Age-dependent Development Research Articles

Age-dependent functional development pattern in neonatal brain: An fMRI-based brain entropy study

The relationship between brain entropy (BEN) and early brain development has been established through animal studies. However, it remains unclear whether the BEN can be used to identify age-dependent functional changes in human neonatal brains and the genetic underpinning of the new neuroimaging marker remains to be elucidated. In this study, we analyzed resting-state fMRI data from the Developing Human Connectome Project, including 280 infants who were scanned at 37.5–43.5 weeks postmenstrual age. The BEN maps were calculated for each subject, and a voxel-wise analysis was conducted using a general linear model to examine the effects of age, sex, and preterm birth on BEN. Additionally, we evaluated the correlation between regional BEN and gene expression levels. Our results demonstrated that the BEN in the sensorimotor-auditory and association cortices, along the ‘S-A’ axis, was significantly positively correlated with postnatal age (PNA), and negatively correlated with gestational age (GA), respectively. Meanwhile, the BEN in the right rolandic operculum correlated significantly with both GA and PNA. Preterm-born infants exhibited increased BEN values in widespread cortical areas, particularly in the visual-motor cortex, when compared to term-born infants. Moreover, we identified five BEN-related genes (DNAJC12, FIG4, STX12, CETN2, and IRF2BP2), which were involved in protein folding, synaptic vesicle transportation and cell division. These findings suggest that the fMRI-based BEN can serve as an indicator of age-dependent brain functional development in human neonates, which may be influenced by specific genes.

Atrial proteomic profiling reveals a switch towards profibrotic gene expression program in CREM-IbΔC-X mice with persistent atrial fibrillation

BackgroundOverexpression of the CREM (cAMP response element-binding modulator) isoform CREM-IbΔC-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. PurposeTo identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. MethodsAtrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. ResultsA total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and structural based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns reminiscent of those seen in humans with persistent AF. ConclusionsThis study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF.

Age-dependent development trends (models) of intestinal significant microbiota species and Eimeria oocysts in coccidia-challenged broiler chickens as affected by dietary encapsulated organic acids and anticoccidial drugs

ABSTRACT The study was conducted to investigate the effect of dietary encapsulated organic acids (EOAs) and anticoccidials on the age-dependent development trend of intestinal Lactobacillus, E. coli, coliforms, and Eimeria in Eimeria spp.-infected broiler chickens from reused litter. In total, 525 mixed-sex 1-day-old broiler chickens were used in an uninfected/un-supplemented control plus a 2 (no EOA or 0.1% EOA) × 3 (no anticoccidial, 0.05% maduramicin, and 0.02% diclazuril) factorial arrangement of treatments as a completely randomized design with five replicates of 15 chickens. Results indicated that the cubic model is the best model for explaining the development trends of the intestinal microbial population in uninfected and infected chickens (affected by the EOAs and anticoccidials). Based on the cubic models, the microbial populations had development trends with a decreasing slope from 1-day-old until the early or middle finisher period. EOAs and anticoccidials, especially their simultaneous usage, improved (P < 0.05) the linear and cubic models’ slope (affected negatively by Eimeria infection). A polynomial model (order = 6) was determined as the best model for explaining the EOAs and anticoccidial effects on the trend of intestinal Eimeria oocysts in infected chickens. The infection peak (which happened at 25 days) was reduced by EOAs and anticoccidials, especially their simultaneous usage. In conclusion, cubic and polynomial (order = 6) regressions are the best models fitted for explaining the microbiota and Eimeria oocysts trends, respectively. EOAs and anticoccidials, especially their simultaneous usage, had beneficial effects on the microbiota and Eimeria development trends and gastrointestinal health in coccidia-infected broiler chickens.‏ RESEARCH HIGHLIGHTS Cubic regression is the best model for explaining intestinal microbiota development. Polynomial regression is the best model for intestinal Eimeria oocysts development. Age-development trends are affected by dietary encapsulated organic acids and anticoccidials.

Comparative transcriptomics analysis identifies crucial genes and pathways during goose spleen development.

