Publications by authors named "Masaki Tanaka"

317 Publications

Efferent and Afferent Connections of Neuropeptide Y Neurons in the Nucleus Accumbens of Mice.

Front Neuroanat 2021 10;15:741868. Epub 2021 Sep 10.

Department of Anatomy and Neurobiology, Graduate School of Medical, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Neuropeptide Y (NPY) is a neural peptide distributed widely in the brain and has various functions in each region. We previously reported that NPY neurons in the nucleus accumbens (NAc) are involved in the regulation of anxiety behavior. Anterograde and retrograde tracing studies suggest that neurons in the NAc project to several areas, such as the lateral hypothalamus (LH) and ventral pallidum (VP), and receive afferent projections from the cortex, thalamus, and amygdala. However, the neural connections between accumbal NPY neurons and other brain areas in mice remain unclear. In this study, we sought to clarify these anatomical connections of NPY neurons in the NAc by investigating their neural outputs and inputs. To selectively map NPY neuronal efferents from the NAc, we injected Cre-dependent adeno-associated viruses (AAVs) into the NAc of NPY-Cre mice. This revealed that NAc NPY neurons exclusively projected to the LH. We confirmed this by injecting cholera toxin b subunit (CTb), a retrograde tracer, into the LH and found that approximately 7-10% of NPY neurons in the NAc were double-labeled for mCherry and CTb. Moreover, retrograde tracing using recombinant rabies virus (rRABV) also identified NAc NPY projections to the LH. Finally, we investigated monosynaptic input to the NPY neurons in the NAc using rRABV. We found that NPY neurons in the NAc received direct synaptic connections from the midline thalamic nuclei and posterior basomedial amygdala. These findings provide new insight into the neural networks of accumbal NPY neurons and should assist in elucidating their functional roles.
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http://dx.doi.org/10.3389/fnana.2021.741868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460764PMC
September 2021

Parallel cognitive processing streams in human prefrontal cortex: Parsing areal-level brain network for response inhibition.

Cell Rep 2021 Sep;36(12):109732

Department of Neurophysiology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Research Institute for Diseases of Old Age, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Sportology Center, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Advanced Research Institute for Health Science, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address:

Multiple cognitive processes are recruited to achieve adaptive behavior. However, it is poorly understood how such cognitive processes are implemented in temporal cascades of human cerebral cortical areas as processing streams to achieve behavior. In the present study, we identify cortical processing streams for response inhibition and examine relationships among the processing streams. Functional magnetic resonance imaging (MRI) and time-resolved single-pulse transcranial magnetic stimulation (TMS) reveal three distinct critical timings of transient disruption in the functionally essential cortical areas that belong to two distinct cerebrocortical networks. Furthermore, single-pulse TMS following suppression of the ventral posterior inferior frontal cortex (vpIFC) with repetitive TMS reveals information flow from the vpIFC to the presupplementary motor area (preSMA) within the same network but not to the dorsal posterior inferior frontal cortex (dpIFC) across different networks. These causal behavioral effects suggest two parallel processing streams (vpIFC-preSMA versus dpIFC-intraparietal sulcus) that act concurrently during response inhibition.
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http://dx.doi.org/10.1016/j.celrep.2021.109732DOI Listing
September 2021

Proposal of an apposite strategy-updating rule for the vaccination game where hubs refer to hubs and lower-degree agents refer to lower-degree agents.

Biosystems 2021 Nov 4;209:104532. Epub 2021 Sep 4.

Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga-shi, Fukuoka, 816-8580, Japan; Faculty of Engineering Sciences, Kyushu University, Japan. Electronic address:

In the vaccination game, the spread of disease and the human decision-making to obtain pre-emptive vaccinations are coordinately united in successive seasons. This is backed both by epidemiological models, such as SIR, and by evolutionary game theory, assuming a given strategy-updating rule. Several rules have been proposed by the community and rely on either the imitation concept or the switching-action concept. The latter directly stipulates whether or not an agent commits to a course of action based on a rule, such as the aspiration concept. In contrast, the former borrowed its fundamental idea from the spatial version of a two-player, two-strategy (2 × 2) game, such as the spatial prisoner's dilemma (SPD). The pairwise Fermi (PW-Fermi) strategy has been heavily employed as the most representative idea. The present study modifies PW-Fermi, which consists of two processes: one for selecting a pairwise opponent to imitate and the other giving the probability of copying from the opponent. Instead of a random selection, our proposed model applies a stochastically skewed selection in which a neighbor who has a similar degree to the focal player is preferentially selected. This specific rule allows us to establish a quite efficient society, in which hub agents spontaneously obtain vaccination, but lower-degree agents do not. To this end, a small number of higher-degree agents, who are exposed to higher infection risk, are urged to be vaccinated, whereas many other agents enjoy free-riding. This produces a relatively small vaccination cost as a social sum and also effectively suppresses the spread of disease, resulting in a small disease cost for society as a whole.
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http://dx.doi.org/10.1016/j.biosystems.2021.104532DOI Listing
November 2021

Healing Effect of Subcutaneous Administration of Granulocyte Colony-Stimulating Factor on Acute Rotator Cuff Injury in a Rat Model.

Tissue Eng Part A 2021 09 24;27(17-18):1205-1212. Epub 2021 Aug 24.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that mobilizes bone marrow-derived cells (BMDCs) to peripheral blood and has been clinically used to treat neutropenia. Previously, we reported that BMDCs migrated into the rotator cuff repair site via peripheral blood in the healing process. However, techniques to accelerate the healing process using the peripheral blood pathway have not been established. We evaluated whether G-CSF has a noteworthy effect on improving rotator cuff healing by enhancing the influx of BMDCs into the peripheral blood. We used Sprague-Dawley rats and chimeric rats, selectively expressing green fluorescent protein (GFP) in BMDCs. Their bilateral supraspinatus tendons were resected and sutured to the greater tuberosity of the humerus using the Masson-Allen technique, and G-CSF was subcutaneously injected for 5 days after surgery. Several GFP-positive cells were observed around the enthesis in the G-CSF-treated group compared with that in the Control group. Histological analysis revealed that the tendon-to-bone maturing scores and the Safranin O-stained cartilaginous areas were significantly higher in G-CSF-injected rats than in the control rats at weeks 4 and 8 after surgery. Consistently, the ultimate force to failure in the G-CSF-treated group significantly increased compared with the Control group at weeks 4 and 8 after surgery. These results suggest that BMDCs mobilized into the peripheral blood after G-CSF administration migrated to the rotator cuff repair area and effectively enhanced rotator cuff healing by promoting tenocyte and cartilage matrix production. In conclusion, the BMDC mobilization technique by G-CSF treatment via peripheral blood will provide a potential therapeutic approach for rotator cuff healing with clinically relevant applications. Impact statement As the retear rate following rotator cuff repair is high, new methods to aid its healing are required. Granulocyte colony-stimulating factor (G-CSF) has been used clinically and may represent a novel approach to treating rotator cuff tear. Herein, using a rat model, we elucidate the kinetics of bone marrow-derived mesenchymal stem cells at the repair site following G-CSF administration and describe the underlying mechanism by which G-CSF can help promote the repair of the rotator cuff.
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http://dx.doi.org/10.1089/ten.tea.2020.0239.ADOI Listing
September 2021

The Role of Neuropeptide Y in the Nucleus Accumbens.

Int J Mol Sci 2021 Jul 7;22(14). Epub 2021 Jul 7.

Department of Basic Geriatrics, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan.

