Sensory and motor representations of internalized rhythms in the cerebellum and basal ganglia.

Both the cerebellum and basal ganglia are involved in rhythm processing, but their specific roles remain unclear. During rhythm perception, these areas may be processing purely sensory information, or they may be involved in motor preparation, as periodic stimuli often induce synchronized movements. Previous studies have shown that neurons in the cerebellar dentate nucleus and the caudate nucleus exhibit periodic activity when the animals prepare to respond to the random omission of regularly repeated visual stimuli. To detect stimulus omission, the animals need to learn the stimulus tempo and predict the timing of the next stimulus. The present study demonstrates that neuronal activity in the cerebellum is modulated by the location of the repeated stimulus and that in the striatum (STR) by the direction of planned movement. However, in both brain regions, neuronal activity during movement and the effect of electrical stimulation immediately before stimulus omission were largely dependent on the direction of movement. These results suggest that, during rhythm processing, the cerebellum is involved in multiple stages from sensory prediction to motor control, while the STR consistently plays a role in motor preparation. Thus, internalized rhythms without movement are maintained as periodic neuronal activity, with the cerebellum and STR preferring sensory and motor representations, respectively.

Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus.

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

Role of right temporoparietal junction for counterfactual evaluation of partner's decision in ultimatum game.

Humans assess the distributions of resources based on their aversion to unfairness. If a partner distributes in an unfair manner even though the partner had a less unfair distribution option, a recipient will believe that the partner should have chosen the counterfactual option. In this study, we investigated the neural basis for fairness evaluation of actual and counterfactual options in the ultimatum game. In this task, a partner chose one distribution option out of two options, and a participant accepted or rejected the option. The behavioral results showed that the acceptance rate was influenced by counterfactual evaluation (CE), among others, as defined by the difference of monetary amount between the actual and counterfactual options. The functional magnetic resonance imaging results showed that CE was associated with the right ventral angular gyrus (vAG) that provided one of convergent inputs to the supramarginal gyrus related to decision utility, which reflects gross preferences for the distribution options. Furthermore, inhibitory repetitive transcranial magnetic stimulation administered to the right vAG reduced the behavioral component associated with CE. These results suggest that our acceptance/rejection of distribution options relies on multiple processes (monetary amount, disadvantageous inequity, and CE) and that the right vAG causally contributes to CE.

Temporal Information Processing in the Cerebellum and Basal Ganglia.

Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent studies on nonhuman primates. In the studies presented in the first half of the chapter, monkeys were trained to make eye movements when a certain amount of time had elapsed since the onset of the visual cue (time production task). The animals had to report time lapses ranging from several hundred milliseconds to a few seconds based on the color of the fixation point. In this task, the saccade latency varied with the time length to be measured and showed stochastic variability from one trial to the other. Trial-to-trial variability under the same conditions correlated well with pupil diameter and the preparatory activity in the deep cerebellar nuclei and the motor thalamus. Inactivation of these brain regions delayed saccades when asked to report subsecond intervals. These results suggest that the internal state, which changes with each trial, may cause fluctuations in cerebellar neuronal activity, thereby producing variations in self-timing. When measuring different time intervals, the preparatory activity in the cerebellum always begins approximately 500 ms before movements, regardless of the length of the time interval being measured. However, the preparatory activity in the striatum persists throughout the mandatory delay period, which can be up to 2 s, with different rate of increasing activity. Furthermore, in the striatum, the visual response and low-frequency oscillatory activity immediately before time measurement were altered by the length of the intended time interval. These results indicate that the state of the network, including the striatum, changes with the intended timing, which lead to different time courses of preparatory activity. Thus, the basal ganglia appear to be responsible for measuring time in the range of several hundred milliseconds to seconds, whereas the cerebellum is responsible for regulating self-timing variability in the subsecond range. The second half of this chapter presents studies related to periodic timing. During eye movements synchronized with alternating targets at regular intervals, different neurons in the cerebellar nuclei exhibit activity related to movement timing, predicted stimulus timing, and the temporal error of synchronization. Among these, the activity associated with target appearance is particularly enhanced during synchronized movements and may represent an internal model of the temporal structure of stimulus sequence. We also considered neural mechanism underlying the perception of periodic timing in the absence of movement. During perception of rhythm, we predict the timing of the next stimulus and focus our attention on that moment. In the missing oddball paradigm, the subjects had to detect the omission of a regularly repeated stimulus. When employed in humans, the results show that the fastest temporal limit for predicting each stimulus timing is about 0.25 s (4 Hz). In monkeys performing this task, neurons in the cerebellar nuclei, striatum, and motor thalamus exhibit periodic activity, with different time courses depending on the brain region. Since electrical stimulation or inactivation of recording sites changes the reaction time to stimulus omission, these neuronal activities must be involved in periodic temporal processing. Future research is needed to elucidate the mechanism of rhythm perception, which appears to be processed by both cortico-cerebellar and cortico-basal ganglia pathways.

