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Background and aims: Children with neurodegenerative disease often have debilitating gastrointestinal (GI) symptoms that may be due at least in part to underappreciated involvement of neurons in the enteric nervous system (ENS), the master regulator of bowel function. Methods: We investigated bowel motility in mouse models of CLN1 and CLN2 disease, neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 (PPT1) and tripeptidyl peptidase-1 (TPP1), respectively. We then explored the integrity of ENS anatomy in immunostained bowel wholemount preparations from these mice. Lastly, we administered adeno-associated viral gene therapy to neonatal mice and determined if this would prevent these newly identified bowel phenotypes. Results: Mouse models of CLN1 and CLN2 disease both displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Neonatal administration of adeno-associated virus-mediated gene therapy prevented bowel transit defects and the loss of many ENS neurons. Conclusions: We show that two neurodegenerative lysosomal storage diseases cause profound and progressive damage to the mouse enteric nervous system and impair bowel motility. We also provide proof-of-principle evidence that gene therapy can prevent enteric nervous system disease. This study may have general therapeutic implications for many inherited neurodegenerative disorders.

To understand the reproductive ecology of a plant species with both selfing and outcrossing reproductive systems, it is important to know how selfed individuals contribute to the maintenance of a population. Further, examination of the magnitude of inbreeding depression after pollination is essential for the accurate measurement of reproductive success. In this study, we investigated the characteristics of viable seeds and seedlings of Rhododendron kaempferi Planch. in a region where the bumblebee pollinator Bombus ardens Smith, 1879 are abundant. In a hand-pollination experiment, the fruit set from self-pollination was 32%, significantly lower than that from outcross-pollination (81%). The number of seeds per fruit from self-pollination was one sixth the number from outcross-pollination. However, the number of seeds per fruit was negatively correlated with the mass per seed. In addition, the germination rate was low when the seed mass was light. Although selfed seeds could germinate, 89% of the seedlings died within a year. The inbreeding depression coefficient one year after sowing was very high (0.89). These results indicate that R. kaempferi shows extremely strong selection for outcrossing but maintains a slight selfing potential in a natural population in central Japan.

Sanfilippo D syndrome (mucopolysaccharidosis type IIID) is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulfatase (GNS). A mouse model was generated by constitutive knockout of the Gns gene. We studied affected mice and controls at 12, 24, 36, and 48 weeks of age for neuropathological markers of disease in the somatosensory cortex, primary motor cortex, ventral posterior nuclei of the thalamus, striatum, hippocampus, and lateral and medial entorhinal cortex. We found significantly increased immunostaining for glial fibrillary associated protein (GFAP), CD68 (a marker of activated microglia), and lysosomal-associated membrane protein-1 (LAMP-1) in Sanfilippo D mice compared to controls at 12 weeks of age in all brain regions. Intergroup differences were marked for GFAP and CD68 staining, with levels in Sanfilippo D mice consistently above controls at all age groups. Intergroup differences in LAMP-1 staining were more pronounced in 12- and 24-week age groups compared to 36- and 48-week groups, as control animals showed some LAMP-1 staining at later timepoints in some brain regions. We also evaluated the somatosensory cortex, medial entorhinal cortex, reticular nucleus of the thalamus, medial amygdala, and hippocampal hilus for subunit c of mitochondrial ATP synthase (SCMAS). We found a progressive accumulation of SCMAS in most brain regions of Sanfilippo D mice compared to controls by 24 weeks of age. Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease pathogenesis and designing preclinical studies to test brain-directed treatments.

The 13th Symposium on Polar Science/Ordinary sessions [OB] Polar biology, Wed. 16 Nov.

The 13th Symposium on Polar Science/Ordinary sessions [OB] Polar biology, Wed. 16 Nov.

The 13th Symposium on Polar Science/Ordinary sessions [OB] Polar biology, Wed. 16 Nov.

Host–guest assemblies of a designed 1,4-bis(diarylamino)naphthalene and V-shaped aromatic amphiphiles consisting of two pentamethylbenzene moieties bridged by an m-phenylene unit bearing two hydrophilic side chains emerged as highly reducing photoredox catalysis systems in water. An efficient demethoxylative hydrogen transfer of Weinreb amides has been developed. The present supramolecular strategy permits facile tuning of visible-light photoredox catalysis in water.

