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Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Background: Several cut-off points for 25-hydroxyvitamin D (25(OH)D) levels have been proposed to determine vitamin D deficiency or insufficiency. However, the level for 25(OH)D deficiency in early infancy remains unclear. The serum 25(OH)D value at which parathyroid hormone level plateaus, called the “inflection point,” is considered the most appropriate criterion for defining an adequate vitamin D status. Methods: This was a single-center retrospective study involving 305 1-month-old and 252 2-month-old Japanese infants. Nonlinear segmented regression analysis was performed based on the correlation between 25(OH)D and parathyroid hormone levels to determine vitamin D deficiency cut-off points. Results: Inflection points were 7.90 ng/mL for 1-month-old (95% confidence interval, 6.31–9.49) and 6.74 ng/mL for 2-month-old (95% confidence interval, 5.80–7.68) Japanese infants, which were lower than previously reported. Cut-off values were also lower in the high-body mass index (BMI) group than in the low-BMI group for both 1-month and 2-month-old infants. Conclusion: These results imply the need for nutritional rickets prevention via policy recommendations in most full-term newborns in Japan. Although validation studies are required, these results can still be used to guide vitamin D insufficiency treatment options in early infancy.

Abstract Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1 −/−) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 −/− mice compared to normal animals. Cln1 −/− mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency.

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

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1–/–) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1–/– mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research.

Abstract 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.

In frogs, males generally use calls to attract conspecific females for breeding. Previous studies suggest that male frogs can effectively attract females by calling from an open environment, which has the advantages of avoiding the diminishing of their calls and increasing attractiveness to females by bimodal (acoustic + visual) signal. However, males calling from open sites, would be more easily detected by predators due to their exposed bodies. Male frogs may need to select a calling site that is suitable for environmental conditions to enhance their survival rate and mating success. In the present study, we examined the selection of calling sites by Pelophylax porosus porosus male, whose predators are mostly diurnal. As a results, P. p. porosus males tended to select vegetation-shaded water surfaces as daytime calling sites and select open water surfaces as night calling sites. Our results suggest that choice of calling sites by P. p. porosus males depends on whether it is daytime or night, because of differences in predation risk between daytime and night. The selection of a calling site suitable for each situation is expected to increase the fitness of the male frogs.

Examination of the efficacy of pollinators that are not morphologically matched to a flower’s shape can deepen our understanding of the main pollinators of a plant species. In central Japan, Rhododendron japonicum is visited much more frequently by bumblebees than by butterflies although its flower shape is more suited for pollination by large butterflies. Here, we observed flower-visiting behaviour of Bombus diversus queens and the alpine black swallowtail butterfly, Papilio maackii, and compared their efficacy as pollinators. Papilio maackii always touched the stigma during a flower visit, whereas B. diversus queens did so during just 54% of their flower visits. As bumblebees visit neighboring flowers of a R. japonicum tree in sequence not like Papilio maackii, we hypothesized that they deliver self pollen to R. japonicum so that the fruit set would be low. However, the fruit set in a bumblebee-dominated area was 72.5%, significantly higher than that by hand-pollination with self pollen (31.4%). This suggests that R. japonicum can obtain sufficient fruits by B. diversus queens although its flower shape morphologically matches to pollination by swallowtail butterflies.

Relationships between flower visitor composition and floral traits help us to understand floral evolution. Swallowtail butterflies have been assumed to be the main pollinators of Rhododendron kaempferi and R. japonicum based on their floral shapes, and R. kaempferi was reported to be pollinated by butterflies in southern Japan. In the mountains of central and northern Japan, however, bumblebees are abundant and candidate pollinators of Rhododendron. We found that visitation frequencies of bumblebees were higher than those of swallowtail butterflies to both of the Rhododendron species at three study sites in the mountains of central Japan. R. japonicum pollen adhered to the bodies of both floral visitors. Further, the nectar sugar concentration of R. kaempferi was in the preference range of bumblebees, whereas that of R. japonicum was suited to both bumblebees and butterflies. Taken together, these findings support the hypothesis that bumblebees are potentially also important pollinators of R. kaempferi and R. japonicum in mountains of central Japan, where they are more abundant than swallowtail butterflies.

Fejervarya kawamurai is naturally distributed in the western part of Honshu, Shikoku, Kyushu, and the Ryukyu Islands in Japan. In recent years, the ingression of F. kawamurai has been reported in the Kanto region, and there is concern about the impact of F. kawamurai on the ecosystem. Information on the life history of this invasive species is needed to control this invasive species and to conserve the ecosystems through methods such as eradication and the prevention of population expansion. In the present study, we captured F. kawamurai in paddy fields in Kanagawa Prefecture, and used body size composition method and observed their gonads to attempt to elucidate the life history of this domestic invasive species. The period when F. kawamurai was captured was from first half of April to second half of October, and the breeding season was from first half of May to first half of August. The immature F. kawamurai individuals of both sexes that had finished metamorphosis began to emerge in the first half of July, reaching the body size of mature frogs in August. Immature males matured immediately after overwintering, and immature females matured slightly later, in the first half of May. In addition, the number of mature individuals of both sexes decreased after the first half of July, and none were collected after the second half of August. These results suggest that the surveyed F. kawamurai populations comprised mostly individuals less than one year after metamorphosis. The rapid sexual maturation and alternation of generations of F. kawamurai are considered some of the predominant ecological factors enabling the successful establishment of this frog as a domestic invasive species. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The lipid cell variant of urethral carcinoma (UC) is rare and poorly understood clinicopathologically. A nodular tumor detected in the bladder of an 87-year-old man with asymptomatic gross hematuria was transurethrally resected, and high-grade UC, lipid cell variant, was diagnosed pathologically. The tumor cells resembled lipoblasts and contained numerous cytoplasmic vacuoles. Immunohistochemically, the tumor cells stained positive for the epithelial markers CK7, CK20, EMA, CAM5.2, and 34betaE12 and negative for vimentin and S100. Focal positivity for adipophilin was detected in cytoplasm but not in the vacuoles. These findings suggest that the patient had lipid-producing UC. [ABSTRACT FROM AUTHOR]

Fluoroalkyl end-capped N-(1,1-dimethyl-3-oxobutyl)acrylamide - acryloylmorpholine co-oligomers were prepared by the co-oligomerizations of fluoroalkanoyl peroxides with the corresponding monomers. These fluorinated co-oligomers exhibited a lower critical solution temperature (LCST) characteristic in aqueous solutions. Of particular interest, a steep time dependence of contact angle values for dodecane was observed from 40 to 60 °C to decrease their values, effectively, on the modified PMMA poly(methyl methacrylate) film surface treated with fluorinated co-oligomer possessing the LCST:  36 °C (in water), although such a steep time dependence was not observed from 20 to 30 °C. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]