Atomic Imaging of Interface Defects in an Insulating Film on Diamond.

The insulator/semiconductor interface structure is the key to electric device performance, and much interest has been focused on understanding the origin of interfacial defects. However, with conventional techniques, it is difficult to analyze the interfacial atomic structure buried in the insulating film. Here, we reveal the atomic structure at the interface between an amorphous aluminum oxide and diamond using a developed electron energy analyzer for photoelectron holography. We find that the three-dimensional atomic structure of a C-O-Al-O-C bridge between two dimer rows of the hydrogen-terminated diamond surface. Our results demonstrate that photoelectron holography can be used to reveal the three-dimensional atomic structure of the interface between a crystal and an amorphous film. We also find that the photoelectron intensity originating from the C-O bonds is strongly related to the interfacial defect density. We anticipate significant progress in the study of amorphous/crystalline interfaces based on their three-dimensional atomic structures analysis.

Spontaneous formation of metastable orientation with well-organized permanent dipole moment in organic glassy films.

The performance of organic optoelectronic and energy-harvesting devices is largely determined by the molecular orientation and resultant permanent dipole moment, yet this property is difficult to control during film preparation. Here, we demonstrate the active control of dipole direction-that is, vector direction and magnitude-in organic glassy films by physical vapour deposition. An organic glassy film with metastable permanent dipole moment orientation can be obtained by utilizing the small surface free energy of a trifluoromethyl unit and intramolecular permanent dipole moment induced by functional groups. The proposed molecular design rule could pave a way toward the formation of spontaneously polarized organic glassy films, leading to improvement in the performance of organic molecular devices.

Origin of Unexpected Ir3+ in a Superconducting Candidate Sr2IrO4 System Analyzed by Photoelectron Holography.

The reason for the absence of superconductivity in Sr2IrO4 was estimated by photoelectron spectra and photoelectron holograms. The analysis of the La photoelectron hologram concluded that La atoms are substituted to Sr sites. Two O 1s peaks were observed and were identified as the oxygens in the IrO2 and SrO planes by photoelectron holography and density functional theory (DFT) calculations. In the Ir 4f spectrum of Sr2IrO4, an unexpected Ir3+ peak was observed as much as 50% of all of the Ir. The photoelectron hologram of Ir3+ showed a displacement of about 0.15 Å. This displacement is thought to be due to the oxygen vacancies in the IrO2 plane. These oxygen vacancies and the associated local displacement of the atoms might inhibit superconductivity in spite of sufficient electron doping.

Roles of Stress Response in Autophagy Processes and Aging-Related Diseases.

The heat shock factor 1 (HSF1)-mediated stress response pathway and autophagy processes play important roles in the maintenance of proteostasis. Autophagy processes are subdivided into three subtypes: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Recently, molecular chaperones and co-factors were shown to be involved in the selective degradation of substrates by these three autophagy processes. This evidence suggests that autophagy processes are regulated in a coordinated manner by the HSF1-mediated stress response pathway. Recently, various studies have demonstrated that proteostasis pathways including HSF1 and autophagy are implicated in longevity. Furthermore, they serve as therapeutic targets for aging-related diseases such as cancer and neurodegenerative diseases. In the future, these studies will underpin the development of therapies against various diseases.

SOCS7-Derived BC-Box Motif Peptide Mediated Cholinergic Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 µM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

Temporal Prediction Signals for Periodic Sensory Events in the Primate Central Thalamus.

Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single-neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed a transient response, but after several cycles, the direction of firing modulation reversed and the activity decreased for each repetitive stimulus. The time course of Switch-type activity was well explained by the weighted sum of activities of the other types of neurons. Furthermore, for only Switch-type neurons the activity just before stimulus omission significantly correlated with behavioral latency, indicating that this type of neuron may carry a more advanced signal in the system detecting stimulus omission. These results suggest that the central thalamus may transmit integrated signals to the cerebral cortex for temporal information processing, which are necessary to accurately predict rhythmic event timing.SIGNIFICANCE STATEMENT Several cortical and subcortical regions are involved in temporal information processing, and the thalamus will play a role in functionally linking them. The present study aimed to clarify how the paralaminar part of the thalamus transmits and modifies signals for temporal prediction of rhythmic events. Three types of thalamic neurons exhibited periodic activity when monkeys attempted to detect a single omission of isochronous repetitive stimuli. The activity of one type of neuron correlated with the behavioral latency and appeared to be generated by integrating the signals carried by the other types of neurons. Our results revealed the neuronal signals in the thalamus for temporal prediction of sensory events, providing a clue to elucidate information processing in the thalamocortical pathways.

Hypothalamic interaction with reward-related regions during subjective evaluation of foods.

The reward system implemented in the midbrain, ventral striatum, orbitofrontal cortex, and ventromedial prefrontal cortex evaluates and compares various types of rewards given to the organisms. It has been suggested that autonomic factors influence reward-related processing via the hypothalamus, but how the hypothalamus modulates the reward system remains elusive. In this functional magnetic resonance imaging study, the hypothalamus was parcellated into individual hypothalamic nuclei performing different autonomic functions using boundary mapping parcellation analyses. The effective interaction during subjective evaluation of foods in a reward task was then investigated between the human hypothalamic nuclei and the reward-related regions. We found significant brain activity decrease in the paraventricular nucleus (PVH) and lateral nucleus in the hypothalamus in food evaluation compared with monetary evaluation. A psychophysiological interaction analysis revealed dual interactions between the PVH and (1) midbrain region and (2) ventromedial prefrontal cortex, with the former correlated with the stronger tendency of participants toward food-seeking. A dynamic causal modeling analysis further revealed unidirectional interactions from the PVH to the midbrain and ventromedial prefrontal cortex. These results suggest that the PVH in the human hypothalamus interacts with the reward-related regions in the cerebral cortex via multiple pathways (i.e., the midbrain pathway and ventromedial prefrontal pathway) to evaluate rewards for subsequent decision-making.

NADP+-dependent l-arginine dehydrogenase from Pseudomonas velonii: Purification, characterization and application to an l-arginine assay.

l-Arginine dehydrogenase (L-ArgDH) is an amino acid dehydrogenase which catalyzes the reversible oxidative deamination of l-arginine to the oxo analog in the presence of NAD(P)+. We here found the gene homolog of L-ArgDH in genome data of Pseudomonas veronii and succeeded in expression of P. veronii JCM11942 gene in E. coli. The gene product exhibited strong NADP+-dependent L-ArgDH activity. The enzyme was unstable, but markedly stabilized by the addition of 10% glycerol. The enzyme first purified to homogeneity consisted of a homodimeric protein with a molecular mass of about 65 kDa. The enzyme selectively catalyzed NADP+-dependent l-arginine oxidation with maximal activity at pH 9.5. The apparent Km values for l-arginine and NADP+ were 2.5 and 0.21 mM, respectively. The nucleotide sequence coding the enzyme gene was determined and the amino acid sequence was deduced from the nucleotide sequence. The simple colorimetric microassay for l-arginine using the enzyme was achieved.

Cold snare polypectomy for superficial non-ampullary duodenal epithelial tumor: a prospective clinical trial (pilot study).

BACKGOUND: Cold snare polypectomy (CSP) can minimize the risk of adverse events and has become a standard treatment for small colorectal polyps. CSP might also be suitable for small superficial non-ampullary duodenal epithelial tumors (SNADETs). This study aimed to evaluate the safety of CSP for SNADETs. METHODS: The major indication criteria were as follows: (1) endoscopically diagnosed SNADET, (2) ≤ 10 mm, and (3) a single primary lesion. CSP was performed using an electrosurgical snare without electrocautery. Follow-up endoscopy and scar biopsy were performed 3 months after CSP. The primary endpoint was the delayed adverse events rate. RESULTS: In total, 21 patients were enrolled. Two and 19 lesions were located in the duodenal bulb and 2nd portion, respectively; the median lesion size was 8 mm. CSP was attempted for all lesions; three lesions could not be resected without electrocautery and were removed by conventional endoscopic mucosal resection (EMR). The rate of spurting bleeding after CSP was 0%. The median procedure time was 12 min, the median resected specimen size was 12 mm, and the rate of en bloc resection was 81% (17/21). No adverse events were observed intraoperatively, with no delayed adverse events after CSP. Histopathology revealed 15 adenomas, 4 cancers (intramucosal), and 2 non-neoplastic lesions. The horizontal margins were negative/positive/undetermined in 9, 1, and 11 cases, respectively. All vertical margins were negative. Only one recurrence was detected by follow-up endoscopy 3 months after CSP. CONCLUSIONS: CSP can be performed safely for small SNADETs. CLINICAL TRIAL REGISTRATION: This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index.htm ), and the registration number is UMIN000019157.