As the largest peripheral lymphoid organ in poultry, the spleen plays an essential role in regulating the body's immune capacity. However, compared with chickens and ducks, information about the age- and breed-related changes in the goose spleen remains scarce. In this study, we systematically analyzed and compared the age-dependent changes in the morphological, histological, and transcriptomic characteristics between Landes goose (LG; Anser anser) and Sichuan White goose (SWG; Anser cygnoides). The results showed a gradual increase in the splenic weights for both LG and SWG until week 10, while their splenic organ indexes reached the peak at week 6. Meanwhile, the splenic histological indexes of both goose breeds continuously increased with age, reaching the highest levels at week 30. The red pulp (RP) area was significantly higher in SWG than in LG at week 0, while the splenic corpuscle (AL) diameter was significantly larger in LG than in SWG at week 30. At the transcriptomic level, a total of 1710 and 1266 differentially expressed genes (DEGs) between week 0 and week 30 were identified in spleens of LG and SWG, respectively. Meanwhile, a total of 911 and 808 DEGs in spleens between LG and SWG were identified at weeks 0 and 30, respectively. Both GO and KEGG enrichment analysis showed that the age-related DEGs of LG or SWG were dominantly enriched in the Cell cycle, TGF-beta signaling, and Wnt signaling pathways, while most of the breed-related DEGs were enriched in the Neuroactive ligand-receptor interaction, Cytokine-cytokine receptor interaction, ECM-receptor interaction, and metabolic pathways. Furthermore, through construction of protein-protein interaction networks using significant DEGs, it was inferred that three hub genes including BUB1, BUB1B, and TTK could play crucial roles in regulating age-dependent goose spleen development while GRIA2, GRIA4, and RYR2 could be crucial for the breed-specific goose spleen development. These data provide novel insights into the splenic developmental differences between Chinese and European domestic geese, and the identified crucial pathways and genes are helpful for a better understanding of the mechanisms regulating goose immune functions.

Baseline Structural Connectomics Data of Healthy Brain Development Assessed with Multi-Modal Magnetic Resonance Imaging

Diffusion magnetic resonance imaging (MRI) tractography is a powerful tool for non-invasively studying brain architecture and structural integrity by inferring fiber tracts based on water diffusion profiles. This study provided a thorough set of baseline data of structural connectomics biomarkers for 809 healthy participants between the ages of 1 and 35 years. The data provided can help to identify potential biomarkers that may be helpful in characterizing physiological and anatomical neurodevelopmental changes linked with healthy brain maturation and can be used as a baseline for comparing abnormal and pathological development in future studies. Our results demonstrate statistically significant differences between the sexes, representing a potentially important baseline from which to establish healthy growth trajectories. Biomarkers that correlated with age, potentially representing useful methods for assessing brain development, are also presented. This baseline information may facilitate studies that identify abnormal brain development associated with a variety of pathological conditions as departures from healthy sex-specific age-dependent neural development. Our findings are the result of combining the use of mainstream analytic methods with in-house-developed open-source software to help facilitate reproducible analyses, inclusive of many potential biomarkers that cannot be derived from existing software packages. Assessing relationships between our identified regional tract measurements produced by our technology and participant characteristics/phenotypic data in future analyses has tremendous potential for the study of human neurodevelopment.

Immunoproteasome deficiency results in age-dependent development of epilepsy.

The immunoproteasome is a central protease complex required for optimal antigen presentation. Immunoproteasome activity is also associated with facilitating the degradation of misfolded and oxidized proteins, which prevents cellular stress. While extensively studied during diseases with increasing evidence suggesting a role for the immunoproteasome during pathological conditions including neurodegenerative diseases, this enzyme complex is believed to be mainly not expressed in the healthy brain. In this study, we show an age-dependent increase in polyubiquitination in the brains of wild-type mice, accompanied by an induction of immunoproteasomes, which was most prominent in neurons and microglia. In contrast, mice completely lacking immunoproteasomes (triple-knockout mice), displayed a strong increase in polyubiquitinated proteins already in the young brain and developed spontaneous epileptic seizures, beginning at the age of 6 months. Injections of kainic acid led to high epilepsy-related mortality of aged triple-knockout mice, confirming increased pathological hyperexcitability states. Notably, the expression of the immunoproteasome was reduced in the brains of patients suffering from epilepsy. In addition, the aged triple-knockout mice showed increased anxiety, tau hyperphosphorylation and degeneration of Purkinje cell population with the resulting ataxic symptoms and locomotion alterations. Collectively, our study suggests a critical role for the immunoproteasome in the maintenance of a healthy brain during ageing.

Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17.