We present systematic theoretical results on thermoelectric effects in semimetals based on the variational method of the linearized Boltzmann equation. Inelastic electron-hole scattering is known to play an important role in the unusual transport of semimetals, including the broad $T^2$ temperature dependence of the electrical resistivity and the strong violation of the Wiedemann-Franz law. By treating the inelastic electron-hole scattering more precisely beyond the relaxation time approximation, we show that the Seebeck coefficient when compensated depends on the screening length of the Coulomb interaction as well as the Lorenz ratio (the ratio of thermal to electric conductivity due to electrons divided by temperature). It is found that deviations from the compensation condition significantly increase the Seebeck coefficient, along with crucial suppressions of the Lorenz ratio. The result indicates that uncompensated semimetals with the electron-hole scattering have high thermoelectric efficiency when the phonon contribution to thermal conductivity is suppressed., 8 pages, 4 figures + Supplemental Material

Vitamin D seasonality has been reported in adults and children, suggesting that sunlight exposure has effects on 25(OH)D production. While vitamin D deficiency among infants has received significant attention, little is known about the extent to which vitamin D status during early infancy is affected by sunlight exposure. Here, we retrospectively analysed serum 25(OH)D levels of 692 samples obtained from healthy infants aged 1–2 months born at Saitama City Hospital, Japan (latitude 35·9° North) between August 2017 and September 2021. Data regarding the frequency of outdoor activities, formula intake and BMI were also collected and analysed. Month-to-month comparisons of vitamin D levels revealed significant variation in 25(OH)D levels in breastfed infants starting at 2 months, with maximal and minimal levels in September and January, respectively. An outdoor activity score of 0 was most common at 1 month (83·9 %) and a score of 3 was most common at 2 months (81·2 %), suggesting an increased amount of sunlight exposure at 2 months. Multiple linear regression analysis revealed the amount of formula intake to be significantly associated with vitamin D status at both 1 (t = 17·96) and 2 months (t = 16·30). Our results comprise the first evidence that seasonal variation of vitamin D begins at 2 months among breastfed infants from East Asia, though dietary intake appears to be the major determinant of vitamin D status. These findings provide new insights into the influence of dietary and non-dietary factors on vitamin D status during early infancy.

A strategy to improve running performance at the end of a triathlon (TR) is minimizing fatigue from the preceding exercise. However, little is known about decrease in TR compared to isolated running (IR) performance and the degree at which it changes. This study examined the decrease in TR performance compared with IR performance and the degree of change in the sprint triathlon competition results. We searched the web (http://www.jtu.or.jp/) for the official result times of certification competitive events from 2013 to 2016 of the Japan Triathlon Union and elite categories participating in the Asia Cup Osaka sprint triathlon from 2013 to 2016 of the International Triathlon Union. Data of 236 athletes who finished IR and TR in the same year were analyzed. The average time was significantly longer in TR than in IR and the effect size was large, regardless of competition years and sex (p < 0.01). The IR time variation (coefficient of variation) was 3.7?8.2%, while the rate of change in performance variation was 35.6?95.0%. The overall triathlon time and the rate of change in performance were significantly correlated (Speaman?rs = 0.47?0.76, p < 0.05). TR performance was lower than the IR performance and the degree varied widely among individuals. For elite triathletes who have homogeneous IR performance, a minimal decrease in TR compared to IR performance effectively increases sprint triathlon success.

A metal-free and operationally simple strategy for the generation of various α-monofluoroalkyl radicals has been developed. A combination of 1,4-bis(diarylamino)naphthalene photocatalyst and sulfoximine-based fluoroalkylating reagents is the key to success. The protocol can be applied to modular synthesis of β-monofluoroketones through radical monofluoroalkylation of alkenyl acetates.

Organic photoredox catalysis has become a useful tool for the development of metal-free radical reactions. Recently, we have reported that 1,4-bis(diphenylamino)naphthalene N serves as an efficient...