Neuropeptide Y (NPY), an abundant peptide in the central nervous system, is expressed in neurons of various regions throughout the brain. The physiological and behavioral effects of NPY are mainly mediated through Y1, Y2, and Y5 receptor subtypes, which are expressed in regions regulating food intake, fear and anxiety, learning and memory, depression, and posttraumatic stress. In particular, the nucleus accumbens (NAc) has one of the highest NPY concentrations in the brain. In this review, we summarize the role of NPY in the NAc. NPY is expressed principally in medium-sized aspiny neurons, and numerous NPY immunoreactive fibers are observed in the NAc. Alterations in NPY expression under certain conditions through intra-NAc injections of NPY or receptor agonists/antagonists revealed NPY to be involved in the characteristic functions of the NAc, such as alcohol intake and drug addiction. In addition, control of mesolimbic dopaminergic release via NPY receptors may take part in these functions. NPY in the NAc also participates in fat intake and emotional behavior. Accumbal NPY neurons and fibers may exert physiological and pathophysiological actions partly through neuroendocrine mechanisms and the autonomic nervous system.
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http://dx.doi.org/10.3390/ijms22147287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307209PMC
July 2021

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

Histochem Cell Biol 2021 Sep 15;156(3):239-251. Epub 2021 Jun 15.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, β, 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 ERRβ, 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.
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http://dx.doi.org/10.1007/s00418-021-01998-7DOI Listing
September 2021

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

Am J Gastroenterol 2021 07;116(7):1398-1405

Division of Endoscopy, Shizuoka Cancer Center, Nagaizumi-cho, Suntogun, Shizuoka, Japan.

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.
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http://dx.doi.org/10.14309/ajg.0000000000001320DOI Listing
July 2021

Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers.

Cancer Chemother Pharmacol 2021 Sep 24;88(3):393-402. Epub 2021 May 24.

Department of Medical Oncology, Tohoku University Hospital, Seiryo-machi 1-1, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Purpose: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer.

Methods: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations.

Results: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036).

Discussion: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug.

Trial Registration Number: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).
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http://dx.doi.org/10.1007/s00280-021-04277-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316169PMC
September 2021

[Pyogenic granuloma in small intestine associated with Cowden's disease in a patient with gastrointestinal bleeding:a case report].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(5):462-472

Department of Internal Medicine II, Shimane University.

A 57-year-old female with a history of Cowden's disease was referred to our hospital because of black stool, loss of consciousness, and severe anemia. Upper and lower gastrointestinal endoscopy findings could not confirm the source of hemorrhage. Capsule endoscopy (CE) of the small intestine showed an active exudative hemorrhagic site near the ileum, although a definitive diagnosis was difficult. In a double balloon enteroscopy examination, it was difficult to observe the entire small intestine due to adhesions and the responsible lesion could not be confirmed, even when ink spots were applied to the deepest observation points through the mouth and anus. Hemostasis spontaneously occurred, and then anemia occurred again approximately 1 month later and a second CE examination was performed including passage of an ink stick through the oral side, which revealed an exudative elevated polyp with erosion and a white moss appearance in the ileum. Partial ileal resection was performed and pyogenic granuloma of the small intestine was the diagnosis. We report here a case of pyogenic granuloma of the small intestine associated with Cowden's disease.
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http://dx.doi.org/10.11405/nisshoshi.118.462DOI Listing
May 2021

Free ticket, discount ticket or intermediate of the best of two worlds - Which subsidy policy is socially optimal to suppress the disease spreading?

J Theor Biol 2021 07 18;520:110682. Epub 2021 Mar 18.

Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga-shi, Fukuoka 816-8580, Japan; Faculty of Engineering Sciences, Kyushu University, Kasuga-koen, Kasuga-shi, Fukuoka 816-8580, Japan.

