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Abstract Vaginal birth causes pelvic floor injury which may lead to urinary incontinence. Cell therapy has been proposed to assist in functional recovery. We aim to assess if intra-arterial injection of rat mesoangioblasts (MABs) and stable Vascular Endothelial Growth Factor (VEGF)-expressing MABs, improve recovery of urethral and vaginal function following simulated vaginal delivery (SVD). Female rats (n = 86) were assigned to either injection of saline (control), allogeneic-MABs (MABsallo), autologous-MABs (MABsauto) or allogeneic-MABs transduced to stably expressed VEGF (MABsallo-VEGF). One hour after SVD, 0.5 × 106 MABs or saline were injected into the aorta. Primary outcome was urethral (7d and 14d) and vaginal (14d) function; others were bioluminescent imaging for cell tracking (1, 3 and 7d), morphometry (7, 14 and 60d) and mRNAseq (3 and 7d). All MABs injected rats had external urethral sphincter and vaginal function recovery within 14d, as compared to only half of saline controls. Functional recovery was paralleled by improved muscle regeneration and microvascularization. Recovery rate was not different between MABsallo and MABsauto. MABsallo-VEGF accelerated functional recovery and increased GAP-43 expression at 7d. At 3d we detected major transcriptional changes in the urethra of both MABsallo and MABsallo-VEGF-injected animals, with upregulation of Rho/GTPase activity, epigenetic factors and dendrite development. MABSallo also upregulated transcripts that encode proteins involved in myogenesis and downregulated pro-inflammatory processes. MABsallo-VEGF also upregulated transcripts that encode proteins involved in neuron development and downregulated genes involved in hypoxia and oxidative stress. At 7d, urethras of MABsallo-VEGF-injected rats showed downregulation of oxidative and inflammatory response compared to MABSallo. Intra-arterial injection of MABsallo-VEGF enhances neuromuscular regeneration induced by untransduced MABs and accelerates the functional urethral and vaginal recovery after SVD.

Abstract Global transcriptome studies demonstrated the existence of unique plant responses under combined stress which are otherwise not seen during individual stresses. In order to combat combined stress plants use signaling pathways and ‘cross talk’ mediated by hormones involved in stress and growth related processes. However, interactions among hormones’ pathways in combined stressed plants are not yet known. Here we studied dynamics of different hormones under individual and combined drought and pathogen infection in Arabidopsis thaliana by liquid chromatography-mass spectrometry (LC-MS) based profiling. Our results revealed abscisic acid (ABA) and salicylic acid (SA) as key regulators under individual drought and pathogen stress respectively. Under combined drought and host pathogen stress (DH) we observed non-induced levels of ABA with an upsurge in SA and jasmonic acid (JA) concentrations, underscoring their role in basal tolerance against host pathogen. Under a non-host pathogen interaction with drought (DNH) stressed plants, ABA, SA and JA profiles were similar to those under DH or non-host pathogen alone. We propose that plants use SA/JA dependent signaling during DH stress which antagonize ABA biosynthesis and signaling pathways during early stage of stress. The study provides insights into hormone modulation at different time points during combined stress.

Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data., (© 2023. Springer Nature Limited.)

Infants make spontaneous movements from the prenatal period. Several studies indicate that an atypical pattern of body motion during infancy could be utilized as an early biomarker of autism spectrum disorders (ASD). However, to date, little is known about whether the body motion pattern in neonates is associated with ASD risk. The present study sought to clarify this point by examining, in a longitudinal design, the link between features of spontaneous movement at about two days after birth and ASD risk evaluated using the Modified Checklist for Autism in Toddlers by their caregivers at 18 months old. The body movement features were quantified by a recently developed markerless system of infant body motion analysis. Logistic regression analysis revealed that ASD risk at 18 months old is associated with the pattern of spontaneous movement at the neonatal stage. Further, logistic regression based on body movement features during sleep shows better performance in classifying high- and low-risk infants than during the awake state. These findings raise the possibility that early signs of ASD risk may emerge at a developmental stage far earlier than previously thought., (© 2023. Springer Nature Limited.)

Imiquimod (IMQ) is widely used as animal model of psoriasis, a chronic inflammatory skin disorder. Although topical application of IMQ to back skin causes splenomegaly in mice, how the spleen affects the psoriasis-like phenotype of IMQ-treated mice remains unclear. In this study, we analyzed the cellular composition of spleen and measured metabolites in blood of IMQ-treated mice. We also investigated whether splenectomy influences the degree of skin inflammation and pathology in IMQ-treated mice. Flow cytometry showed that the numbers of CD11b + Ly6c + neutrophils, Ter119 + proerythroblasts, B220 + B cells, F4/80 + macrophages, and CD11c + dendritic cells in the spleen were significantly higher in IMQ-treated mice compared to control mice. An untargeted metabolomics analysis of blood identified 14 metabolites, including taurine and 2,6-dihydroxybenzoic acid, whose levels distinguished the two groups. The composition of cells in the spleen and blood metabolites positively correlated with the weight of the spleen. However, splenectomy did not affect IMQ-induced psoriasis-like phenotypes compared with sham-operated mice, although splenectomy increased the expression of interleukin-17A mRNA in the skin of IMQ-treated mice. These data suggest that the spleen does not play a direct role in the development of psoriasis-like phenotype on skin of IMQ-treated mice, though IMQ causes splenomegaly., (© 2022. The Author(s).)

