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Giant Depolarizing Potentials (GDPs) and Early Sharp Waves (eSPWs) are the major patterns of neuronal network activity in the developing hippocampus of neonatal rodents in vitro and in vivo, respectively. Because of certain similarities in their electrographic traits, GDPs and eSPWs were originally considered as homologous patterns. Here, we compared electrographic features and current density profiles of field GDPs (fGDPs) and eSPWs using extracellular multisite silicon probe recordings from neonatal rat CA1 hippocampus. We found that fGDPs in hippocampal slices were much less in amplitude than eSPWs, and were characterized by electronegativity and current sinks in CA1 pyramidal cell layer and stratum radiatum, and positive waves/sources in stratum lacunosum-moleculare. eSPWs in vivo showed a remarkably different depth profile, with positivity and current source in the CA1 pyramidal cell layer, and negativity/sinks in stratum radiatum and stratum lacunosum-moleculare. Current sinks of CA3-evoked responses corresponded to sinks of fGDPs and eSPWs in the stratum radiatum. However, current sinks of entorhinal inputs - evoked responses in stratum lacunosum-moleculare, which were characteristic of eSPWs, were absent in fGDPs. In addition, fGDPs more strongly modulated neuronal firing in CA1 compared to eSPWs. Thus, we show important differences in the electrographic properties of GDPs and eSPWs that challenge the homology of these two activity patterns., Competing Interests: Declaration of Competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Early nutritional challenges can lead to permanent metabolic changes, increasing risk of developing chronic diseases later in life. Total parenteral nutrition (TPN) is a life-saving nutrition regimen, used especially in intrauterine growth-restricted (IUGR) neonates. Early TPN feeding alters metabolism, but whether these alterations are permanent is unclear. Programmed metabolism is likely caused by epigenetic changes due to imbalances of methyl nutrients., Objectives: We sought to determine whether feeding TPN in early life would increase risk of developing dyslipidemia in adulthood and whether supplementing the methyl nutrients betaine and creatine to TPN would prevent this development. We also sought to determine whether IUGR exacerbates the effects of neonatal TPN on lipid metabolism in adulthood., Methods: Female piglets (n = 32; 7 d old) were used in 4 treatments: 24 normal-weight piglets were randomly assigned to sow-fed (SowFed), standard TPN (TPN-control), and TPN with betaine and creatine (TPN-B+C); 8 IUGR piglets were fed control TPN (TPN-IUGR) as a fourth group. After 2 wk of treatment, all pigs were then fed a standard solid diet. At 8 mo old, central venous catheters were implanted to conduct postprandial fat tolerance tests., Results: Feeding TPN in the neonatal period led to dyslipidemia in adulthood, as indicated by higher postprandial triglyceride (TG) levels in TPN-control (P < 0.05), compared with SowFed. IUGR piglets were particularly sensitive to neonatal TPN feeding, as TPN-IUGR piglets developed obesity and dyslipidemia in adulthood, as indicated by greater backfat thickness (P < 0.05), higher liver TG (P < 0.05), slower postprandial TG clearance (P < 0.05), and elevated fasting plasma nonhigh-density lipoprotein-cholesterol (P < 0.01), and nonesterified fatty acids (P < 0.001), compared with TPN-control., Conclusions: Feeding TPN in early life increases the risk of developing dyslipidemia in adulthood, especially in IUGR neonates; however, methyl nutrient supplementation to TPN did not prevent TPN-induced changes in lipid metabolism., Competing Interests: Conflict of interest RFB is an Editorial Board Member for the Journal of Nutrition and played no role in the Journal’s evaluation of the manuscript. All other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of preterm infants that is associated with life-long morbidities. Inflammatory insults contribute to BPD pathogenesis. Although the proinflammatory cytokine, IL-17a, plays a role in various neonatal inflammatory disorders, its role in BPD pathogenesis is unclear. To test the hypothesis that blocking IL-17a signaling decreases lipopolysaccharide (LPS)-mediated experimental BPD in neonatal mice, wild-type mice were injected intraperitoneally with phosphate-buffered saline or LPS during the saccular lung developmental phase. Pulmonary IL-17a expression was determined by enzyme-linked immunosorbent assay and by flow cytometry. LPS-injected mice had higher pulmonary IL-17a protein levels and IL-17a + and IL-22 + cells. γδ T cells, followed by non-T lymphoid cells, were the primary producers of IL-17a. Wild-type mice were then injected intraperitoneally with isotype antibody (Ab) or IL-17a Ab, while they were treated with phosphate-buffered saline or LPS, followed by quantification of lung inflammatory markers, alveolarization, vascularization, cell proliferation, and apoptosis. LPS-mediated alveolar simplification, apoptosis, and cell proliferation inhibition were significantly greater in mice treated with isotype Ab than in those treated with IL-17a Ab. Furthermore, STAT1 activation and IL-6 levels were significantly greater in LPS-exposed mice treated with isotype Ab than in those treated with IL-17a Ab. The study results indicate that blocking IL-17a signaling decreases LPS-mediated experimental BPD., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Weaning is a decisive event in piglets' life. This study aimed to evaluate whether the inclusion of fish oil, rich in eicosapentaenoic and docosahexaenoic acids (EPA and DHA), in sow and piglet diets, increased the concentration of anti-inflammatory molecules in the blood of weaned piglets and whether the effect was dependent on the pigs being born with either low or a high birth BW (bBW). Thirty-six sows in four consecutive batches were randomly distributed between a control diet with animal fat (15 g/kg in gestation and 30 g/kg in lactation) or a n-3 long-chain fatty acid diet (LCFA; totally or half replacing animal fat by fish oil during gestation and lactation, respectively) from service until weaning (ca. 28 days). At birth, the two lightest (LBW) and the two heaviest (HBW) piglets in each litter were identified and, at weaning, grouped in pens by pairs prioritising their bBW. Pens were further distributed into a control (30 g/kg animal fat) or n-3 LCFA diet (totally replacing animal fat by fish oil) for 28 days. At the end of the trial, blood was collected from piglets in the first batch (n = 48). Serum fatty acids (FAs) were quantified by GC, plasma oxylipins by