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Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival. Editor's summary: Neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2) are pediatric neurodegenerative disorders caused by loss-of-function mutations in PPT1 and TPP1, respectively. Although gastrointestinal problems are common for both forms of neuronal ceroid lipofuscinosis (NCL), it has been unclear how the enteric nervous system is affected by the disease. Here, Ziółkowska et al. report diminished bowel function in mouse models of CLN1 and CLN2. The enteric nervous system developed normally in these mice but degenerated subsequently. Viral-mediated delivery of PPT1 or TPP1 to neonatal mice could reduce neurodegeneration, ameliorate bowel function, and extend survival. These results highlight the importance of the enteric nervous system in the NCLs. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

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. Key words: bumblebee, germination, inbreeding depression, rhododendron, seed. Afin de comprendre l'ecologie de la reproduction d'especes vegetales dont les systemes de reproduction sont a la fois endogames et par croisements eloignes, il est important de savoir comment les individus endogames contribuent au maintien d'une population. De plus, l'examen de l'ampleur de la depression de consanguinite apres la pollinisation est essentiel pour mesurer precisement le succes de la reproduction. Dans cette etude, les auteurs ont examine les caracteristiques des graines et des plantules viables de Rhododendron kaempferi Planch. dans une region ou le bourdon pollinisateur Bombus ardens Smith, 1879 est abondant. Lors d'une experience de pollinisation manuelle, la nouaison issue de l'autopollinisation etait de 32 %, soit nettement moins que celle issue de la pollinisation croisee (81 %). Le nombre de graines par fruit provenant de l'autopollinisation etait un sixieme de celui provenant de la pollinisation croisee. Cependant, le nombre de graines par fruit etait correle negativement avec le poids par graine. Par ailleurs, le taux de germination etait faible lorsque le poids des graines etait leger. Bien que les graines endogames aient pu germer, 89 % des plantules mouraient au cours de la premiere annee. Le coefficient de depression de consanguinite un an apres le semis etait tres eleve (0,89). Ces resultats indiquent que R. kaempferi presente une selection extremement forte pour les croisements eloignes, mais maintient un leger potentiel d'autofecondation dans une population naturelle du centre du Japon. [Traduit par la Redaction] Mots-cles : bourdon, germination, depression de consanguinite, rhododendron, graine., Introduction Inbreeding depression, defined as the reduction in fitness of progeny derived from inbreeding relative to that of progeny derived from outcrossing, has long been an important topic in the [...]

Introduction The neuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative lysosomal storage disorders affecting children and young adults (1). Classic late infantile NCL, or CLN2 disease, is one of [...], 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 [Cln2.sup.R207X] 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 [Cln2.sup.R207X] 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.

Plant reproduction is often inhibited by herbivorous leaf damage, which affects the resource pool allocated for reproduction. Rhododendron kaempferi var. kaempferi is a semi‐evergreen shrub widely distributed in Japan, and its leaves are occasionally damaged by sawfly larvae (Arge similis). This species is partially self‐compatible, but its selfed seedlings suffer from inbreeding depression. Our study aimed to clarify (1) the magnitude of herbivorous damage under natural conditions, (2) the effects of foliage damage on seed number and mass, and (3) the possibility of selective abortion of selfed seeds to maintain outcrossed seed production under resource limitation. In the 2022 survey, 2 of the 20 ramets observed were collectively parasitized by sawfly larvae, and the most damaged ramet had a 59.6% foliage loss. In contrast, the herbivorous damage in 2023 was consistently low throughout the growing season, averaging a 3.2% loss. Leaf excision reduced the seed number per fruit (i.e., low seed‐set rate) but did not affect the individual seed mass. The outcrossing rate of the excision treatment (81.7%) was significantly higher than that of the control (72.0%). The values of seed‐set rate × outcrossing rate were 0.172 for the excision treatment and 0.171 for the control, nearly equal. Our results indicated that (1) sawfly larvae damage was concentrated on a few specific plants, (2) intense foliage damage reduced seed number but not seed mass, and (3) R. kaempferi mitigated the decline in outcrossed seed production by the abortion of selfed seeds when leaves were intensively damaged. [ABSTRACT FROM AUTHOR]

Introduction In contrast to other monogenic causes of neurodegeneration such as mitochondrial and peroxisomal disease (1, 2), the majority of fatal lysosomal storage disorders (LSDs) are caused by a deficiency [...], 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 palmitoylprotein 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.sup.-/-]) and CLN1rr15x sheep to assess how to potentially scale up for translation. In [Cln1.sup.-/-]mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In [CLN1.sup.R151X] 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.

Buergeria buergeri is a stream-breeding rhacophorid frog. The sexual dimorphism in body size is significant in this species, which might be advantageous for its movement within the stream in an amplected state. However, the fertilisation rate of egg masses decreases as the body size difference between both sexes in the amplectant pair increases because the distance between the cloacae increases. In this study, we examined the mating pattern of B. buergeri and the relationship between female/male SVL ratio in the amplectant pair and fertilisation rate, and the swimming ability within the stream. As a result, when the female/male SVL ratio was less than 1.45, the fertilisation rate reached a plateau (nearly 100%). However, the fertilisation rate decreased as the female/male SVL ratio increased when this ratio was greater than 1.45. Moreover, a significant positive correlation was observed between the female/male SVL ratio and swimming ability. These results suggest that there was a trade-off between fertilisation rate and swimming ability via the female/male SVL ratio. In the field, we observed a significant positive correlation between male and female SVLs in 16 amplectant pairs, with a mean female/male SVL ratio of 1.44. Our experimental results suggest that when the female/male SVL ratio is 1.44, the fertilisation rate is close to 100%, and the swimming ability can be maintained at an intermediate level. Therefore, B. buergeri adopts a size-assortative mating and maintains the female/male SVL ratio of approximately 1.44 to balance both fertilisation rate and swimming ability, thereby increasing reproductive success. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The etiology of Bednar's aphthae remains unclear. Our aim was to investigate the incidence of, and factors associated with, Bednar's aphthae in a Japanese newborn cohort. Methods: A retrospective cross‐sectional study was conducted on neonates discharged from the well‐baby nursery at Saitama City Hospital, Japan. The principal investigator carefully examined each neonate's oral cavity, up to and including the pharynx, with a light‐emitting diode (LED) headlight to determine the presence of Bednar's aphthae. Maternal and neonatal clinical characteristics were first compared between neonates with and those without Bednar's aphthae by univariate analysis. Variables with significant inter‐group differences upon univariate analysis were entered into a multivariable logistic‐regression model. Results: This study enrolled 1996 infants. We observed Bednar's aphthae in 9.3% of the Japanese newborn infants who were included. When restricted to infants who were born via vaginal delivery, 13.2% of them had aphthae. Multivariable logistic regression analysis identified vaginal delivery (odds ratio = 6.19, p < 0.0001) in Model 1, and vaginal delivery (odds ratio = 6.73, p < 0.0001) and birth weight (odds ratio = 0.9995, p = 0.034) in Model 2 as independent risk factors for the disease. Conclusion: This is the first report of the prevalence of Bednar's aphthae among Japanese neonates. Vaginal delivery was identified as the strongest risk factor. Although confounding between mode of delivery and mechanical stimuli associated with sucking was not found in this study, the findings pave the way for a better understanding of the etiology of Bednar's aphthae. [ABSTRACT FROM AUTHOR]