Photoisomerization of lipids has been well studied. As for the eyes, photoisomerization from 11-cis isomer to all-trans-retinal is well-known as the first step of the visual transduction in the photoreceptors. In addition to that, there would be other ocular lipids that undergo photoisomerization, which may be involved in ocular health and function. To explore any photoisomerizable lipids in the eyes, the nonirradiated and sunlight-irradiated eyeball extracts were subjected to liquid chromatography-mass spectrometry analysis, followed by the identification of the decreased lipid species in the irradiated extracts. Surprisingly, more than nine hundred lipid species were decreased in the irradiated extracts. Three lipid species, coenzyme Q10 (CoQ10), triglyceride(58:4), and coenzyme Q9, were decreased both significantly (p < 0.05) and by more than two-fold, where CoQ10 showed the most significant decrease. Later, photoisomerization was identified as the prominent cause underlying the decrease of CoQ10. Interestingly, CoQ10 in the sunlight-irradiated fresh eyeballs was also isomerized. Both the visible light and ultraviolet radiation were capable of producing CoQ10 isomer, while the latter showed rapid action. This study is believed to enhance our understanding of the biochemistry and photodamage of the eye and can potentially contribute to the advancement of opto-lipidomics., (© 2022. The Author(s).)

Initiation and execution of complex learned vocalizations such as human speech and birdsong depend on multiple brain circuits. In songbirds, neurons in the motor cortices and basal ganglia circuitry exhibit preparatory activity before initiation of song, and that activity is thought to play an important role in successful song performance. However, it remains unknown where a start signal for song is represented in the brain and how such a signal would lead to appropriate vocal initiation. To test whether neurons in the midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) show activity related to song initiation, we carried out extracellular recordings of VTA/SNc single units in singing juvenile male zebra finches. We found that a subset of VTA/SNc units exhibit phasic activity precisely time-locked to the onset of the song bout, and that the activity occurred specifically at the beginning of song. These findings suggest that phasic activity in the VTA/SNc represents a start signal that triggers song vocalization., (© 2021. The Author(s).)

Behaviors driven by intrinsic motivation are critical for development and optimization of physical and brain functions, but their underlying mechanisms are not well studied due to the complexity and autonomy of the behavior. Songbirds, such as zebra finches, offer a unique opportunity to study neural substrates of intrinsic motivation because they spontaneously produce many renditions of songs with highly-quantifiable structure for vocal practice, even in the absence of apparent recipients ("undirected singing"). Neural substrates underlying intrinsic motivation for undirected singing are still poorly understood partly because singing motivation cannot be easily manipulated due to its autonomy. Also, undirected singing itself acts as an internal reward, which could increase singing motivation, leading to difficulty in measuring singing motivation independent of singing-associated reward. Here, we report a simple procedure to easily manipulate and quantify intrinsic motivation for undirected singing independent of singing-associated reward. We demonstrate that intrinsic motivation for undirected singing is dramatically enhanced by temporary suppression of singing behavior and the degree of enhancement depends on the duration of suppression. Moreover, by examining latencies to the first song following singing suppression as a measure of singing motivation independent of singing-associated reward, we demonstrate that intrinsic singing motivation is critically regulated by dopamine through D2 receptors. These results provide a simple experimental tool to manipulate and measure the intrinsic motivation for undirected singing and illustrate the importance of zebra finches as a model system to study the neural basis of intrinsically-motivated behaviors., (© 2021. The Author(s).)

Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring's HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children's Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring's body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387-1.969) for the impact of maternal smoking during pregnancy on their offspring's smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring's HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring's neurological impairment even after pregnancy., (© 2021. The Author(s).)

Fear is an adaptive emotion that elicits defensive behavioural responses against aversive threats in animals. In mammals, serotonin receptors (5-HTRs) have been shown to modulate fear-related neural circuits in the basolateral amygdala complex (BLA). To understand the phylogenetic continuity of the neural basis for fear, it is important to identify the neural circuit that processes fear in other animals. In birds, fear-related behaviours were suggested to be processed in the arcopallium/amygdala complex and modulated by the serotonin (5-HT) system. However, details about the distribution of 5-HTRs in the avian brain are very sparsely reported, and the 5-HTR that is potentially involved in fear-related behaviour has not been elucidated. In this study, we showed that orthologs of mammalian 5-HTR genes that are expressed in the BLA, namely 5-HTR1A, 5-HTR1B, 5-HTR2A, 5-HTR2C, 5-HTR3A, and 5-HTR4, are expressed in a part of the chick arcopallium/amygdala complex called the dorsal arcopallium. This suggests that serotonergic regulation in the dorsal arcopallium may play an important role in regulating fear-related behaviour in birds. Our findings can be used as a basis for comparing the processing of fear and its serotonergic modulation in the mammalian amygdala complex and avian arcopallium/amygdala complex.