ultra-HPLC-MS, and plasma immune indicators by ELISA. An interaction between piglet diet and bBW for average daily gain (P = 0.020) and average daily feed intake (P = 0.014) during the whole postweaning indicated that dietary n-3 LCFA-promoted LBW piglets to have a similar growth and intake than HBW piglets reaching 1.5 kg average BW more at the end of the postweaning period than LBW control piglets. Fish oil in piglet diets also increased the concentrations of total n-3 FA, EPA and DHA (all P < 0.001), their resultant oxylipins, particularly their hydroxy derivatives from lipoxygenase enzymatic pathway (all P < 0.001) and tended to increase immunoglobulin M (P = 0.067) in blood. Regarding the bBW category, LBW piglets tend to increase tumour necrosis factor α in plasma (P = 0.083) compared to HBW. It is concluded that fish oil in postweaning diets could enhance the daily gain and feed intake of LBW piglets, increasing the concentration of serum n-3 FAs and their derived oxylipins in plasma., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia., Methods: Neonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey's post-hoc tests for group comparisons., Results: Pup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024)., Conclusion: Our findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD's neuroprotective effects. Further research is essential to explore CBD's clinical applications and its potential role in treating human neurodevelopmental disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 © 2024 The Japanese Society of Child Neurology. Elsevier B.V. Published by Elsevier B.V. All rights reserved.)

Background: Repeated exposure to sevoflurane during early developmental stages is a risk factor for social behavioural disorders, but the underlying neuropathological mechanisms remain unclear. As the hippocampal cornu ammonis area 2 subregion (CA2) is a critical centre for social cognitive functions, we hypothesised that sevoflurane exposure can lead to social behavioural disorders by disrupting neuronal activity in the CA2., Methods: Neonatal mice were anaesthetised with sevoflurane 3 vol% for 2 h on postnatal day (PND) 6, 8, and 10. Bulk RNA sequencing of CA2 tissue was conducted on PND 12. Social cognitive function was assessed by behavioural experiments, and in vivo CA2 neuronal activity was recorded by multi-channel electrodes on PND 60-65., Results: Repeated postnatal exposure to sevoflurane impaired social novelty recognition in adulthood. It also caused a decrease in the synchronisation of neuronal spiking, gamma oscillation power, and spike phase-locking between GABAergic spiking and gamma oscillations in the CA2 during social interaction. After sevoflurane exposure, we observed a reduction in the density and dendritic complexity of CA2 GABAergic neurones, and decreased expression of transcription factors critical for GABAergic neuronal development after., Conclusions: Repeated postnatal exposure to sevoflurane disturbed the development of CA2 GABAergic neurones through downregulation of essential transcription factors. This resulted in impaired electrophysiological function in adult GABAergic neurones, leading to social recognition deficits. These findings reveal a potential electrophysiological mechanism underlying the long-term social recognition deficits induced by sevoflurane and highlight the crucial role of CA2 GABAergic neurones in social interactions., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

In the past, we demonstrated that oligodeoxynucleotides containing CpG motifs (CpG-ODN) mimicking bacterial DNA, stimulate the innate immune system of neonatal broiler chickens and protect them against Escherichia coli and Salmonella Typhimurium (S. Typhimurium) septicemia. The first line of innate immune defense mechanism is formed by heterophils and plays a critical protective role against bacterial septicemia in avian species. Therefore, the objectives of this study were 1) to explore the kinetics of CpG-ODN mediated antibacterial mechanisms of heterophils following single or twice administration of CpG-ODN in neonatal broiler chickens and 2) to investigate the kinetics of the immunoprotective efficacy of single versus twice administration of CpG-ODN against S. Typhimurium septicemia. In this study, we successfully developed and optimized flow cytometry-based assays to measure phagocytosis, oxidative burst, and degranulation activity of heterophils. Birds that received CpG-ODN had significantly increased (p < 0.05) phagocytosis, oxidative burst, and degranulation activity of heterophils as early as 24 h following CpG-ODN administration. Twice administration of CpG-ODN significantly increased the phagocytosis activity of heterophils. In addition, our newly developed CD107a based flow cytometry assay demonstrated a significantly higher degranulation activity of heterophils following twice than single administration of CpG-ODN. However, the oxidative burst activity of heterophils was not significantly different between birds that received CpG-ODN only once or twice. Furthermore, delivery of CpG-ODN twice increased immunoprotection against S. Typhimurium septicemia compared to once but the difference was not statistically significant. In conclusion, we demonstrated enhanced bactericidal activity of heterophils after administration of CpG-ODN to neonatal broiler chickens. Further investigations will be required to identify other activated innate immune cells and the specific molecular pathways associated with the CpG-ODN mediated activation of heterophils., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

One hundred and forty bitches and their offspring (689 puppies) were involved in this study. The influence of different maternal features such as age, breed (brachycephalic/non-brachycephalic), previous births (primiparous/multiparous), health status (complete/incomplete) and litter size over the type of cesarean sections (scheduled/emergency), the neonatal survival, and the incidence of congenital malformations were also examined. Scheduled cesareans were predominant (104/140), of which 90 % were brachycephalic breeds and females were mostly between 2 and 4 years old (54.8 %), multiparous (88.4 %) and with a correct health status (67.3 %). Emergency cesarean sections mainly involved non-brachycephalic breeds (80 %) and were carried out mostly in females under 4 years of age (72.2 %), primiparous (77.7 %), with incomplete health status and a large litter size (47.2 %). Perinatal mortality was notably higher in emergency C-sections (3.25 % and 13.3 %, scheduled and emergency C-sections, respectively); the highest incidence of neonatal mortality was recorded in