, beam splitters made of edge-polished perfect Si(220) crystals were employed. We characterized the beam properties of the SDO system, and investigated its capabilities for beam manipulation and diagnostics. First, it was confirmed that shot-to-shot non-invasive diagnostics of pulse energies for both branches in the SDO system was feasible. Second, nearly ideal and identical focal profiles for both branches were obtained with a spot size of ∼1.5 µm in full width at half-maximum. Third, a spatial overlap of the two focused beams with a sub-µm accuracy was achieved by fine tuning of the SDO system. Finally, a reliable tunability of the delay time between two pulses was confirmed. The time interval was measured with an X-ray streak camera by changing the path length of the variable-delay branch. Errors from the fitted line were evaluated to be as small as ±0.4 ps over a time range of 60 ps.

Characterization of temporal coherence of hard X-ray free-electron laser pulses with single-shot interferograms.

Temporal coherence is one of the most fundamental characteristics of light, connecting to spectral information through the Fourier transform relationship between time and frequency. Interferometers with a variable path-length difference (PLD) between the two branches have widely been employed to characterize temporal coherence properties for broad spectral regimes. Hard X-ray interferometers reported previously, however, have strict limitations in their operational photon energies, due to the specific optical layouts utilized to satisfy the stringent requirement for extreme stability of the PLD at sub-ångström scales. The work presented here characterizes the temporal coherence of hard X-ray free-electron laser (XFEL) pulses by capturing single-shot interferograms. Since the stability requirement is drastically relieved with this approach, it was possible to build a versatile hard X-ray interferometer composed of six separate optical elements to cover a wide photon energy range from 6.5 to 11.5 keV while providing a large variable delay time of up to 47 ps at 10 keV. A high visibility of up to 0.55 was observed at a photon energy of 10 keV. The visibility measurement as a function of time delay reveals a mean coherence time of 5.9 ±â€…0.7 fs, which agrees with that expected from the single-shot spectral information. This is the first result of characterizing the temporal coherence of XFEL pulses in the hard X-ray regime and is an important milestone towards ultra-high energy resolutions at micro-electronvolt levels in time-domain X-ray spectroscopy, which will open up new opportunities for revealing dynamic properties in diverse systems on timescales from femto-seconds to nanoseconds, associated with fluctuations from ångström to nanometre spatial scales.

Quality of life and nutritional consequences after aboral pouch reconstruction following total gastrectomy for gastric cancer: randomized controlled trial CCG1101.

BACKGROUND: Total gastrectomy has detrimental effects on postoperative nutritional status and quality of life (QOL), but it is often unavoidable in the treatment of gastric cancer. Roux-en-Y (RY) is the most common reconstruction method following total gastrectomy. Trials to explore other means of reconstruction have been conducted but have failed to identify a method that is globally accepted. METHODS: Aboral pouch reconstruction (AP), in which an anisoperistaltic jejunal pouch is created in the Y limb of the RY reconstruction, is considered effective and technically feasible. A prospective randomized trial was conducted to compare AP with RY. Gastric cancer patients requiring total gastrectomy for R0 resection were randomly assigned during surgery to receive either RY (n = 51) or AP (n = 49). Postoperative QOL as assessed by the EORTC QLQ-C30 and STO22, body composition, and morbidity were compared between the two reconstruction methods. The physical functioning score of the QLQ-C30 was selected as the primary endpoint. RESULTS: The incidences of postoperative complications were similar between the two groups (29 % in the RY group and 27 % in the AP group). No significant difference was observed in the physical functioning score, and the superiority of AP was demonstrated only for the nausea and vomiting score at 12 months (p = 0.041) and the reflux score at 1 month (p = 0.036). No significant differences were observed in body composition or serum biochemistry. CONCLUSIONS: Although AP was safely implemented, no increased benefits in nutritional or QOL-related parameters were observed for this method over RY within 12 months postoperatively.

Long-term quality of life after laparoscopic distal gastrectomy for early gastric cancer: results of a prospective multi-institutional comparative trial.