With the aid of the evolutionary vaccination game on a scale-free network, we design a new subsidy policy, named degree dependent subsidy, where cooperative agents get incentives according to their connectivity or degree. That is, agents, having a greater degree, receive a higher incentive, and vice versa. Here we presume that vaccinators are cooperative agents. The new scheme can be said to an intermediate policy between two previously studies policies, namely free ticket and flat discount policies. The former policy distributes free tickets to cooperative hub agents as a priority, whereas the latter dispenses a fixed discount to every cooperator. We compare the efficiency of each policy in terms of having a less infectious state with a minimum social cost. While investigating the performance of the three policies in terms of average social payoff-which takes into account the cost of vaccination as well as infection-the free ticket scheme is found to be the most appealing policies among the three when the budget for subsidy is quite low. The degree dependent subsidy policy outperforms others for a moderate budget size, while the flat discount policy requires a higher budget to effectively suppress the disease. We further estimate threshold levels of the subsidy budget for each policy beyond which subsidizing results in excessive use of vaccination. As a whole, concerning vaccination coverage and final epidemic size, the degree-dependent subsidy scheme outperforms the flat discount scheme, but is dominated by the free ticket policy.
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http://dx.doi.org/10.1016/j.jtbi.2021.110682DOI Listing
July 2021

Spontaneous grouping of saccade timing in the presence of task-irrelevant objects.

PLoS One 2021 16;16(3):e0248530. Epub 2021 Mar 16.

Department of Physiology, Hokkaido University School of Medicine, Sapporo, Japan.

Sequential movements are often grouped into several chunks, as evidenced by the modulation of the timing of each elemental movement. Even during synchronized tapping with a metronome, we sometimes feel subjective accent for every few taps. To examine whether motor segmentation emerges during synchronized movements, we trained monkeys to generate a series of predictive saccades synchronized with visual stimuli which sequentially appeared for a fixed interval (400 or 600 ms) at six circularly arranged landmark locations. We found two types of motor segmentations that featured periodic modulation of saccade timing. First, the intersaccadic interval (ISI) depended on the target location and saccade direction, indicating that particular combinations of saccades were integrated into motor chunks. Second, when a task-irrelevant rectangular contour surrounding three landmarks ("inducer") was presented, the ISI significantly modulated depending on the relative target location to the inducer. All patterns of individual differences seen in monkeys were also observed in humans. Importantly, the effects of the inducer greatly decreased or disappeared when the animals were trained to generate only reactive saccades (latency >100 ms), indicating that the motor segmentation may depend on the internal rhythms. Thus, our results demonstrate two types of motor segmentation during synchronized movements: one is related to the hierarchical organization of sequential movements and the other is related to the spontaneous grouping of rhythmic events. This experimental paradigm can be used to investigate the underlying neural mechanism of temporal grouping during rhythm production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963089PMC
October 2021

Ketamine-Induced Alteration of Working Memory Utility during Oculomotor Foraging Task in Monkeys.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 6.

Department of Physiology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan

Impairments of working memory (WM) are commonly observed in a variety of neurodegenerative disorders but they are difficult to quantitatively assess in clinical cases. Recent studies in experimental animals have used low-dose ketamine (an NMDA receptor antagonist) to disrupt WM, partly mimicking the pathophysiology of schizophrenia. Here, we developed a novel behavioral paradigm to assess multiple components of WM and applied it to monkeys with and without ketamine administration. In an oculomotor foraging task, the animals were presented with 15 identical objects on the screen. One of the objects was associated with a liquid reward, and monkeys were trained to search for the target by generating sequential saccades under a time constraint. We assumed that the occurrence of recursive movements to the same object might reflect WM dysfunction. We constructed a "foraging model" that incorporated (1) memory capacity, (2) memory decay, and (3) utility rate; this model was able to explain more than 92% of the variations in behavioral data obtained from three monkeys. Following systemic administration of low dosages of ketamine, the memory capacity and utility rate were dramatically reduced by 15% and 57%, respectively, while memory decay remained largely unchanged. These results suggested that the behavioral deficits during the blockade of NMDA receptors were mostly due to the decreased usage of short-term memory. Our oculomotor paradigm and foraging model appear to be useful for quantifying multiple components of WM and could be applicable to clinical cases in future studies.
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http://dx.doi.org/10.1523/ENEURO.0403-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026253PMC
June 2021

Effects of Optogenetic Suppression of Cortical Input on Primate Thalamic Neuronal Activity during Goal-Directed Behavior.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Mar 23.