Complex learned behaviors, like bird song and human speech, develop under the influence of both genetic and environmental factors. Accordingly, learned behaviors comprise species specificity and individual variability. Auditory information plays a critical role in vocal learning by songbirds, both to memorize tutor songs and to monitor own vocalizations. Nevertheless, audition-deprived songbirds develop structured, species-specific song patterns. It remains to be elucidated how the auditory input contributes to the development of individual variability of song characteristics. Here we show that an open-ended vocal learner, the canary, annually recapitulates individually unique songs without audition. Although the total number of syllable types was reduced by auditory deprivation, other vocal phenotypes examined in the syllable, phrase, and syntax of songs were conserved between the 1 st and 2 nd years, both in deafened and intact birds. In deafened canaries, approximately 60% of the syllables were yearly reproduced with consistent acoustic features, whereas the remaining syllables were replaced with new ones in an annual cycle of song development. These results indicate that the open-ended vocal learning of canaries involves an audition-independent mechanism for the development of recurrent song idiosyncrasy.

Polychlorinated biphenyls (PCBs), like other persistent organic pollutants, are accumulating throughout the food chain and pose health threats to humans, especially children and foetuses. There is no protocol for reducing the contamination levels of the PCBs in humans. This study identified food items and cooking methods that reduce serum PCB levels by analysing data collected from the Chiba Study of Mother and Child Health. The sample size was 194 subjects. Serum PCB levels were measured using gas chromatography-electron capture negative ionization quadrupole mass spectrometry. Information on dietary habits was obtained from a brief diet history questionnaire that included questions about food items and cooking methods. Food items were categorized into food groups, and nutrient levels were calculated based on food item consumption. Principal component analysis and lasso regression were used as statistical methods. The analyses of food items and nutrients suggested that food items rich in dietary fibre reduce avoidable exposure to PCBs, as could grilling and deep frying of food, which could reduce avoidable exposure to serum PCBs in mothers and foetuses. (174 words).

Learned vocalizations are a crucial acoustic biosignal conveying individual traits in many species. Songbirds learn song patterns by listening to a tutor song and performing vocal practice during a sensitive developmental period. However, when and how individual differences in song patterns develop remain unknown. Here, we report that individual differences in vocal output exist even at the earliest song development stage, called subsong. Experiments involving the manipulation of both breeding pairs and song tutoring conditions revealed that the parental pair combination contributes to generating familial differences in syllable duration and variability in the subsong of offspring. Furthermore, after deafening, juveniles immediately changed their subsong by shortening the syllable durations but maintained the individual variability of their subsong temporal patterns, suggesting both auditory-sensitive modification and independent intrinsic regulation of vocal output. These results indicate that the temporal patterns of subsong are not merely disordered vocalization but are regulated by familial bias with sensitivity to auditory feedback, thus generating individual variability at the initiation of vocal development.

The CRISPR/Cas9 system is capable of editing multiple genes through one-step zygote injection. The preexisting method is largely based on the co-injection of Cas9 DNA (or mRNA) and guide RNAs (gRNAs); however, it is unclear how many genes can be simultaneously edited by this method, and a reliable means to generate transgenic (Tg) animals with multiple gene editing has yet to be developed. Here, we employed non-inheritable maternal Cas9 (maCas9) protein derived from Tg mice with systemic Cas9 overexpression (Cas9 mice). The maCas9 protein in zygotes derived from mating or in vitro fertilization of Tg/+ oocytes and +/+ sperm could successfully edit the target genome. The efficiency of such maCas9-based genome editing was comparable to that of zygote microinjection-based genome editing widely used at present. Furthermore, we demonstrated a novel approach to create "Cas9 transgene-free" gene-modified mice using non-Tg (+/+) zygotes carrying maCas9. The maCas9 protein in mouse zygotes edited nine target loci simultaneously after injection with nine different gRNAs alone. Cas9 mouse-derived zygotes have the potential to facilitate the creation of genetically modified animals carrying the Cas9 transgene, enabling repeatable genome engineering and the production of Cas9 transgene-free mice.

In ribosome biogenesis, a large fraction of ribosomes is used for producing ribosomal proteins themselves. Here, we applied simulation and experimentation to determine what fraction of ribosomes should be allocated for the synthesis of ribosomal proteins to optimize cellular economy for growth. We define the "r-fraction" as the fraction of mRNA of the ribosomal protein genes out of the total mRNA, and we simulated the effect of the r-fraction on the number of ribosomes. We then empirically measured the amount of protein and RNA in fission yeast cells cultured with high and low nitrogen sources. In the cells cultured with a low nitrogen source, the r-fraction decreased from 0.46 to 0.42 with a 40% reduction of rRNA, but the reduction of the total protein was smaller at 30%. These results indicate that the r-fraction is internally controlled to optimize the efficiency of protein synthesis at a limited cellular cost.