young females (<2, 2-4 years old), primiparous and with incomplete health status. Congenital anomalies were observed in 4.50 % (31/689) of the puppies, with anasarca (38.71 %) and cleft palate (29.03 %) being the most frequently observed malformations. A higher incidence of congenital malformations was detected in puppies from dams with incomplete sanitary health and from inbreeding cross. Overall, the study provides valuable insights into the complex interplay between maternal characteristics and cesarean outcomes. Appropriate genetic selection, good sanitary health conditions, and the age of the reproducers, are pivotal factors in planning for gestation and improving the survival of neonates., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to postnatal systemic inflammation is associated with increased risk of brain injury in preterm infants, leading to impaired maturation of the cerebral cortex and adverse neurodevelopmental outcomes. However, the optimal method for identifying cortical dysmaturation is unclear. Herein, we compared the utility of electroencephalography (EEG), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) at different recovery times after systemic inflammation in newborn rats., Methods: Sprague Dawley rat pups of both sexes received single-daily lipopolysaccharide (LPS; 0.3 mg/kg i.p.; n = 51) or saline (n = 55) injections on postnatal days (P)1, 2, and 3. A subset of these animals were implanted with EEG electrodes. Cortical EEG was recorded for 30 min from unanesthetized, unrestrained pups at P7, P14, and P21, and in separate groups, brain tissues were collected at these ages for ex-vivo MRI analysis (9.4 T) and Golgi-Cox staining (to assess neuronal morphology) in the motor cortex., Results: Postnatal inflammation was associated with reduced cortical pyramidal neuron arborization from P7, P14, and P21. These changes were associated with dysmature EEG features (e.g., persistence of delta waveforms, higher EEG amplitude, reduced spectral edge frequency) at P7 and P14, and higher EEG power in the theta and alpha ranges at P21. By contrast, there were no changes in cortical DTI or NODDI in LPS rats at P7 or P14, while there was an increase in cortical fractional anisotropy (FA) and decrease in orientation dispersion index (ODI) at P21., Conclusions: EEG may be useful for identifying the early evolution of impaired cortical development after early life postnatal systemic inflammation, while DTI and NODDI seem to be more suited to assessing established cortical changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Musculoskeletal abnormalities in neonate equids represent a common condition, which includes angular limb deformities, defective carpal/tarsal bone ossification, contracted limb and mandibular/maxillary prognathism. The present case report described the presentation and surgical management of multiple musculoskeletal abnormalities in a mule foal. A newborn mule foal was presented for several musculoskeletal abnormalities, such as angular deviation from the sagittal plane of both carpal joints, hind limb ligament laxity, and severe mandibular prognathism. Surgical management of mandibular prognathism was then treated through the application of a tension orthodontic wire. Postoperatively, there was a significant improvement in the correction of mandibular malocclusion and no further correction was needed. Management of other anomalies was mainly conservative, with stall rest and exercise limitations, with a considerable improvement in the first month of life. Thus, jaw malformations might be observed also in mule foals, and might be associated with multiple congenital abnormalities. Early recognition, appropriate management, and surgical treatment were essential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The objective of this study was to investigate how the cumulative expulsion interval, litter size, and birth order influence the characteristics of newborn piglets from hyperprolific sows, as well as their intake of colostrum. Analysis was conducted on the temporal aspects of parturition in 254 sows, including 3920 piglets. Newborn piglet characteristics examined encompassed delivery time, birth order, birth status, umbilical cord rupture, meconium staining, delivery ease, birth weight, blood oxygen saturation, and heart rate. From the raw data, colostrum intake, birth interval, and cumulative birth interval of each piglet were computed. Piglets were sorted based on the cumulative expulsion interval into nine categories: 0-30, 31-60, 61-90, 91-120, 121-150, 151-180, 181-210, 211-240, and >240 min. Litter sizes were categorized into three groups: 10-13, 14-17, and ≥18 piglets per litter. The birth-order ranking referred to the piglet's position within a litter and was categorized into four quartiles: 1, 2, 3, and 4. On average, the expulsion interval, cumulative expulsion interval, and colostrum consumption were 14.8 ± 21.8 min, 138.6 ± 155.7 min, and 407.6 ± 162.1 g, respectively. In litters with ≥18 piglets, the percentage of piglets with inadequate colostrum intake (<300 g) was higher compared to litters with 10-13 piglets (33.1 % vs. 12.9 %, P < 0.001) and 14-17 piglets (23.9 %, P < 0.001). The occurrence of stillbirths in the fourth quartile of the litter was higher than in the first (16.0 % vs. 2.2 %, P < 0.001), second (4.0 %, P < 0.001), and third (7.8 %, P < 0.001) quartiles. Among litters with ≥18 piglets, those born in the third quartile exhibited lower colostrum consumption compared to those born in the first quartile (346.0 ± 9.9 vs. 391.4 ± 8.6 g, P = 0.028). Colostrum intake decreased with longer cumulative expulsion intervals, evident from a notable decline starting at 90 min post-farrowing compared to piglets born within the first 30 min (P = 0.004). Interestingly, colostrum consumption exhibited a negative correlation with the cumulative expulsion interval (P < 0.001), but not with individual piglet expulsion intervals (P = 0.460). Piglets born with meconium staining were most prevalent among those with a cumulative expulsion interval of >240 min. In summary, both the cumulative expulsion interval and birth-order ranking significantly impact the physiological characteristics of newborn piglets and their colostrum intake. Colostrum consumption decreases and newborn piglet characteristics change with higher cumulative expulsion intervals. Identifying piglets at high risk of hypoxia and implementing appropriate treatments and management strategies within an optimal timeframe could aid pig producers in reducing pre-weaning mortality among piglets born to hyperprolific sows., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hypoxic-ischemic