Department of Physiology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

The motor thalamus relays signals from subcortical structures to the motor cortical areas. Previous studies in songbirds and rodents suggest that cortical feedback inputs crucially contribute to the generation of movement-related activity in the motor thalamus. In primates, however, it remains uncertain whether the corticothalamic projections may play a role in shaping neuronal activity in the motor thalamus. Here, using an optogenetic inactivation technique with the viral vector system expressing halorhodopsin, we investigated the role of cortical input in modulating thalamic neuronal activity during goal-directed behavior. In particular, we assessed whether the suppression of signals originating from the supplementary eye field at the corticothalamic terminals could change the task-related neuronal modulation in the oculomotor thalamus in monkeys performing a self-initiated saccade task. We found that many thalamic neurons exhibited changes in their firing rates depending on saccade direction or task event, indicating that optical stimulation exerted task-specific effects on neuronal activity beyond the global changes in baseline activity. These results suggest that the corticothalamic projections might be actively involved in the signal processing necessary for goal-directed behavior. However, we also found that some thalamic neurons exhibited overall, non-task-specific changes in the firing rate during optical stimulation, even in control animals without vector injections. The stimulation effects in these animals started with longer latency, implying a possible thermal effect on neuronal activity. Thus, our results not only reveal the importance of direct cortical input in neuronal activity in the primate motor thalamus, but also provide useful information for future optogenetic studies.
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http://dx.doi.org/10.1523/ENEURO.0511-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009665PMC
June 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

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

J Neurosci 2021 03 15;41(9):1917-1927. Epub 2021 Jan 15.

Department of Physiology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan

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. 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.
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http://dx.doi.org/10.1523/JNEUROSCI.2151-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939086PMC
March 2021

Highly Efficient Near-Infrared Electrofluorescence from a Thermally Activated Delayed Fluorescence Molecule.

Angew Chem Int Ed Engl 2021 Apr 3;60(15):8477-8482. Epub 2021 Mar 3.

Center for Organic Photonics and Electronics Research (OPERA) and Department of Applied Chemistry, Kyushu University, 744 Motooka, Nishi, Fukuoka, 819-0395, Japan.

Near-IR organic light-emitting diodes (NIR-OLEDs) are potential light-sources for various sensing applications as OLEDs have unique features such as ultra-flexibility and low-cost fabrication. However, the low external electroluminescence (EL) quantum efficiency (EQE) of NIR-OLEDs is a critical obstacle for potential applications. Here, we demonstrate a highly efficient NIR emitter with thermally activated delayed fluorescence (TADF) and its application to NIR-OLEDs. The NIR-TADF emitter, TPA-PZTCN, has a high photoluminescence quantum yield of over 40 % with a peak wavelength at 729 nm even in a highly doped co-deposited film. The EL peak wavelength of the NIR-OLED is 734 nm with an EQE of 13.4 %, unprecedented among rare-metal-free NIR-OLEDs in this spectral range. TPA-PZTCN can sensitize a deeper NIR fluorophore to achieve a peak wavelength of approximately 900 nm, resulting in an EQE of over 1 % in a TADF-sensitized NIR-OLED with high operational device durability (LT >600 h.).
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http://dx.doi.org/10.1002/anie.202016089DOI Listing
April 2021

Precise Exciton Management of Quaternary Emission Layers for Highly Stable Organic Light-Emitting Diodes Based on Thermally Activated Delayed Fluorescence.

ACS Appl Mater Interfaces 2020 Nov 25;12(45):50668-50674. Epub 2020 Oct 25.

Center for Organic Photonics and Electronics Research (OPERA), Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.