Sweep imaging with Fourier transform as a tool with MRI for evaluating the effect of teriparatide on cortical bone formation in an ovariectomized rat model.

BACKGROUND: Teriparatide (TPTD) is a drug for osteoporosis that promotes bone formation and improves bone quality. However, the effects of TPTD on cortical bone are not well understood. Sweep imaging with Fourier transform (SWIFT) has been reported as a useful tool for evaluating bound water of cortical bone, but it has yet to be used to investigate the effects of TPTD on cortical bone. This study aimed to evaluate the consequences of the effect of TPTD on cortical bone formation using SWIFT. METHODS: Twelve-week-old female Sprague-Dawley rats (n = 36) were reared after ovariectomy to create a postmenopausal osteoporosis model. They were divided into two groups: the TPTD and non-TPTD groups. Rats were euthanized at 4, 12, and 24 weeks after initiating TPTD treatment. Tibial bones were evaluated using magnetic resonance imaging (MRI) and bone histomorphometry. In MRI, proton density-weighted imaging (PDWI) and SWIFT imaging were performed. The signal-to-noise ratio (SNR) was calculated for each method. The same area evaluated by MRI was then used to calculate the bone formation rate by bone histomorphometry. Measurements were compared using the Mann-Whitney U-test, and a P-value of < 0.05 was considered significant. RESULTS: PDWI-SNR was not significantly different between the two groups at any time point (P = 0.589, 0.394, and 0.394 at 4, 12, and 24 weeks, respectively). Contrarily, SWIFT-SNR was significantly higher in the TPTD group than in the non-TPTD group at 4 weeks after initiating treatment, but it was not significantly different at 12 and 24 weeks (P = 0.009, 0.937, and 0.818 at 4, 12, and 24 weeks, respectively). The bone formation rate assessed by histomorphometry was significantly higher in the TPTD group than in the non-TPTD group at all timepoints (P < 0.05, all weeks). In particular, at 4 weeks, the bone formation rate was markedly higher in the TPTD group than in the non-TPTD group (P = 0.028, 1.98 ± 0.33 vs. 0.09 ± 0.05 µm3/µm2/day). CONCLUSIONS: SWIFT could detect increased signals of bound water, reflecting the effect of TPTD on the cortical bone. The signal detected by SWIFT reflects a marked increase in the cortical bone formation rate.

Clinical trials of Cry j 1 and Cry j 2 T-cell epitope peptide-expressing rice in patients with Japanese cedar pollinosis.

BACKGROUND: In allergic models, administration of rice that expresses a hybrid peptide consisting of 7 major T cell epitopes of Cry j 1 and Cry j 2 (7Crp), suppressed allergic symptoms, IgE elevation and specific T cell response to Japanese cedar pollen. OBJECTIVE: To evaluate the efficacy and safety of 7Crp-expressing rice in patients with Japanese cedar pollinosis. METHODS: A 24-week randomized, double-blind, placebo-controlled study was performed to see the efficacy of 7Crp on allergic symptoms using scoring systems, in which 45 patients were assigned to take either 5 g, 20 g test rice, or placebo daily. A 96-week open study was also conducted to determine its inhibitory effect on serum IgE and T cell proliferative response for Japanese cedar pollen, in which 10 patients consumed 5 g test rice daily. RESULTS: No adverse events associated with the test rice occurred, and the intake rate was more than 96%. The test rice did not show suppression of symptoms related to Japanese cedar pollinosis within 24 weeks. However, intake of 5 g test rice led to a significant decrease in T cell response to Japanese cedar pollen during and after the second disperse season in a 96-week open trial, whereas the specific IgE titer remained unchanged. CONCLUSIONS: Tolerability and safety of 7Crp-expressing rice was accepted. Daily intake of up to 20 g transgenic rice did not provide beneficial effects on Japanese cedar pollinosis within 24 weeks, however, continuous intake of 5 g rice might reduce allergen specific T cell response.