The Tau58/2 and Tau58/4 mouse lines expressing 0N4R tau with a P301S mutation mimic aspects of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In a side-by-side comparison, we report the age-dependent development of cognitive, motor, and behavioral deficits in comparison with the spatial-temporal evolution of cellular tau pathology in both models. We applied the SHIRPA primary screen and specific neuromotor, behavioral, and cognitive paradigms. The spatiotemporal development of tau pathology was investigated immunohistochemically. Levels of sarkosyl-insoluble paired helical filaments were determined via a MesoScale Discovery biomarker assay. Neuromotor impairments developed from age 3 months in both models. On electron microscopy, spinal cord neurofibrillary pathology was visible in mice aged 3 months; however, AT8 immunoreactivity was not yet observed in Tau58/4 mice. Behavioral abnormalities and memory deficits occurred at a later stage (>9 months) when tau pathology was fully disseminated throughout the brain. Spatiotemporally, tau pathology spread from the spinal cord via the midbrain to the frontal cortex, while the hippocampus was relatively spared, thus explaining the late onset of cognitive deficits. Our findings indicate the face and construct validity of both Tau58 models, which may provide new, valuable insights into the pathologic effects of tau species in vivo and may consequently facilitate the development of new therapeutic targets to delay or halt neurodegenerative processes occurring in tauopathies.

The development of blood protein profiles in extremely preterm infants follows a stereotypic evolution pattern

BackgroundPreterm birth is the leading cause of neonatal mortality and morbidity. Early diagnosis and interventions are critical to improving the clinical outcomes of extremely premature infants. Blood protein profiling during the first months of life in preterm infants can shed light on the role of early extrauterine development and provide an increased understanding of maturation after extremely preterm birth and the underlying mechanisms of prematurity-related disorders.MethodsWe have investigated the blood protein profiles during the first months of life in preterm infants on the role of early extrauterine development. The blood protein levels were analyzed using next generation blood profiling on 1335 serum samples, collected longitudinally at nine time points from birth to full-term from 182 extremely preterm infants.ResultsThe protein analysis reveals evident predestined serum evolution patterns common for all included infants. The majority of the variations in blood protein expression are associated with the postnatal age of the preterm infants rather than any other factors. There is a uniform protein pattern on postnatal day 1 and after 30 weeks postmenstrual age (PMA), independent of gestational age (GA). However, during the first month of life, GA had a significant impact on protein variability.ConclusionsThe unified pattern of protein development for all included infants suggests an age-dependent stereotypic development of blood proteins after birth. This knowledge should be considered in neonatal settings and might alter the clinical approach within neonatology, where PMA is today the most dominant age variable.

Catheter ablation (CA) for atrial fibrillation and atrial tachycardia in the elderly: Results from a large single center study in 293 patients over 80 years old

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The increasing incidence of atrial arrhythmias in the elderly is mostly adjudicated to the age-dependent development of arhythmic substrate. In recent years, CA has become a standard approach in treating atrial fibrillation (AF) and left and right atrial flutter (AFlut). Data regarding safety and efficacy of CA in patients over 80 years old remains scarce. This study aims to report on our high-volume center experience regarding the safety and efficacy of CA in a large cohort of patients &amp;gt;80 years of age. Methods All patients &amp;gt;80 years undergoing de-novo-CA for AF or AFlut (parox. AF n=85, 29%; pers. AF n=146, 49.8%; left-/right- AFlut n=62, 21.2%) in our institution between 01/2016 and 12/2020 were included (n=293; mean age 82.3 ± 2.27 years). For safety analysis, all complications requiring intervention or causing sequels occurring during or up to 30 days after CA were collected. For efficacy, AF/Aflut-free survival was analysed after a blanking period (3 months) using 7-day Holter ECGs. Results Baseline characteristics are shown in table 1. Most patients suffered from multiple cardiovascular co-morbidities (CHA2DS2-VASc-score 4.45 ± 1.15), &amp;gt;30% were on reduced OAC. Isolation of all pulmonary veins (PV) and/or termination of AFlut with demonstration of bidirectional block across the ablation line was achieved in all patients (procedure success 100%). During a follow-up of 400 ± 446 days, 61.4% of patients remained in stable sinus rhythm after 1.56 ± 0.81 ablations (Figure 1). Single procedure outcome was significantly higher in paroxysmal AF compared to persistent AF (p = 0.03, s. Figure 1b). 32 patients (10.9%) were lost to follow-up. In 17 patients (5.8%) complications occurred: 1 case of pericardial tamponade during PVI and CA of PVCs (LA and CS). 2 patients suffered a stroke within a week after CA of persistent AF and left AFlut, 1 TIA occurred after CA of persistent AF. All patients had been under uninterrupted full-dose OAC. Major groin complications occurred in 13 patients (4.4%). 3 arterial bleeds treated by covered stent implant, 7 pseudoaneurysms needing thrombin injections, 2 infections of the puncture site and 1 patient requiring surgical treatment for a large hematoma. 9 patients underwent pacemaker implantation shortly after CA due to underlying symptomatic sick-sinus-syndrome or higher degree AV-blocks demasked in sinus rhythm, none were procedure-related. Conclusion De novo catheter ablation of AF and AFlut in very old patients is safe and effective. In paroxysmal AF, ablation success rates seem to be similar to those in younger patients and are significantly higher than for persistent AF. After 1.56 ablation procedures, &amp;gt;60% of patients were free of arrhythmia, suggesting that the supposed atrial remodelling does not preclude an interventional treatment approach.