Simultaneous achievement of both high electroluminescence efficiency and high operational stability in organic light-emitting diodes (OLEDs) is required for their use in various practical applications. Although OLEDs based on thermally activated delayed fluorescence-assisted fluorescence (TAF) are considered to possess a promising device architecture to exploit the full potential of OLEDs, the operational stability of such systems still requires further improvement. In this study, a quaternary emission layer consisting of a combination of TAF and mixed-host systems is developed. OLEDs containing this emission layer show improved operational stability through the management of exciton generation processes while maintaining high electroluminescence efficiency. Furthermore, a gradient of the mixed ratio of the co-host matrix is used to optimize the recombination zone profile in the emission layer, leading to 17 times improvement of the operational lifetime compared with that of the corresponding single-host-based device. This research provides a simple and general method to develop highly stable TAF-OLEDs.
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http://dx.doi.org/10.1021/acsami.0c15208DOI Listing
November 2020

Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance.

Diabetes Res Clin Pract 2020 Nov 22;169:108461. Epub 2020 Sep 22.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan. Electronic address:

Aims: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants.

Methods: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data.

Results: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance.

Conclusions: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.
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http://dx.doi.org/10.1016/j.diabres.2020.108461DOI Listing
November 2020

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Brain Commun 2020 14;2(1):fcz048. Epub 2020 Jan 14.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation ( = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425345PMC
January 2020

Ubiquitin, Autophagy and Neurodegenerative Diseases.

Cells 2020 09 2;9(9). Epub 2020 Sep 2.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Ubiquitin signals play various roles in proteolytic and non-proteolytic functions. Ubiquitin signals are recognized as targets of the ubiquitin-proteasome system and the autophagy-lysosome pathway. In autophagy, ubiquitin signals are required for selective incorporation of cargoes, such as proteins, organelles, and microbial invaders, into autophagosomes. Autophagy receptors possessing an LC3-binding domain and a ubiquitin binding domain are involved in this process. Autophagy activity can decline as a result of genetic variation, aging, or lifestyle, resulting in the onset of various neurodegenerative diseases. This review summarizes the selective autophagy of neurodegenerative disease-associated protein aggregates via autophagy receptors and discusses its therapeutic application for neurodegenerative diseases.
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http://dx.doi.org/10.3390/cells9092022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563958PMC
September 2020

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

FASEB J 2020 10 26;34(10):13239-13256. Epub 2020 Aug 26.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1096/fj.202000492RDOI Listing
October 2020

Novel Tetrafunctional Probes Identify Target Receptors and Binding Sites of Small-Molecule Drugs from Living Systems.

ACS Chem Biol 2020 09 20;15(9):2364-2373. Epub 2020 Aug 20.

Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima 771-0192, Japan.

Significant advancement of chemoproteomics has contributed to uncovering the mechanism of action (MoA) of small-molecule drugs by characterizing drug-protein interactions in living systems. However, cell-membrane proteins such as G protein-coupled receptors (GPCRs) and ion channels, due to their low abundance and unique biophysical properties associated with multiple transmembrane domains, can present challenges for proteome-wide mapping of drug-receptor interactions. Herein, we describe the development of novel tetrafunctional probes, consisting of (1) a ligand of interest, (2) 2-aryl-5-carboxytetrazole (ACT) as a photoreactive group, (3) a hydrazine-labile cleavable linker, and (4) biotin for enrichment. In live cell labeling studies, we demonstrated that the ACT-based probe showed superior reactivity and selectivity for labeling on-target GPCR by mass spectrometry analysis compared with control probes including diazirine-based probes. By leveraging ACT-based cleavable probes, we further identified a set of representative ionotropic receptors, targeted by CNS drugs, with remarkable selectivity and precise binding site information from mouse brain slices. We anticipate that the robust chemoproteomic platform using the ACT-based cleavable probe coupled with phenotypic screening should promote identification of pharmacologically relevant target receptors of drug candidates and ultimately development of first-in-class drugs with novel MoA.
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http://dx.doi.org/10.1021/acschembio.0c00335DOI Listing
September 2020

Connectivity-based localization of human hypothalamic nuclei in functional images of standard voxel size.