Mammals have circadian clocks, which consist of the central clock in the suprachiasmatic nucleus and the peripheral clocks in the peripheral tissues. The effect of exercise on phase of peripheral clocks have been reported in rodents but not in humans. Continuous sampling is necessary to assess the phase of the circadian rhythm of peripheral clock gene expressions. It has been assumed that the expression of the genes in leukocyte may be “an accessible window to the multiorgan transcriptome.” The present study aimed to examine whether exercise affects the level and phase of clock gene expression in human leukocytes. Eleven young men participated in three trials, in which they performed a single bout of exercise at 60% V̇o2max for 1 h beginning either at 0700 (morning exercise) or 1600 (afternoon exercise) or no exercise (control). Blood samples were collected at 0600, 0900, 1200, 1500, 1800, 2100, and 2300 and at 0600 the next morning, to assess diurnal changes of clock gene expression in leukocytes. Brain and muscle ARNT-like protein 1 ( Bmal1) expression level increased after morning and afternoon exercise, and Cryptochrome 1 ( Cry1) expression level increased after morning exercise. Compared with control trial, acrophase of Bmal1 expression tended to be earlier in morning exercise trial and later in afternoon exercise trial. Acrophase of Cry1 expression was earlier in morning exercise trial but not affected by afternoon exercise. Circadian locomotor output cycles kaput ( Clock), Period 1–3 ( Per1–3), and Cry2 expression levels and those acrophases were not affected by exercise. The present results suggest a potential role of a single bout of exercise to modify peripheral clocks in humans. NEW & NOTEWORTHY The present study showed that a single bout of exercise affected peripheral clock gene expression in human leukocytes and the effect of exercise depended on when it was performed. Brain and muscle ARNT-like protein 1 ( Bmal1) expression was increased after exercises performed in the morning and afternoon. Cryptochrome 1 ( Cry1) expression was also increased after the morning exercise. The effect of exercise on acrophase of Bmal1 depended on the time of the exercise: advanced after morning exercise and delayed after afternoon exercise.

AimsCLN2 disease is a fatal inherited childhood neurodegenerative disorder. Although a disease-modifying therapy now exists, a fundamental lack of understanding of disease pathogenesis has hampered development of more effective therapies. To better understand the cellular pathophysiology of CLN2 disease, we investigated the nature and progression of neuropathological and neurological changes in the recently generated Cln2R207X mouse.MethodsWe have detailed microglial activation, astrogliosis, cytokine and chemokine expression, and neuron loss across the forebrain and spinal cords of Cln2R207X mice, along with quantitative gait analysis. We also performed long-term electroencephalography (EEG) recordings to characterize seizure activity, a clinically-relevant phenotype yet to be defined in any CLN2 disease model.ResultsHistology revealed early localized microglial activation months before neuron loss in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. These pathological changes were more pronounced and occurred in the cortex before the thalamus or spinal cord. There were early-onset and progressive changes in the expression of specific chemokines and cytokines including IL-33, IP-10, and MIP-1α. Gait analysis revealed impaired performance only at disease end stage. EEG recordings revealed robust and progressive epileptiform activity from disease mid-stage including spontaneous seizures, which were accompanied by a profound loss of cortical GABAergic interneurons.ConclusionsOur data reveal novel phenotypes in Cln2R207X mice that differ markedly in their timing and progression through the CNS from other NCL mouse models. Our findings provide new insights on CLN2 disease pathogenesis and clinically-relevant readouts for future therapeutic studies.

Objectives Increased cardiorespiratory responses and changes in muscle activity and running kinematics occur in running after cycling compared with isolated running. Nevertheless, little is known about the causes of these changes. Cycling exercise decreases the stretch-shortening cycle (SSC) function, which can influence subsequent running. This study aimed to clarify whether the decrease in SSC function after cycling causes cardiorespiratory and biomechanical changes in subsequent running. Design Cross-sectional laboratory study. Participants were divided into two groups based on SSC function: an SSC dec group (those with decreased SSC function after cycling) and an SSC non-dec group (those without decreased SSC function after cycling). Methods Eighteen participants (10 triathletes and 8 runners) completed maximal aerobic tests for running and cycling. After these sessions, a submaximal run-cycle-run test was performed to compare between control run (no preceding cycle) and transition run (preceded by cycling). A jump test was administered before and after the submaximal cycling. SSC function was calculated as the ratio of the jump height to the time spent in contact with the ground (reactive strength index). Gas exchange measures, heart rate, and gait parameters were collected throughout the test. Results Oxygen uptake and ventilation were increased by cycling in the SSC dec group but not in the SSC non-dec group. In both groups, there were no significant differences in the gait parameters between control and transition runs. Conclusions The decrease in SSC function after cycling would increase cardiorespiratory responses in subsequent running.