brain damage (HIBD) in the perinatal period is an important cause of cerebral damage and long-term neurological sequelae, and can place much pressure on families and society. Our previous study demonstrated that miRNA-326 reduces neuronal apoptosis by up-regulating the δ-opioid receptor (DOR) under oxygen-glucose deprivation in vitro. In the present study, we aimed to explore the neuroprotective effects of the miRNA-326/DOR axis by inhibiting apoptosis in HIBD using neonatal miRNA-326 knockout mice. Neonatal C57BL/6 mice, neonatal miRNA-326 knockout mice, and neonatal miRNA-326 knockout mice intraperitoneally injected with the DOR inhibitor naltrindole were treated with hypoxic-ischemia (HI). Neurological deficit scores, magnetic resonance imaging, terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling, and Caspase-3, Bax, and B-cell lymphoma 2 (Bcl-2) expression were evaluated on day 2 after HI. Neurobehavioral analyses were performed on days 2 and 28 after HI. Additionally, the Morris water maze test was conducted on days 28. Compared with HI-treated neonatal C57BL/6 mice, HI-treated neonatal miRNA-326 knockout mice had higher neurological deficit scores, smaller cerebral infarction areas, and improved motor function, reaction ability, and long-term spatial learning and memory. These effects were likely the result of inhibiting apoptosis; the DOR inhibitor reversed these neuroprotective effects. Our findings indicate that miRNA-326 knockout plays a neuroprotective effect in neonatal HIBD by inhibiting apoptosis via the target gene DOR., Competing Interests: Declaration of Competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated., Methods: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed., Results: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement., Conclusion: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aging leads to biochemical and biomechanical changes in skin, with biological and functional consequences. Despite extensive literature on skin aging, there is a lack of studies which investigate the maturation of the tissue and connect the microscopic changes in the skin to its macroscopic biomechanical behavior as it evolves over time. The present work addresses this knowledge gap using multiscale characterization of skin in a murine model considering newborn, adult and aged mice. Monotonic uniaxial loading, tension relaxation with change of bath, and loading to failure tests were performed on murine skin samples from different age groups, complemented by inflation experiments and atomic force microscopy indentation measurements. In parallel, skin samples were characterized using histological and biochemical techniques to assess tissue morphology, collagen organization, as well as collagen content and cross-linking. We show that 1-week-old skin differs across nearly all measured parameters from adult skin, showing reduced strain stiffening and tensile strength, a thinner dermis, lower collagen content and altered crosslinking patterns. Surprisingly, adult and aged skin were similar across most biomechanical parameters in the physiologic loading range, while aged skin had lower tensile strength and lower stiffening behavior at large force values. This correlates with altered collagen content and cross-links. Based on a computational model, differences in mechanocoupled stimuli in the skin of the different age groups were calculated, pointing to a potential biological significance of the age-induced biomechanical changes in regulating the local biophysical environment of dermal cells. STATEMENT OF SIGNIFICANCE: Skin microstructure and the emerging mechanical properties change with age, leading to biological, functional and health-related consequences. Despite extensive literature on skin aging, only very limited quantitative data are available on microstructural changes and the corresponding macroscopic biomechanical behavior as they evolve over time. This work provides a wide-range multiscale mechanical characterization of skin of newborn, adult and aged mice, and quantifies microstructural correlations in tissue morphology, collagen content, organization and cross-linking. Remarkably, aged skin retained normal hydration and normal biomechanical function in the physiological loading range but showed significantly reduced properties at super-physiological loading. Our data show that age-related microstructural differences have a profound effect not only on tissue-level properties but also on the cell-level biophysical environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The most common and efficient iron supply to prevent neonatal anaemia in piglets is the injection of iron dextran or gleptoferron. This treatment is problematic in organic farms because organic specifications strictly limit the use of chemically synthesised allopathic drugs. Based on the observation that piglets raised outdoors rarely develop anaemia, we hypothesised that piglets satisfy their iron needs by ingesting soil from their environment. Therefore, we compared the efficacy of a 100-mg intramuscular iron dextran injection (Iron, 8 litters, n = 98 piglets) at 4 days (d) of age (d4), to a daily ad libitum supply of dried soil (Soil, 8 litters, n = 101) or dried peat-like river silt (Peat, 8 litters, n = 102) from d4 to weaning (at 49 days of age, d49). Pigs were raised according to organic farming rules. Blood was collected on three males and three females per litter on d4, 20, 41, 50 and 69. BW was similar in the three groups on d4, 20, 41, 50 and 69 (P > 0.1). During the experiment, piglets were affected by a severe digestive E. coli episode but litter mortality rate between d4 and d69 did not differ between groups (P > 0.1). Blood haemoglobin concentration (Hb) was similar in all groups on d4, 50 and 69. However, on d20, Hb was higher in Peat and Iron groups than in the Soil group (P < 0.001), and on d41 and d50, Hb was higher in the Peat group than in Iron and Soil groups (P < 0.001). Mean red blood cell volume (RBCV) remained stable over time in the Peat group. In comparison, RBCV dropped in the Soil group on d20 and d41 (P < 0.001), and in the Iron group on d41 (P < 0.001). Soil and Iron group RBCV returned values similar to the Peat group by d69 (P > 0.1). In conclusion, soil supply in the pen was not sufficient to ensure a satisfactory iron intake in piglets, unlike peat-like river silt, which enable to reach haemoglobin concentrations above 80 mg/mL for over 90% of the piglets from d20 and, over 100% of piglets at weaning. The daily supply of the silt proved more efficient than the 100-mg iron injection beyond 20 days., (Copyright © 2024. Published by Elsevier B.V.)