Neuroimage 2020 11 29;221:117205. Epub 2020 Jul 29.

Department of Neurophysiology, Juntendo University School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Age, Juntendo University School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University School of Medicine, Tokyo, Japan; Advanced Research Institute for Health Science, Juntendo University School of Medicine, Tokyo, Japan. Electronic address:

Despite their critical roles in autonomic functions, individual hypothalamic nuclei have not been extensively investigated in humans using functional magnetic resonance imaging, partly due to the difficulty in resolving individual nuclei contained in the small structure of the hypothalamus. Areal parcellation analyses enable discrimination of individual hypothalamic nuclei but require a higher spatial resolution, which necessitates long scanning time or large amounts of data to compensate for the low signal-to-noise ratio in 3T or 1.5T scanners. In this study, we present analytic procedures to estimate likely locations of individual nuclei in the standard 2-mm resolution based on our higher resolution dataset. The spatial profiles of functional connectivity with the cerebral cortex for each nucleus in the medial hypothalamus were calculated using our higher resolution dataset. Voxels in the hypothalamus in standard resolution images from the Human Connectome Project (HCP) database that predominantly shared connectivity profiles with the same nucleus were subsequently identified. Voxels representing individual nuclei, as identified with the analytic procedures, were reproducible across 20 HCP datasets of 20 subjects each. Furthermore, the identified voxels were spatially separate. These results suggest that these analytic procedures are capable of refining voxels that represent individual hypothalamic nuclei in standard resolution. Our results highlight the potential utility of these procedures in various settings such as patient studies, where lengthy scans are infeasible.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117205DOI Listing
November 2020

Functional Organization for Response Inhibition in the Right Inferior Frontal Cortex of Individual Human Brains.

Cereb Cortex 2020 11;30(12):6325-6335

Department of Neurophysiology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.

The right inferior frontal cortex (IFC) is critical to response inhibition. The right IFC referred in the human studies of response inhibition is located in the posterior part of the inferior frontal gyrus and the surrounding regions and consists of multiple areas that implement distinct functions. Recent studies using resting-state functional connectivity have parcellated the cerebral cortex and revealed across-subject variability of parcel-based cerebrocortical networks. However, how the right IFC of individual brains is functionally organized and what functional properties the IFC parcels possess regarding response inhibition remain elusive. In the present functional magnetic resonance imaging study, precision functional mapping of individual human brains was adopted to the parcels in the right IFC to evaluate their functional properties related to response inhibition. The right IFC consisted of six modules or subsets of subregions, and the spatial organization of the modules varied considerably across subjects. Each module revealed unique characteristics of brain activity and its correlation to behavior related to response inhibition. These results provide updated functional features of the IFC and demonstrate the importance of individual-focused approaches in studying response inhibition in the right IFC.
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http://dx.doi.org/10.1093/cercor/bhaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609925PMC
November 2020

Dissociable Networks of the Lateral/Medial Mammillary Body in the Human Brain.

Front Hum Neurosci 2020 18;14:228. Epub 2020 Jun 18.

Department of Neurophysiology, Juntendo University School of Medicine, Tokyo, Japan.

The mammillary body (MB) has been thought to implement mnemonic functions. Although recent animal studies have revealed dissociable roles of the lateral and medial parts of the MB, the dissociable roles of the lateral/medial MB in the human brain is still unclear. Functional connectivity using resting-state functional magnetic resonance imaging (fMRI) provides a unique opportunity to noninvasively inspect the intricate functional organization of the human MB with a high degree of spatial resolution. The present study divided the human MB into lateral and medial parts and examined their functional connectivity with the hippocampal formation, tegmental nuclei, and anterior thalamus. The subiculum of the hippocampal formation was more strongly connected with the medial part than with the lateral part of the MB, whereas the pre/parasubiculum was more strongly connected with the lateral part than with the medial part of the MB. The dorsal tegmental nucleus was connected more strongly with the lateral part of the MB, whereas the ventral tegmental nucleus showed an opposite pattern. The anterior thalamus was connected more strongly with the medial part of the MB. These results confirm the extant animal literature on the lateral/medial MB and provide evidence on the parallel but dissociable systems involving the MB that ascribe mnemonic and spatial-navigation functions to the medial and lateral MBs, respectively.
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http://dx.doi.org/10.3389/fnhum.2020.00228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316159PMC
June 2020

Initial Computed Tomography Findings of Long and Distended Colon Are Risk Factors for the Recurrence of Sigmoid Volvulus.