Multivariate mixed-effects models for stand characteristics of hybrid aspen plantations in southern Finland and southern Sweden

Hybrid aspen, a hybrid between the European aspen and North American trembling aspen (Populus tremula L. × P. tremuloides Michx.), is a promising species because of its fast-growth and its suitability for multi-purpose use. However, models for predicting the age-dependent development of stand characteristics are still missing. The main objectives of this study were therefore to develop the models for predicting stand characteristics of hybrid aspen plantations and to validate the model applicability. The target response variables were stand basal area (BA), basal area-weighted mean diameter (DG) and basal area-weighted mean height (HG). Data were obtained from clonal hybrid aspen trials in southern Finland and southern Sweden. Multivariate mixed-effects modelling was used to estimate the parameters of seemingly unrelated regression for BA, DG, and HG. Model fit provided the following predictor variables: stand age (AGE), the number of trees per hectare (TPH), site index (SI), growing degree-days (GDD5), soil and site type, and thinning treatment. The chosen predictors differed slightly by response variable, but all parameters were highly significant (P < 0.0001), and model goodness-of-fit statistics presented high accuracy: RMSE of 2.59 m2 ha−1 for BA, 1.21 cm for DG, 1.05 m for HG in arithmetic scale. The applied simulations illustrated clear differences in the predicted development of stand characteristics when input variables SI, TPH or GDD5 changed. The developed models were assessed to be easily applicable and useful for predicting the stand and tree characteristics of clonal hybrid aspen plantations, especially for the stands with AGE ≤ 30 years and TPH ≤ 2000 trees ha−1.

Complexity and regulation of age-dependent alternative splicing in Brachypodium distachyon.

Alternative splicing (AS) is a gene regulatory mechanism that generates multiple transcripts of the same gene precursor by the spliceosome complex, promoting messenger RNA complexity, and proteome diversity. Although AS is extensively studied in response to environmental stresses, whether it mediates age-dependent development and how it is adjusted by growth transitions are largely unknown. Here, we comprehensively explored the AS landscape at different developmental stages in the grass model plant Brachypodium (Brachypodium distachyon). We identified abundant coding genes and noncoding transcripts subject to dynamic AS regulation during juvenile, adult, and reproductive transitions. Moreover, we revealed that SC35-LIKE SPLICING FACTOR 33 (SCL33), a serine/arginine-rich splicing factor in spliceosomes, plays a redundant and antagonistic role with its putative paralog, SCL33L, in regulating intron assembly across distinct developmental stages. In addition, we determined global AS variations in microRNA156 (miR156)-overproducing plants, in which growth transitions are delayed, and found that SPLs were regulated by miR156 in intron retention alteration in addition to mRNA clearance and translation inhibition manners. Finally, we demonstrated a complex regulatory process of age-dependent AS events in B. distachyon that was coincidently or separately regulated by miR156 and SCL33/SCL33L. These results illustrate a substantial machinery of AS that mediates phase transitions in plants.