While the benefits of early antiretroviral therapy (ART) initiation in perinatally infected infants are well documented, early initiation is not always possible in postnatal pediatric HIV infections. The timing of ART initiation is likely to affect the size of the latent viral reservoir established, as well as the development of adaptive immune responses, such as the generation of neutralizing antibody responses against the virus. How these parameters impact the ability of infants to control viremia and the time to viral rebound after ART interruption is unclear and has never been modeled in infants. To investigate this question we used an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT and either given ART at 4-7 days post-infection (early ART condition), at 2 weeks post-infection (intermediate ART condition), or at 8 weeks post-infection (late ART condition). These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. To gain insight into early after analytic treatment interruption (ATI), we constructed mathematical models to investigate the effect of time of ART initiation in delaying viral rebound when treatment is interrupted, focusing on the relative contributions of latent reservoir size and autologous virus neutralizing antibody responses. We developed a stochastic mathematical model to investigate the joint effect of latent reservoir size, the autologous neutralizing antibody potency, and CD4+ T cell levels on the time to viral rebound for RMs rebounding up to 60 days post-ATI. We find that the latent reservoir size is an important determinant in explaining time to viral rebound in infant macaques by affecting the growth rate of the virus. The presence of neutralizing antibodies can also delay rebound, but we find this effect for high potency antibody responses only. Finally, we discuss the therapeutic implications of our findings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Conway has served as a consultant for Excision BioTherapeutics and Merck. Dr. Permar serves a consultant for Moderna, Merck, Pfizer, GSK, Dynavax, and Hoopika on their CMV vaccine program and has led a sponsored program with Moderna and Merck on CMV vaccines., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages secreted proteins most consistent with an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1α (HIF-1α). In contrast, adult macrophages secreted proteins consistent with a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1α dependent macrophage responses that may be targeted to calibrate the innate immune response during stress and inflammation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intrauterine growth restriction (IUGR) is defined as inadequate foetal growth during gestation. In response to placenta insufficiency, IUGR piglets prioritise brain development as a survival mechanism. This adaptation leads to a higher brain-to-liver weight ratio (BrW/LW) at birth. This study assessed the potential of using morphometric traits to estimate brain (BrW) and liver (LW) weights, enabling non-invasive diagnosis of IUGR in newborn piglets. At birth, body weight (BtW) of individual piglets (n = 144) was recorded. One day (± 1) after birth, BrW and LW were measured with computed tomography (n = 94) or by weighing the organs after natural death or euthanasia (n = 50). Additionally, 20 morphometric traits were captured from images of each piglet and correlated with the BrW and LW. The morphometric traits that showed a r ≥ 0.70 in linear correlation with the BrW or LW were selected. Each selected trait was combined as an independent variable with BtW to develop multiple linear regression models to predict the BrW and LW. Six models were chosen based on the highest adjusted R 2 value: three for estimating BrW and three for LW. The dataset was then randomly divided into a training (75% of the data) and a testing (remaining 25%) subsets. Within the training subset, three equations to predict the BrW and three to predict the LW were extrapolated from the six selected models. The equations were then applied to the testing subset. The accuracy of the equations in predicting organ weight was assessed by calculating mean absolute and mean absolute percentage error (MAE and MAPE) between predicted and actual BrW and LW. To predict the BrW/LW, an equation including BtW and the two morphometric traits which better predicted BrW and LW was used. In the testing dataset, the equation combining ear distance and BtW better estimated the BrW. The equation performed with a MAE of 1.95 and a MAPE of 0.06 between the true and estimated weight of the brain. For the liver, the equation combining the abdominal area delimited by a square and BtW displayed the best performance, with a MAE of 9.29 and a MAPE of 0.17 between the true and estimated weight. Finally, the MAE and MAPE between the actual and estimated BrW/LW were 0.14 and 0.17, respectively. These findings suggest that specific morphometric traits can be used to estimate brain and liver weights, facilitating accurate and non-invasive identification of IUGR in newborn piglets., (Copyright © 2024 Agroscope. Published by Elsevier B.V. All rights reserved.)