The timing of exercise plays an important role in the effect of the exercise on physiological functions, such as substrate oxidation and circadian rhythm. Exercise exerts different effects on the glycemic response to exercise and meal intake depending on when the exercise performed. Here, we comprehensively investigated the effects of the timing (morning or afternoon) of exercise on glucose fluctuation on the basis of several indices: glycemic variability over 24 h (24‐h SD), J‐index, mean amplitude of glucose excursions (MAGE), continuous overall net glycemic action (CONGA), and detrended fluctuation analysis (DFA). Eleven young men participated in 3 trials in a repeated measures design in which they performed a single bout of exercise at 60% of their maximal oxygen uptake for 1 h beginning either at 7:00 (morning exercise), 16:00 (afternoon exercise), or no exercise (control). Glucose levels were measured using a continuous glucose monitoring system (CGMs). Glucose fluctuation was slightly less stable when exercise was performed in the afternoon than in the morning, indicated by higher CONGA at 2 h and α2 in DFA in the afternoon exercise trial than in the control trial. Additionally, decreased stability in glucose fluctuation in the afternoon exercise trial was supported by the descending values of the other glucose fluctuation indices in order from the afternoon exercise, morning exercise, and control trials. Meal tolerance following exercise was decreased after both exercise trials. Glucose levels during exercise were decreased only in the afternoon exercise trial, resulting in less stable glucose fluctuations over 24 h., Comprehensive analyses of multiple indices revealed that the effects of exercise on glucose fluctuation depends on the timing of the exercise. Glucose fluctuation was slightly less stable when exercise was performed in afternoon with higher insulin levels (red) than in morning with lower insulin levels (blue). The effect of differences in the timing of exercise on glucose fluctuation may be due to differences in glucose level changes during exercise.

Background: Personalized neoantigen-based therapies are being actively developed with several clinical trials currently ongoing. The standard methodology to identify patient specific neoantigens relies on computational algorithms for analyzing mutation, expression, and HLA profiles from patients’ NGS data. However, clinical reports have thus far showed that the number of actionable neoantigens was not as high as originally expected. One possible reason is due to a lack of appropriate prediction models, especially for immunogenicity, which is largely hindered by a scarcity of training data based on in vivo vaccination models. In addition, HLA allele status and/or impurity and heterogeneity in tumor samples are other factors affecting the selection efficiency. Methods: We have developed a computational pipeline to identify neoantigens from patients’ WES and RNA-Seq data. Our HLA assessment not only determines HLA types but also detects HLA LOH events from WES and down-regulation of HLA gene expression from RNA-Seq taking into account tumor purity. The neoantigen candidates were ranked based on a presentation score calculated by a regression model optimized with publicly available immunopeptidome data. We tested our top-ranked neoantigen peptides by immunizing them into HLA-A02:01, A24:02, B07:02, and B35:01-transgenic mice and performed ELISPOT to determine positive or negative in vivo immune responses. Furthermore, we trained a neural network to define an immunogenicity score based on the results from the transgenic mouse experiments. Results: We generated NGS data from over 100 clinical samples and analyzed the data using our computational pipeline. We observed a wide range in the tumor mutational burden and tumor purity of our samples, and HLA LOH was frequently observed. From 27 patient cases, 275 of HLA-A02:01-, A24:02-, B07:02-, or B35:01-predicted neoantigen epitopes were tested in transgenic mice and confirmed that the rate of positively reacted epitopes increased in a correlated manner to the presentation score, achieving 82% positive rate in top scored 35 epitopes and 47% in overall 275 epitopes. We further developed an immunogenicity prediction model and tested its performance in additional clinical samples. By integrating it into the selection criteria, we achieved higher positive rate than using the presentation score solely. Conclusions: We have developed a robust computational pipeline to identify putatively actionable neoantigens from patients’ WES and RNA-Seq data. We detected frequent HLA LOH events indicating that this is a common mechanism of immune evasion. We also showed the feasibility of improving prediction algorithms using HLA-transgenic mice. Accurate prediction performance enables us to decrease the number of vaccine antigens to be immunized per patient, leading to a decrease in the manufacturing cost and complexity in quality control. Citation Format: Kazushi Hiranuka, Keigo Takahashi, Dave Tang, Noriko Watanabe, Takashi Yamada, Yuji Mishima, Norihiro Fujinami, Manami Shimomura, Toshihiro Suzuki, Tetsuya Nakatsura, Norihiro Nakamura. A novel computational pipeline supported with in vivo vaccination models for identification and validation of neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6389.