Metacognitions and interoceptive sensibility in the perception of premonitory urges in tic disorders across the lifespan

Metacognitions and interoceptive sensibility in the perception of premonitory urges in tic disorders across the lifespan Abstract. Objective: Depending on contextual factors, the prevalence of premonitory urges (PU) in patients with tic disorders (TD) increases with age and varies both intra- and interindividually. In youth, PUs correlate with metacognitions. In both youth and adults, interoceptive sensibility is altered compared to healthy controls. We examined the relationship between PUs, tics, metacognitions, and interoceptive sensibility across the lifespan regarding tic severity. Method: In an online survey, 53 participants reported their PUs on the Premonitory Urge for Tics Scale (PUTS) and tic severity on the Symptom Checklist for Tic Disorders (SBB-TIC). We assessed interoceptive sensibility via the Body Perception Questionnaire (BPQ-A) and metacognitions regarding tics with the Belief About Tics Scale (BATS). Results: Adults scored higher on the PUTS than youth. In youth, interoceptive sensibility increased with age; interoceptive sensibility correlated with PUTS. Metacognitions and interoceptive sensibility explained a significant amount of variance in premonitory urges, even after controlling for tic severity and age. Conclusions: The presumed cause of age-dependent development of PUs in youth lies in their neurophysiological maturing processes. However, negative metacognitions and interoceptive abilities also play an important role in the development and maintenance of PU and might be of therapeutic use in the treatment of TD.

A mouse model of naturally occurring age-related cognitive impairment.

Age-related cognitive impairment (ARCI) is a neurological condition that affects millions of older people, but little is known about the increased risk of developing more severe neurodegeneration and dementia. Preclinical research is needed to understand the mechanisms of the impairment and the neuropathology associated with it. We have characterized a model of naturally occurring ARCI in the C57BL/6J mouse strain that shows an age-dependent development of cognitive impairment. As in people, some mice have little cognitive impairment while others have more severe cognitive impairment. Therefore, mice can be categorized as resistant or susceptible and the two groups can be studied for behavioral and neuropathology differences. Preliminary observations show no difference in strength and agility test scores between ARCI resistant and susceptible mice of either sex suggesting the cognitive impairment in ARCI susceptible mice is not accompanied by impairment in daily living activities, similar to ARCI in humans. The hippocampal area of the brain from ARCI susceptible mice shows evidence of an increase in the inflammatory cytokine MCP-1 compared to ARCI resistant mice, suggesting inflammation may be associated with ARCI. These preliminary observations suggest that ARCI in C57BL/6J mice could be a high-impact model to study how resilience to brain aging may predict resilience to dementia associated with Alzheimer's disease and other age-related neurological conditions.

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

The TgF344 rat model of Alzheimer’s disease (AD) provides a comprehensive neuropathology presentation, with age-dependent development of tau tangles, amyloid-beta (A{beta}) plaques, neuronal loss, and increased gliosis. The behavioral trajectory of this model, particularly relating to spatial learning and memory, has yet to be fully characterized. The current experiment evaluated spatial working and reference memory performance, as well as several physiological markers of health, at 3 key age points in female TgF344-AD rats: 6-months, 9-months, and 12-months. At 6 months of age, indications of working and reference memory impairments were observed in transgenic (Tg) rats on the water radial-arm maze, a complex task that requires working and reference memory simultaneously; at 12 months old, Tg impairments were observed for two working memory measures on this task. Notably, no impairments were observed at the 9-month timepoint on this maze. For the Morris maze, a measure of spatial reference memory, Tg rats demonstrated significant impairment relative to wildtype (WT) controls at all 3 age-points. Frontal cortex, entorhinal cortex, and dorsal hippocampus were evaluated for A{beta}1–42 expression via western blot in Tg rats only. Analyses of A{beta}1–42 expression revealed age-dependent increases in all 3 regions critical to spatial learning and memory. Measures of physiological health, including heart, uterine, and body weights, revealed unique age-specific outcomes for female Tg rats, with the 9-month timepoint identified as critical for further research within the trajectory of AD-like behavior, physiology, and pathology.

Differential age-dependent development of inter-area brain connectivity in term and preterm neonates

BackgroundAmong preterm infants, higher morbidities of neurological disturbances and developmental delays are critical issues. Resting-state networks (RSNs) in the brain are suitable measures for assessing higher-level neurocognition. Since investigating task-related brain activity is difficult in neonates, assessment of RSNs provides invaluable insight into their neurocognitive development.MethodsThe participants, 32 term and 71 preterm neonates, were divided into three groups based on gestational age (GA) at birth. Cerebral hemodynamic activity of RSNs was measured using functional near-infrared spectroscopy in the temporal, frontal, and parietal regions.ResultsHigh-GA preterm infants (GA ≥ 30 weeks) had a significantly stronger RSN than low-GA preterm infants and term infants. Regression analyses of RSNs as a function of postnatal age (PNA) revealed a steeper regression line in the high-GA preterm and term infants than in the low-GA infants, particularly for inter-area brain connectivity between the frontal and left temporal areas.ConclusionsSlower PNA-dependent development of the frontal–temporal network found only in the low-GA group suggests that significant brain growth optimal in the intrauterine environment takes place before 30 weeks of gestation. The present study suggests a likely reason for the high incidence of neurodevelopmental impairment in early preterm infants.ImpactResting-state fNIRS measurements in three neonate groups differing in gestational age (GA) showed stronger networks in the high-GA preterm infants than in the term and low-GA infants, which was partly explained by postnatal age (PNA).Regression analyses revealed a similar PNA-dependence in the development of the inter-area networks in the frontal and temporal lobes in the high-GA and term infants, and significantly slower development in the low-GA infants.These results suggest that optimal intrauterine brain growth takes place before 30 weeks of gestation. This explains one of the reasons for the high incidence of neurodevelopmental impairment in early preterm infants.

Age-dependent development in protein digestibility and intestinal morphology in weaned pigs fed different protein sources

Today, weaner diets are optimised using digestibility coefficients obtained from grower-finisher pigs, which may overestimate the digestibility in weaners. The aim of this study was to evaluate the standardised ileal digestibility (SID) of CP and amino acids (AAs), and the intestinal morphology in pigs 0–4 weeks postweaning when fed different protein sources. The experiment included 128 pigs weaned at day 28 and the protein sources were wheat, soybean meal (SBM), enzyme-treated soybean meal (ESBM), hydrothermally treated rapeseed meal (HRSM) and casein. The experiment was conducted as a difference method study including wheat in all diets. Eight pigs were slaughtered on the day of weaning (day 0) and six pigs/treatment were slaughtered at days 7, 14, 21, and 28 postweaning. The SID of CP and AA, as average over the four weeks, was lowest for ESBM and highest for wheat and casein, with SBM and HRSM being intermediate. The SID of CP and AA increased (both linear and quadratic, P < 0.05) over time after weaning. The average SID of CP for all protein sources postweaning was 0.38, 0.59, 0.76, and 0.71 on days 7, 14, 21, and 28, respectively. These differences were significant (P < 0.05) between days 7 and 21, and between days 7 and 28 (P < 0.05), whereas there tended to be a difference between days 7 and 14 (P = 0.06). Protein source did not affect the small intestinal morphology response parameters, whereas time after weaning did. Villous height and villous height to crypt depth ratio differed (P < 0.05) between the days 0 and 7, with shorter villi and a higher ratio at day 7. Crypt depth was not altered between days 0 and 7, or between days 7 and 14. For villi density, crypt density and small intestinal length, a significant increase from days 7 to 14 was observed, but there was no further increase to or difference between days 21 and 28. In conclusion, the low SID of CP in casein on day 7 (0.50) illustrates the challenges related to protein digestion in weanling pigs. The SID of CP and AA is very low during the first two weeks postweaning and time after weaning is more important for protein digestibility, than the source of protein. Fewer mature epithelial cells and less absorptive area in the small intestine in the early postweaning period may partly explain the poor protein digestibility.

Age-dependent changes of gut-associated lymphoid tissue in one to four-month-old turkeys: A histological study

Gut-associated lymphoid tissue (GALT) has a pivotal role in the health of birds as the first line of defense against foodborne pathogens. On the other hand, this part of immune system is important for successful development of vaccines. Due to scarcity of knowledge on GALT of turkey as a major industrial species, this study aimed to evaluate histological features of GALT in this species. A total of 40 clinically healthy BUT6 turkeys from both sexes at the age of 1, 2, 3, and 4 months were included in the study. Samples were immediately removed after slaughter from different parts of the gut, including pharyngeal tonsil, cervical oesophagus, oesophageal tonsil, proventriculus, pyloric tonsil, ileum, Meckel’s diverticulum, caecal tonsil, the middle and apex of caecum, rectum, and cloaca. After fixation and routine procedures followed by hematoxylin-eosin staining, samples were studied histologically under light microscope. In addition, photomicrographs were taken from sections and were analysed for histomorphometric parameters using Zeiss Axio vision rel.4.8 software. According to the results, in one-month-old turkeys, lymphatic tissues in pharyngeal tonsil, pyloric tonsil, proventriculus, caecal tonsil, middle, and apex of caecum, Meckel’s diverticulum, and cloaca were completely developed, while in some other parts such as the cervical oesophagus and the rectum lymphatic structures were absent. In the ileum, the Peyer’s patch was observed as an aggregated structure, although the diffuse lymphatic tissue has properly evolved. In two months old turkeys, the dense lymphatic tissue including primary and secondary lymphatic follicles, was present in cervical oesophagus, Peyer’s patch, rectum, and cloaca. Many histomorphometric parameters of lymphoid tissue also developed age-dependently. In four months old birds the dense lymphatic tissue was obvious in all examined specimens. Moreover, no signs of tissue atrophy were seen at the age of four months (prepuberty) in the GALT specimens. In conclusion, the GALT of turkeys was histologically quite similar to those of other birds and these structures showed an age-dependent development from 1 to 4 months of age.

Postnatal development of inner lamina II interneurons of the rat medullary dorsal horn.

Pain processing in young mammals is immature. Despite the central role of the medullary dorsal horn (MDH) in processing orofacial sensory information, the maturation of the neurons within the MDH has been largely overlooked. Combining in vitro electrophysiological recordings and 3D morphological analysis over the first postnatal month in rats, we investigated the age-dependent development of the neurons within the inner lamina II (IIi) of the MDH. We show the lamina IIi neuronal population transition into a more hyperpolarized state, with modification of the action potential waveform, and a shift from single spiking, at early postnatal ages, to tonic firing and initial bursting at later stages. These physiological changes are associated with a strong structural remodelling of the neuronal morphology with most of the modifications occurring after the third postnatal week. Among the lamina IIi neuronal population, the subpopulation of interneurons expressing the γ isoform of the protein kinase C (PKCγ+) are key elements for the circuits underlying facial mechanical allodynia. How do they develop from the rest of the lamina IIi constitute an important question that remained to be addressed. Here, we show that PKCγ+ interneurons display electrophysiological changes over time comparable with the PKCγ- population. However, they show a distinctive increase of the soma volume and primary branches length, as opposed to the PKCγ- population. Together, our data demonstrate a novel pattern of late postnatal maturation of lamina IIi interneurons, with a spotlight on PKCγ+ interneurons, that may be relevant for the development of orofacial sensitivity.

Pathway-Specific Defects in T, B, and NK Cells and Age-Dependent Development of High IgE in Mice Heterozygous for a CADINS-Associated Dominant Negative CARD11 Allele.

CARD11 is a multidomain scaffold protein required for normal activation of NF-κB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-κB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.

How Visual Word Decoding and Context-Driven Auditory Semantic Integration Contribute to Reading Comprehension: A Test of Additive vs. Multiplicative Models.

Theories of reading comprehension emphasize decoding and listening comprehension as two essential components. The current study aimed to investigate how Chinese character decoding and context-driven auditory semantic integration contribute to reading comprehension in Chinese middle school students. Seventy-five middle school students were tested. Context-driven auditory semantic integration was assessed with speech-in-noise tests in which the fundamental frequency (F0) contours of spoken sentences were either kept natural or acoustically flattened, with the latter requiring a higher degree of contextual information. Statistical modeling with hierarchical regression was conducted to examine the contributions of Chinese character decoding and context-driven auditory semantic integration to reading comprehension. Performance in Chinese character decoding and auditory semantic integration scores with the flattened (but not natural) F0 sentences significantly predicted reading comprehension. Furthermore, the contributions of these two factors to reading comprehension were better fitted with an additive model instead of a multiplicative model. These findings indicate that reading comprehension in middle schoolers is associated with not only character decoding but also the listening ability to make better use of the sentential context for semantic integration in a severely degraded speech-in-noise condition. The results add to our better understanding of the multi-faceted reading comprehension in children. Future research could further address the age-dependent development and maturation of reading skills by examining and controlling other important cognitive variables, and apply neuroimaging techniques such as functional magmatic resonance imaging and electrophysiology to reveal the neural substrates and neural oscillatory patterns for the contribution of auditory semantic integration and the observed additive model to reading comprehension.