Aims: Neonatal necrotizing enterocolitis (NEC) is a leading cause of intestine inflammatory disease, and macrophage is significantly activated during NEC development. Posttranslational modifications (PTMs) of proteins, particularly ubiquitination, play critical roles in immune response. This study aimed to investigate the effects of ubiquitin-modified proteins on macrophage activation and NEC, and discover novel NEC-related inflammatory proteins., Materials and Methods: Proteomic and ubiquitin proteomic analyses of intestinal macrophages in NEC/healthy mouse pups were carried out. In vitro macrophage inflammation model and in vivo NEC mouse model, as well as clinical human samples were used for further verification the inhibitor of nuclear factor-κB kinase α (IKKα) ubiquitination on NEC development through Western blot, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry., Key Findings: We report here that IKKα was a new ubiquitin-modified protein during NEC through ubiquitin proteomics, and RING finger protein 31 (RNF31) acted as an E3 ligase to be involved in IKKα degradation. Inhibition of IKKα ubiquitination and degradation with siRNF31 or proteasome inhibitor decreased nuclear factor-κB (NF-κB) activation, thereby decreasing the expression of pro-inflammatory factors and M1 macrophage polarization, resulting in reliving the severity of NEC., Significance: Our study suggests the activation of RNF31-IKKα-NF-κB axis triggering NEC development and suppressing RNF31-mediated IKKα degradation may be therapeutic strategies to be developed for NEC treatment., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

An established technology to create cloned animals is through the use of somatic cell nuclear transfer (SCNT), in which reprogramming the somatic cell nucleus to a totipotent state by enucleated oocyte cytoplasm is a necessary process, including telomere length reprogramming. The limitation of this technology; however, is that the live birth rate of offspring produced through SCNT is significantly lower than that of IVF. Whether and how telomere length play a role in the development of cloned animals is not well understood. Only a few studies have evaluated this association in cloned mice, and fewer still in cloned cows. In this study, we investigated the difference in telomere length as well as the abundance of some selected molecules between newborn deceased cloned calves and normal cows of different ages either produced by SCNT or via natural conception, in order to evaluate the association between telomere length and abnormal development of cloned cows. The absolute telomere length and relative mitochondrial DNA (mtDNA) copy number were determined by real-time quantitative PCR (qPCR), telomere related gene abundance by reverse-transcription quantitative PCR (RT-qPCR), and senescence-associated β-galactosidase (SA-β-gal) expression by SA-β-gal staining. The results demonstrate that the newborn deceased SCNT calves had significantly shortened telomere lengths compared to newborn naturally conceived calves and newborn normal SCNT calves. Significantly lower mtDNA copy number, and significantly lower relative abundance of LMNB1 and TERT, higher relative abundance of CDKN1A, and aberrant SA-β-gal expression were observed in the newborn deceased SCNT calves, consistent with the change in telomere length. These results demonstrate that abnormal telomere shortening, lower mtDNA copy number and abnormal abundance of related genes were specific to newborn deceased SCNT calves, suggesting that abnormally short telomere length may be associated with abnormal development in the cloned calves., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The renin angiotensin system (RAS) has been studied for its effects on various neurological disorders. The identification of functional receptors for Ang-(1-7) and Ang II peptides in astrocytes highlights the physiological modulation and the important role of these cells in the central nervous system. The present study aims to understand the role of RAS peptides, particularly Ang-(1-7) and Ang II, in the secretion of trophic factors by astrocytes and their effects on hippocampal neurons. We used primary cultures of astrocytes and neurons from the hippocampus of either sex neonate of Wistar strain rats. In the present study, we demonstrated that the treatment of astrocytes with Ang-(1-7) acts on the modulation of these cells, inducing reactive astrogliosis, identified through the increase in the expression of GFAP. Furthermore, we obtained a conditioned medium from astrocytes treated with Ang-(1-7), which in addition to promoting the secretion of neurotrophic factors essential for neuronal-glial interactions that are fundamental for neuritogenesis and neuronal survival, showed a neuroprotective effect against glutamatergic excitotoxicity. In turn, Ang II does not exhibit the same effects on astrocyte modulation, exacerbating deleterious effects on brain RAS. Neuron-astrocyte interactions have been shown to be an integral part of the central effects mediated by RAS, and this study has significantly contributed to the understanding of the biochemical mechanisms involved in the functioning of this system., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Previous studies suggest that being overweight and obese is capable of altering brain function during critical periods due to the higher plasticity of the brain during development. However, more literature still needs to be on the immediate effect of overnutrition and serotonin modulation in brain areas. In this study, we aimed to evaluate the effects of serotoninergic manipulation on oxidative stress and pro-inflammatory markers in the brainstem and hypothalamus of overnourished rats. The fluoxetine treatment was performed from postnatal day 3 (PND3) to postnatal day 21 (PND21) to evaluate mitochondrial function, oxidative balance, and the mRNA levels of monoaminergic molecules such as serotonin and dopamine, pro-inflammatory cytokines, and BDNF. Neonatal overnutrition induces molecular and biochemical changes in the brainstem and hypothalamus. These nutritional disturbances during lactation dysregulate energy balance and cellular redox, inducing oxidative stress. Conversely, modulation of the serotoninergic system through pharmacological use of fluoxetine was able to reverse the deleterious effects of overnutrition during lactation, enabling better brain development and delaying the development of pathologies and oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Perinatal asphyxia is one of the major causes of neonatal death at birth. Survivors can progress but often suffer from long-term sequelae. We aim to determine the effects of perinatal asphyxia on mitochondrial dynamics and whether mesenchymal stem cell secretome (MSC-S) treatment can alleviate the deleterious effects., Materials and Methods: Animals were subjected to 21 min of asphyxia at the time of delivery. MSC-S or vehicle was intranasally administered 2 h post-delivery. Mitochondrial mass (D-loop, qPCR), mitochondrial dynamics proteins (Drp1, Fis1 and OPA1, Western blot), mitochondrial dynamics (TOMM20, Immunofluorescence), as well as mitochondrial membrane potential (ΔΨ m ) (Safranin O) were evaluated at P1 and P7 in the hippocampus., Key Findings: Perinatal asphyxia increased levels of mitochondrial dynamics proteins Drp1 and S-OPA1 at P1 and Fis1 at P7. Mitochondrial density and mass were decreased at P1. Perinatal asphyxia induced sex-specific differences, with increased L-OPA1 in females at P7 and increased mitochondria circularity. In males, asphyxia-exposed animals exhibited a reduced ΔΨ m at P7. MSC-S treatment normalised levels of mitochondrial dynamics proteins involved in fission., Significance: This study provides novel insights into the effects of perinatal asphyxia on mitochondrial dynamics in the developing brain and on the therapeutic opportunities provided by mesenchymal stem cell secretome treatment. It also highlights on the relevance of considering sex as a biological variable in perinatal brain injury and therapy development. These findings contribute to the development of targeted, personalised therapies for infants affected by perinatal asphyxia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polyhexamethyleneguanidine phosphate (PHMG-P) is a biocide of guanidine family that can cause a fatal lung damage if exposed directly to the lungs. No reports exist regarding the toxicity of PHMG-P in neonatal animals. Therefore, this study aimed to determine PHMG-P toxicity in neonatal and 8-week-old mice after they were intranasally instilled with 1.5 mg/kg, 3 mg/kg, and 4.5 mg/kg PHMG-P. PHMG-P lung exposure resulted in more severe pulmonary toxicity in adult mice than in newborn mice. In the high-dose group of newborn mice, a minimal degree of inflammatory cell infiltration and fibrosis in the lung were detected, whereas more severe pathological lesions including granulomatous inflammation, fibrosis, and degeneration of the bronchiolar epithelium were observed in adult mice. At day 4, C-C motif chemokine ligand 2 (CCL2), a potent chemokine for monocytes, was upregulated but recovered to normal levels at day 15 in newborn mice. However, increased CCL2 and IL-6 levels were sustained at day 15 in adult mice. When comparing the differentially expressed genes of newborn and adult mice through RNA-seq analysis, there were expression changes in several genes associated with inflammation in neonates that were similar or different from those in adults. Although no significant lung damage occurred in newborns, growth inhibition was observed which was not reversed until the end of the experiment. Further research is needed to determine how growth inhibition from neonatal exposure to PHMG-P affects adolescent and young adult health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Abstract: Epidemiological studies report opposing influences of infection on childhood B-cell acute lymphoblastic leukemia (B-ALL). Although infections in the first year of life appear to exert the largest impact on leukemia risk, the effect of early pathogen exposure on the fetal preleukemia cells (PLC) that lead to B-ALL has yet to be reported. Using cytomegalovirus (CMV) infection as a model early-life infection, we show that virus exposure within 1 week of birth induces profound depletion of transplanted E2A-PBX1 and hyperdiploid B-ALL cells in wild-type recipients and in situ-generated PLC in Eμ-ret mice. The age-dependent depletion of PLC results from an elevated STAT4-mediated cytokine response in neonates, with high levels of interleukin (IL)-12p40-driven interferon (IFN)-γ production inducing PLC death. Similar PLC depletion can be achieved in adult mice by impairing viral clearance. These findings provide mechanistic support for potential inhibitory effects of early-life infection on B-ALL progression and could inform novel therapeutic or preventive strategies., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: To evaluate the cell proliferation and death, and structural morphology of the pancreatic islet cells of the rats with hyperglycemia in the first month of life and compare to those of the control rats., Main Methods: Female Sprague-Dawley newborn rats received Streptozotocin (a beta-cytotoxic drug) at birth for diabetes induction. Control and hyperglycemic animals were euthanized on different days of life: 5, 10, 15, and 30. The pancreas was collected and processed for immunohistochemical analysis of cleaved Caspase-3 (cell death), Ki-67 (cell proliferation), PDX-1 (transcription factor responsible for insulin synthesis), and endocrine hormones (insulin, glucagon, and somatostatin)., Key Findings: Control females showed a higher percentage (%) of Ki-67-positive( + ) cells on D10 and D15, a higher % of insulin + and somatostatin + cells on D15 and D30, a lower % of PDX-1 + cells on D10, and a higher % of glucagon + cells on D10 and D30. Hyperglycemic females showed a lower % of Ki-67 + cells on D15, a higher % of cleaved Caspase-3 + cells on D15, and insulin + cells on D15 and D30. In the comparison among the experimental groups, the hyperglycemic females showed an increased % of cleaved Caspase-3 + and Ki-67 + cells and a lower % of PDX-1 + cells., Significance: This study enabled a better understanding of the abnormal pancreas development regarding cellular proliferation, apoptosis, and hormonal synthesis in the neonatal period. Thus, the pancreatic islets of hyperglycemic rats do not reestablish the normal endocrine cell population, and cellular apoptosis overcame the proliferative activity of these cells., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Ubiquitination is an enzymatic modification involving ubiquitin chains, that can be reversed by deubiquitination (DUB) enzymes. Ubiquitin-specific protease 7 (USP7), which is also known as herpes virus-associated ubiquitin-specific protease (HAUSP), has been shown to play a vital role in cardiovascular diseases. However, the underlying molecular mechanism by which USP7 regulates cardiomyocyte function has not been reported., Methods: To understand the physiological function of USP7 in the heart, we constructed cardiomyocyte-specific USP7 conditional knockout mice., Results: We found that homozygous knockout mice died approximately three weeks after birth, while heterozygous knockout mice grew normally into adulthood. Severe cardiac dysfunction, hypertrophy, fibrosis, and cell apoptosis were observed in cardiomyocyte-specific USP7 knockout mice, and these effects were accompanied by disordered mitochondrial dynamics and cardiometabolic-related proteins., Conclusions: In summary, we investigated changes in the growth status and cardiac function of cardiomyocyte-specific USP7 knockout mice, and preliminarily explored the underlying mechanism., Competing Interests: Declaration of competing interest Authors declared that there were no known conflicts of interest associated with this publication., (Copyright © 2024. Published by Elsevier B.V.)