[Hepatic MALT lymphoma associated with chronic hepatitis B in a patient on trial therapy of Entecavir and H. pylori eradication therapy - case report].

A 65-year-old woman with a history of chronic hepatitis B was referred to our hospital for the examination of abdominal lymphadenopathy and diffuse lesions in the liver. Endoscopic ultrasound-guided fine-needle aspiration biopsy and liver biopsy were performed, and mucosa-associated lymphoid tissue (MALT) lymphoma was found in both. Based on the results of various images, a diagnosis of primary hepatic MALT lymphoma, Ann Arbor classification stage IV was reached at. Entecavir administration, H. pylori eradication therapy, and chemotherapy were performed, and remission was induced. The tumor condition remained unchanged after H. pylori eradication therapy and Entecavir administration. Subsequently, she became symptomatic, so chemotherapy was performed, leading to remission. We herein report a case of hepatic MALT lymphoma associated with chronic hepatitis B.

GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease.

Parkinson's disease (PD) is characterized by dopaminergic (DA) cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant (dm) mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only dm mice showed a significant reduction in DA cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Dm mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while dm mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo.

Tip-in Endoscopic Mucosal Resection for 15- to 25-mm Colorectal Adenomas: A Single-Center, Randomized Controlled Trial (STAR Trial).

INTRODUCTION: One-piece endoscopic mucosal resection (EMR) for lesions >15 mm is still unsatisfactory, and attempted 1-piece EMR for lesions >25 mm can increase perforation risk. Therefore, modifications to ensure 1-piece EMR of 15- to 25-mm lesions would be beneficial. The aim of this study was to investigate whether Tip-in EMR, which anchors the snare tip within the submucosal layer, increases en bloc resection for 15- to 25-mm colorectal lesions compared with EMR. METHODS: In this prospective randomized controlled trial, patients with nonpolypoid colorectal neoplasms of 15-25 mm in size were recruited and randomly assigned in a 1:1 ratio to undergo Tip-in EMR or standard EMR, stratified by age, sex, tumor size category, and tumor location. The primary endpoint was the odds ratio of en bloc resection adjusted by location and size category. Adverse events and procedure time were also evaluated. RESULTS: We analyzed 41 lesions in the Tip-in EMR group and 41 lesions in the EMR group. En bloc resection was achieved in 37 (90.2%) patients undergoing Tip-in EMR and 30 (73.1%) who had EMR. The adjusted odds ratio of en bloc resection in Tip-in EMR vs EMR was 3.46 (95% confidence interval: 1.06-13.6, P = 0.040). The Tip-in EMR and EMR groups did not differ significantly in adverse event rates (0% vs 4.8%) or median procedure times (7 vs 5 minutes). DISCUSSION: In this single-center randomized controlled trial, we found that Tip-in EMR significantly improved the en bloc resection rate for nonpolypoid lesions 15-25 mm in size, with no increase in adverse events or procedure time.

Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, ß, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRß, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.

Novel metabolic system for lactic acid via LRPGC1/ERRγ signaling pathway.

Lactic acid (LA) is a byproduct of glycolysis resulting from intense exercise or a metabolic defect in aerobic processes. LA metabolism is essential to prevent lactic acidosis, but the mechanism through which LA regulates its own metabolism is largely unknown. Here, we identified a LA-responsive protein, named LRPGC1, which has a distinct role from PGC1α, a key metabolic regulator, and report that LRPGC1 particularly mediates LA response to activate liver LA metabolism. Following LA stimulation, LRPGC1, but not PGC1α, translocates from the cytoplasm to the nucleus through deactivation of nuclear export signals, interacts with the nuclear receptor ERRγ, and upregulates TFAM, which ensures mitochondrial biogenesis. Knockout of PGC1 gene in HepG2 hepatocarcinoma cells decreased the LA consumption and TFAM expression, which were rescued by LRPGC1 expression, but not by PGC1α. These LRPGC1-induced effects were mediated by ERRγ, concomitantly with mitochondrial activation. The response element for LRPGC1/ERRγ signaling pathway was identified in TFAM promoter. Notably, the survival rate of a mouse model of lactic acidosis was reduced by the liver-targeted silencing of Lrpgc1, while it was significantly ameliorated by the pharmacological activation of ERRγ. These findings demonstrate LA-responsive transactivation via LRPGC1 that highlight an intrinsic molecular mechanism for LA homeostasis.