BACKGROUND: The aim of this study was to compare the postoperative health-related quality of life (HRQOL) between open and laparoscopic distal gastrectomy. METHODS: A multi-institutional nonrandomized study was conducted. Patients with clinical T1 gastric cancer were prospectively enrolled and underwent distal gastrectomy by either the open or laparoscopic approach. HRQOL was measured using the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 and the site-specific module for gastric cancer. Questionnaires were completed at baseline and at 1, 3, 6, and 12 months postoperatively. Clinicopathological characteristics and short-term outcome including postoperative morbidity and HRQOL were compared between the approaches. RESULTS: A total of 145 patients (open, n = 72; laparoscopic, n = 73) were enrolled between September 2008 and January 2011 and analyzed. The laparoscopic approach was associated with longer operating time, less blood loss, and a similar incidence of postoperative complications. At each time point, the questionnaires were retrieved from more than 90 % of the patients. The worst scores for most of the scales were observed at 1 month postoperatively and improved thereafter. No statistically significant differences were observed regarding physical functioning, the primary endpoint. On the other hand, role, emotional, cognitive, and social functioning scores were superior in the laparoscopic group at 6 and 12 months postoperatively. Symptom scales including fatigue, pain, eating restriction, taste problems, and anxiety were better in the laparoscopic group before 6 months but not at 12 months. CONCLUSIONS: The study was considered to be negative because no benefit of the laparoscopic approach was observed in terms of physical functioning. However, more favorable scores for some of the symptom scales during the first 6 months and several functioning scales at 12 months after surgery suggest a potential benefit of the laparoscopic approach.

Enhancement of C2C12 differentiation by perfluorocarbon-mediated oxygen delivery.

We have studied the effect of enhanced oxygen delivery by perfluorocarbons on the differentiation of C2C12 cells. The extent of differentiation was assessed by means of phase contrast/fluorescence microscopy, active tension measurement and the glucose consumption/lactate production rates. We found that enhanced oxygen delivery is suitable for full differentiation of C2C12 cells.

[A case of advanced gastric cancer that a medical therapy effect was provided grade 3 by a histopathological diagnosis after long-term chemotherapy].

A 64-year-old man underwent long-term chemotherapy for advanced gastric cancer with para-aortic lymph node metastasis (cT3 N3 M0 P0, cStage IV). S-1 (120 mg/day) was orally administered for 14 days and CDDP (60 mg/m2) was administered 10 times by intravenous drip on day 8. Next, paclitaxel (PTX 80 mg/m2) was administered 12 times by intravenous drip on days 1, 8 and 15. After 10 S-1/CDDP courses and 12 paclitaxel courses, the lymph node swelling decreased in size, but the tumor increased. CPT-11 (100 mg/m2) was administered as third-line therapy by intravenous drip on days 1, 8, 15 and 22. A partial response (PR) was obtained after 2 courses, but due to severe pyloric stenosis, a food passage disorder appeared. We performed distal gastrectomy with D2 lymph node dissection. The histological diagnosis revealed a complete disappearance of cancer cells in the stomach and lymph nodes.

Aberrant methylation of the CHFR gene in digestive tract cancer.

BACKGROUND: Recently, aberrant methylation of the CHFR gene associated with gene silencing has been reported in several cancers. The methylation status of the CHFR gene was examined in primary esophageal and gastric carcinomas. MATERIALS AND METHODS: The methylation status of the CHFR promoter region and mRNA expression in cancer cell lines were examined first. The methylation status of the CHFR gene in 38 esophageal and 53 gastric cancers was subsequently examined and the correlation between CHFR methylation and the clinicopathological findings was investigated. RESULTS: Aberrant methylation of the CHFR gene was detected in 9 out of 38 (24%) primary esophageal and 16 out of 53 (30%) primary gastric cancers. After methylation analysis of all the samples, the clinicopathological data were correlated with these results. There was a significant difference according to gender (p = 0.0404), indicating that female esophageal cancers were more frequently methylated than male. On the other hand, abnormal methylation was found in esophageal and gastric cancer patients at all clinical stages. CONCLUSION: Aberrant methylation of the CHFR gene was frequently shown in esophageal and gastric cancers. In addition, abnormal methylation was found in these cancer patients at all clinical stages, suggesting that this cancer could be methylated at an early stage.

Aberrant methylation of the CHFR gene is frequently detected in non-invasive colorectal cancer.

BACKGROUND: Aberrant methylation of the CHFR gene associated with gene silencing has been reported in several primary tumors. In order to define the role of CHFR in the tumorigenic pathway of the colorectum, the methylation of CHFR was examined in tumors from colorectal cancer patients. MATERIALS AND METHODS: Ninety-eight colorectal cancer patients were examined using a methylation-specific PCR (MSP) for CHFR CpG island in primary tumors. RESULTS: An aberrant methylation of the CHFR gene was detected in 25 out of 98 (26%) primary colorectal cancers. No methylation was detected in the corresponding normal tissue specimens. This finding suggested that an aberrant methylation of the CHFR gene occurs frequently in colorectal cancers. After a methylation analysis of all samples, the clinicopathological data were correlated with these results. A significant difference was found in the tumor (p = 0.035), thus, indicating that in early colorectal cancer the CHFR gene was more frequently methylated than in advanced cases. CONCLUSION: These findings suggest that CHFR might act as a tumor suppressor in at least some colorectal cancers and that CHFR methylation might, therefore, be a particular phenomenon of early colorectal cancer.