Background: Screening-based intrapartum antibiotic prophylaxis (IAP) has reduced the prevalence of early-onset group B Streptococcus (GBS) infection in newborns. Nevertheless, early-onset disease still occurs despite IAP, and IAP is not effective in preventing late-onset disease. This study aimed to determine the prevalence and risk factors of GBS neonatal umbilical colonization managed by dry cord care in Japan. Methods: Of 735 healthy newborns in the well-baby nursery at Saitama City Hospital, 353 from whom umbilical bacterial swabs were obtained before discharge were included in the analysis. Maternal and neonatal clinical characteristics were retrospectively reviewed. Results: GBS was detected in 4.2% (15/353) of umbilical swabs; 13/15 (86.8%) were born to GBS-negative mothers. The median (IQR) age at umbilical swab collection was 4.0 (4.0–5.0) days. Comparison of clinical characteristics between GBS-positive and negative neonates revealed a significant difference in the proportion of vaginal deliveries (15/15 [100%] in GBS-positive neonates vs. 115/338 [34.0%] in GBS-negative neonates, p

The 11th Symposium on Polar Science/Ordinary sessions: [OB] Polar Biology, Poster presentations, Mon. 16 Nov. - Fri. 18 Dec.

Takahashi, K, Shirai, Y, and Nabekura, Y. Stretch-shortening cycle function of lower limbs after cycling in triathletes. J Strength Cond Res XX(X): 000-000, 2020-Impaired cardiorespiratory response and changes in biomechanical variables occur when running after cycling relative to isolated running. Nevertheless, little is known about the causes of these changes or the training to prevent them. This study aimed (a) to determine whether stretch-shortening cycle (SSC) function decreases after cycling exercise and (b) to determine whether the decreases in SSC function are related to brick training. Eleven male university triathletes performed hopping tests to measure SSC function before and after cycling (30 minutes of cycling at 110% ventilatory threshold). Stretch-shortening cycle function was calculated as the ratio of the jump height to the time spent in contact with the ground (reactive strength index [RSI]). Brick training was evaluated by the total experience of brick training. The RSI significantly decreased after the cycling exercise (-10.7%; p < 0.01), but changes in RSI after cycling did not significantly correlate with the total experience of brick training, despite a large effect size (p < 0.10; r = 0.62). These results suggest that SSC function decreases after cycling and that brick training is potentially useful for inhibiting decreases in SSC function after cycling.

Fuminori Takayama,1,2 Atsushi Aoyagi,3 Keigo Takahashi,2,3 Yoshiharu Nabekura1 1Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan; 2Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan; 3Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan Purpose: Individual variations in response of C-reactive protein (CRP) to acute strenuous exercise are less well known. The purpose of this study was to investigate the relationship between running economy and systemic inflammation following a marathon. Materials and methods: Sixteen college recreational runners participated in this study. To measure maximal oxygen uptake and running economy, the treadmill running test was performed 1–2 weeks before the marathon race. Running economy was defined as oxygen cost (mL/kg/km) at submaximal running. CRP and muscle damage markers (creatine kinase and lactate dehydrogenase) were measured before and 1, 2, and 3 days after the race. Results: All subjects completed the race in 4 hours 7 minutes 43 seconds±44 minute 29 seconds [mean±SD]. The marathon running significantly increased CRP and muscle damage markers. The levels of inflammation and muscle damage peaked after 1 day and remained high throughout the 3-day recovery period compared to that before the race. Spearman correlation analysis showed that the change in CRP level was significantly positively correlated with oxygen cost (r=0.619, P=0.011) but not maximal oxygen uptake. There was no significant relationship in responses between muscle damage markers and CRP. Conclusion: These findings suggest that running economy is related to postmarathon race CRP response. Further study to clarify the cause of the relationship and clinical significance of transient increase in CRP is necessary. Keywords: inflammation, oxygen consumption, C-reactive protein, muscle damage

A 73-year-old man presented with right lower back pain and dysuria. Right hydronephrosis and a large pelvic large mass were seen on computed tomography (CT). Although his prostate-specific antigen (PSA) was 0.5 ng/mL, an irregularly enlarged, stony, hard prostate was palpable on digital rectal examination. A prostate tumor was suspected, and a transrectal prostate biopsy and right transurethral ureteral stent placement were performed. Histological and immunohistochemical studies revealed diffuse large B-cell lymphoma. Positron emission tomography-computed tomography showed abnormal uptake in the stomach, cecum, right obturator lymph nodes, para-aortic lymph nodes, and dorsal left kidney. No abnormal findings were seen on bone marrow histology. Clinical stage IVA was confirmed according to Ann Arbor criteria. The patient achieved a complete response after 8 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone.