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"Rodents Infancy."
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Baby rodents
Provides information about young rodents, including anatomy, habitat, and relatives.
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Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: a randomised controlled study in Kenyan infants
ObjectiveIron-containing micronutrient powders (MNPs) reduce anaemia in African infants, but the current high iron dose (12.5 mg/day) may decrease gut Bifidobacteriaceae and Lactobacillaceae, and increase enteropathogens, diarrhoea and respiratory tract infections (RTIs). We evaluated the efficacy and safety of a new MNP formula with prebiotic galacto-oligosaccharides (GOS) combined with a low dose (5 mg/day) of highly bioavailable iron.DesignIn a 4-month, controlled, double-blind trial, we randomised Kenyan infants aged 6.5–9.5 months (n=155) to receive daily (1) a MNP without iron (control); (2) the identical MNP but with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) (Fe group); or (3) the identical MNP as the Fe group but with 7.5 g GOS (FeGOS group).ResultsAnaemia decreased by ≈50% in the Fe and FeGOS groups (p<0.001). Compared with the control or FeGOS group, in the Fe group there were (1) lower abundances of Bifidobacterium and Lactobacillus and higher abundances of Clostridiales (p<0.01); (2) higher abundances of virulence and toxin genes (VTGs) of pathogens (p<0.01); (3) higher plasma intestinal fatty acid-binding protein (a biomarker of enterocyte damage) (p<0.05); and (4) a higher incidence of treated RTIs (p<0.05). In contrast, there were no significant differences in these variables comparing the control and FeGOS groups, with the exception that the abundance of VTGs of all pathogens was significantly lower in the FeGOS group compared with the control and Fe groups (p<0.01).ConclusionA MNP containing a low dose of highly bioavailable iron reduces anaemia, and the addition of GOS mitigates most of the adverse effects of iron on the gut microbiome and morbidity in African infants.Trial registration numberNCT02118402.
Journal Article
Immune Diseases Associated with TREX1 and STING Dysfunction
The innate immune system is the first line of defense against invading pathogens. One important feature of innate immune recognition is self versus nonself discrimination. The selectivity for microbial ligands is achieved through substrate motif specificity, spatial compartmentalization, and functions of negative regulators. Loss-of-function mutations in negative regulators or gain-of-function mutations in drivers of innate immune signaling have been associated with autoimmune diseases such as lupus, rheumatoid arthritis, inflammatory vasculopathy, and a variety of interferonopathies. This review will focus on TREX1 and STING, which are opposing regulators of the cytosolic DNA-sensing pathway. Tremendous effort over the past decade among academic and clinical research groups has elucidated molecular mechanisms underlying immune diseases associated with TREX1 and STING dysfunction. We have also witnessed rapid therapeutic translation of the molecular findings. Several targeted treatment options or druggable candidates are now available for these once incurable diseases. With great enthusiasm from both academia and industry partners, we look forward to seeing the remaining scientific questions answered and, more importantly, the affected patients benefited from these discoveries.
Journal Article
Antenatal Endotoxin Induces Dysanapsis in Experimental Bronchopulmonary Dysplasia
Abstract
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 μg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro–computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma–airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.
Journal Article
Oral administration of pyrophosphate inhibits connective tissue calcification
Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in
ABCC6
and
ENPP1
, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed that the bioavailability of orally administered PPi is negligible. Here, we demonstrate increased PPi concentration in the circulation of humans after oral PPi administration. Furthermore, in mouse models of PXE and GACI, oral PPi provided via drinking water attenuated their ectopic calcification phenotype. Noticeably, provision of drinking water with 0.3 mM PPi to mice heterozygous for inactivating mutations in
Enpp1
during pregnancy robustly inhibited ectopic calcification in their
Enpp1
−/−
offspring. Our work shows that orally administered PPi is readily absorbed in humans and mice and inhibits connective tissue calcification in mouse models of PXE and GACI. PPi, which is recognized as safe by the FDA, therefore not only has great potential as an effective and extremely low‐cost treatment for these currently intractable genetic disorders, but also in other conditions involving connective tissue calcification.
Synopsis
At variance with previous assumptions, orally administered pyrophosphate appears in the circulation in humans and in mice and attenuates connective tissue calcification in mouse models of pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI).
Elevation of plasma PPi level in individuals who ingested one dose of Na
4
PPi, equivalent to 23% of the maximal tolerable daily dose is enough to transiently restore plasma PPi levels.
Na
4
PPi provided in the drinking water in millimolar concentrations inhibited calcification of the dermal sheet of the vibrissae in PXE and in the GACI mice.
The inhibitory effect of PPi on the calcification of the arteries was as robust as 75–88% in offspring when heterozygous GACI mothers received 0.3 mM PPi exclusively during pregnacy.
Orally taken PPi may represent a simple route to achieve therapeutic solution for treating diseases caused by or accompanied with connective tissue (arterial) calcification.
Graphical Abstract
At variance with previous assumptions, orally administered pyrophosphate appears in the circulation in humans and in mice and attenuates connective tissue calcification in mouse models of pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI).
Journal Article
Acoustic complexity of pup isolation calls in Mongolian hamsters: 3-frequency phenomena and chaos
Abstract
Studying pup isolation calls of wild rodents provides background for developing new early-life animal models for biomedical research and drug testing. This study discovered a highly complex acoustic phenotype of pup isolation calls in 4–5-day-old Mongolian hamsters Allocricetulus curtatus. We analyzed the acoustic structure of 5,010 isolation calls emitted in the broad range of frequencies (sonic, below 20 kHz, and ultrasonic, from 20 to 128 kHz) by 23 pups during 2-min isolation test trials, 1 trial per pup. In addition, we measured 5 body size parameters and the body weight of each pup. The calls could contain up to 3 independent fundamental frequencies in their spectra, the low (f0), the medium (g0), and the high (h0), or purely consisted of chaos in which the fundamental frequency could not be tracked. By presence/absence of the 3 fundamental frequencies or their combinations and chaos, we classified calls into 6 distinctive categories (low-frequency [LF]-f0, LF-chaos, high-frequency [HF]-g0, HF-h0, HF-g0 + h0, and HF-chaos) and estimated the relative abundance of calls in each category. Between categories, we compared acoustic parameters and estimated their relationship with pup body size index. We discuss the results of this study with data on the acoustics of pup isolation calls reported for other species of rodents. We conclude that such high complexity of Mongolian hamster pup isolation calls is unusual for rodents. Decreased acoustic complexity serves as a good indicator of autism spectrum disorders in knockout mouse models, which makes knockout hamster models prospective new wild animal model of neurodevelopmental disorders.
Journal Article
Temperature- and Age-Dependent Seizures in a Mouse Model of Severe Myoclonic Epilepsy in Infancy
Heterozygous loss-of-function mutations in the α subunit of the type I voltage-gated sodium channel $Na_V 1.1$ cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEl), created by heterozygous deletion of $Na_V 1.1$ channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spikeand-wave activity in mSMEl. Combined video-EEG monitoring demonstrated that mSMEl had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P) 17-18 mSMEl had temperature-induced seizures, but nearly all P20-22 and P30-46 mSMEl had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEl become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30-46 mSMEl but not in P20-22 or P17-18 mSMEl, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20-22 mSMEl had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.
Journal Article
Treating Generational Stress: Effect of Paternal Stress on Development of Memory and Extinction in Offspring Is Reversed by Probiotic Treatment
Early-life adversity is a potent risk factor for mental-health disorders in exposed individuals, and effects of adversity are exhibited across generations. Such adversities are also associated with poor gastrointestinal outcomes. In addition, emerging evidence suggests that microbiota-gut-brain interactions may mediate the effects of early-life stress on psychological dysfunction. In the present study, we administered an early-life stressor (i.e., maternal separation) to infant male rats, and we investigated the effects of this stressor on conditioned aversive reactions in the rats' subsequent infant male offspring. We demonstrated, for the first time, longer-lasting aversive associations and greater relapse after extinction in the offspring (F1 generation) of rats exposed to maternal separation (F0 generation), compared with the offspring of rats not exposed to maternal separation. These generational effects were reversed by probiotic supplementation, which was effective as both an active treatment when administered to infant F1 rats and as a prophylactic when administered to F0 fathers before conception (i.e., in fathers' infancy). These findings have high clinical relevance in the identification of early-emerging putative risk phenotypes across generations and of potential therapies to ameliorate such generational effects.
Journal Article
Caregiver maltreatment causes altered neuronal DNA methylation in female rodents
Negative experiences with a caregiver during infancy can result in long-term changes in brain function and behavior, but underlying mechanisms are not well understood. It is our central hypothesis that brain and behavior changes are conferred by early childhood adversity through epigenetic changes involving DNA methylation. Using a rodent model of early-life caregiver maltreatment (involving exposure to an adverse caregiving environment for postnatal days 1–7), we have previously demonstrated abnormal methylation of DNA associated with the brain-derived neurotrophic factor (Bdnf) gene in the medial prefrontal cortex (mPFC) of adult rats. The aim of the current study was to characterize Bdnf DNA methylation in specific cell populations within the mPFC. In the prefrontal cortex, there is approximately twice as many neurons as glia, and studies have recently shown differential and distinctive DNA methylation patterns in neurons versus nonneurons. Here, we extracted nuclei from the mPFC of adult animals that had experienced maltreatment and used fluorescence-activated cell sorting to isolate cell types before performing bisulfite sequencing to estimate methylation of cytosine–guanine sites. Our data indicate that early-life stress induced methylation of DNA associated with Bdnf IV in a cell-type and sex-specific manner. Specifically, females that experienced early-life maltreatment exhibited greater neuronal cytosine–guanine methylation compared to controls, while no changes were detected in Bdnf methylation in males regardless of cell type. These changes localize the specificity of our previous findings to mPFC neurons and highlight the capacity of maltreatment to cause methylation changes that are likely to have functional consequences for neuronal function.
Journal Article
Anogenital Distance from Birth to 2 Years: A Population Study
Background: Anogenital distance (AGD) is sexually dimorphic in rodents anil humans, being 2- to 2. 5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. Objective: This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. Materials and Methods: Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. Results: Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (± SD) at birth was 19.8 ± 6.1 mm in males and 9.1 ± 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex- dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r = 0.20, p = 0.001). Conclusion: We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.
Journal Article