Dig Dis Sci 2021 04 14;66(4):1162-1167. Epub 2020 May 14.

Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Japan.

Background: Sigmoid volvulus is a common condition in elderly patients with elongated colons. Although endoscopic de-torsion is effective as the primary treatment of sigmoid volvulus, elective surgery is recommended because of the high risk of recurrence and high mortality rate.

Aim: The aim of this study was to determine the risk factors for the recurrence of sigmoid volvulus.

Methods: Clinical records of patients treated at Shimane Prefectural Central Hospital were reviewed retrospectively. Among 41 sigmoid volvulus patients who were successfully treated by endoscopic de-torsion and followed up, 30 were observed over 1 year. Among the 30 patients, eight (26.7%) did not experience recurrence, while 22 (73.3%) did. Initial computed tomography (CT) findings indicating the sigmoid colon extending to the diaphragm or ventral to the liver were defined as "extension findings." Extension findings and sigmoid diameter were evaluated in relation to sigmoid volvulus recurrence.

Results: Extension findings were significantly more frequent in the recurrent group (77.3%) than in the nonrecurrent group (25.0%) (P = 0.009). Distended sigmoid colon diameter was significantly larger in the recurrent group (11.7 ± 3.8 cm) than in the nonrecurrent group (7.1 ± 1.1 cm) (P = 0.044). Receiver operating characteristic curve analysis demonstrated that the performance threshold was greater than 8.9 cm. Kaplan-Meier analysis showed the significantly high sigmoid volvulus recurrence rate in the patients with extension findings and a distended sigmoid colon greater than 8.9 cm.

Conclusions: CT findings of a long and distended sigmoid colon in initial sigmoid volvulus are risk factors for the recurrence of sigmoid volvulus.
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http://dx.doi.org/10.1007/s10620-020-06317-zDOI Listing
April 2021

Roles of the Cerebellum in Motor Preparation and Prediction of Timing.

Neuroscience 2021 05 30;462:220-234. Epub 2020 Apr 30.

Department of Physiology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

The cerebellum is thought to have a variety of functions because it developed with the evolution of the cerebrum and connects with different areas in the frontoparietal cortices. Like neurons in the cerebral cortex, those in the cerebellum also exhibit strong activity during planning in addition to the execution of movements. However, their specific roles remain elusive. In this article, we review recent findings focusing on preparatory activities found in the primate deep cerebellar nuclei during tasks requiring deliberate motor control and temporal prediction. Neurons in the cerebellum are active during anti-saccade preparation and their inactivation impairs proactive inhibitory control for saccades. Experiments using a self-timing task show that there are mechanisms for tracking elapsed time and regulating trial-by-trial variation in timing, and that the cerebellum is involved in the latter. When predicting the timing of periodic events, the cerebellum provides more accurate temporal information than the striatum. During a recently developed synchronized eye movement task, cerebellar nuclear neurons exhibited periodic preparatory activity for predictive synchronization. In all cases, the cerebellum generated preparatory activity lasting for several hundred milliseconds. These signals may regulate neuronal activity in the cerebral cortex that adjusts movement timing and predicts the timing of rhythmic events.
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http://dx.doi.org/10.1016/j.neuroscience.2020.04.039DOI Listing
May 2021

Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.

Biomed Chromatogr 2020 Aug 22;34(8):e4853. Epub 2020 May 22.

Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.
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http://dx.doi.org/10.1002/bmc.4853DOI Listing
August 2020
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