Allogeneic intraportal islet transplantation (ITx) has become an established treatment for patients with poorly controlled type 1 diabetes. However, the loss of viable beta-cell mass after transplantation remains a major challenge. Therefore, noninvasive imaging methods for long-term monitoring of the transplant fate are required. In this study, [ 68 Ga]Ga-DOTA-exendin-4 positron emission tomography/computed tomography (PET/CT) was used for repeated monitoring of allogeneic neonatal porcine islets (NPI) after intraportal transplantation into immunosuppressed genetically diabetic pigs. NPI transplantation (3320-15,000 islet equivalents per kg body weight) led to a reduced need for exogenous insulin therapy and finally normalization of blood glucose levels in 3 out of 4 animals after 5 to 10 weeks. Longitudinal PET/CT measurements revealed a significant increase in standard uptake values in graft-bearing livers. Histologic analysis confirmed the presence of well-engrafted, mature islet clusters in the transplanted livers. Our study presents a novel large animal model for allogeneic intraportal ITx. A relatively small dose of NPIs was sufficient to normalize blood glucose levels in a clinically relevant diabetic pig model. [ 68 Ga]Ga-DOTA-exendin-4 PET/CT proved to be efficacious for longitudinal monitoring of islet transplants. Thus, it could play a crucial role in optimizing ITx as a curative therapy for type 1 diabetes., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The gut microbiota and neurological development of neonatal mice are susceptible to environmental factors that may lead to altered behavior into adulthood. However, the role that changed gut microbiota and neurodevelopment early in life play in this needs to be clarified. In this study, by modeling early-life environmental changes by cross-fostering BALB/c mice, we revealed the effects of the environment during the critical period of postnatal development on adult social behavior and their relationship with the gut microbiota and the nervous system. The neural projections exist between the ascending colon and oxytocin neurons in the paraventricular nuclei (PVN), peripheral oxytocin levels and PVN neuron numbers decreased after cross-fostering, and sex-specific alteration in gut microbiota and its metabolites may be involved in social impairments and immune imbalances brought by cross-fostering via the gut-brain axis. Our findings also suggest that social cognitive impairment may result from a combination of PVN oxytocinergic neurons, gut microbiota, and metabolites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The success of immediate adaptation to extrauterine life depends on appropriate lung function, however, elective cesarean section can increase the risk of respiratory distress as a result of reduced pulmonary fluid absorption. This study aimed to evaluate the influence of birth mode on pulmonary clearance and respiratory performance of canine neonates in the transition period. For this purpose, 37 neonates were selected according to the obstetric condition: Vaginal Eutocia (n = 17) and Elective C-section (n = 20). Neonates were evaluated for neonatal vitality score, as well as evaluation of heart and respiratory rates, body temperature and body weight, venous hemogasometric evaluation, blood lactate and glucose, pulse oximetry and radiographic evaluation during the first 24 h of life. Additionally, amniotic fluid electrolyte composition of each puppy was evaluated. There was no influence of the type of delivery on electrolyte composition of canine amniotic fluid and neonatal pulmonary liquid content, analyzed by thoracic X-Rays. On the other hand, elective cesarean section delayed pulmonary adaptation, resulting in hypoxemia and less efficient compensatory response to acid-base imbalance and thermoregulation. In conclusion, elective c-section does not delay pulmonary clearance, whilst alters pulmonary adaptation by less efficient gas exchange and lower oxygenation, hindering the compensatory response to acid-base imbalance during the fetal-neonatal transition in dogs., Competing Interests: Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study assessed the effects of dexamethasone treatment on farrowing performance and piglet traits in the first 5 days of life in multiparous sows, a high-risk group for stillbirths and prolonged farrowing. In this study, 185 multiparous sows (parity 4.25 ± 0.14) were selected on the day of farrowing and divided into three treatments: CON - control, without dexamethasone treatment; DexaPF - treatment with dexamethasone (20 mg im per female) at the time of copious colostrum secretion (pre-farrowing); and DexaFO - treatment with dexamethasone (20 mg im per female) when the first piglet was born (farrowing onset). All sows and their litters were monitored for farrowing duration, obstetric interventions, colostrum yield and intake, newborn piglet traits, and piglet performance until 5 d of age. A subsample of 106 females (∼35 per treatment) had their blood glucose concentration checked hourly shortly after the first piglet was born until the end of farrowing. Additionally, blood samples from 42 litters were collected for immunocrit evaluation. The results showed no differences regarding farrowing duration (CON = 258.02 ± 13.81 min; DexaPF = 251.29 ± 13.60 min; DexaFO = 294.92 ± 13.89 min; P = 0.06) and obstetric intervention rates among treatments (CON = 36.58 ± 6.78 %; DexaPF = 42.16 ± 6.89 %; DexaFO = 48.05 ± 7.08 %; P = 0.45). The blood glucose concentration during farrowing was higher in DexaPF (94.56 ± 1.57 mg/dL; P < 0.001) than in CON (73.50 ± 1.72 mg/dL) and DexaFO (87.94 ± 1.80 mg/dL). No differences were observed regarding total piglets born and born alive, stillborn, newborn piglet vitality, colostrum intake, immunocrit, colostrum yield, and glycemia and rectal temperature at 24 h of age (P ≥ 0.13). Regarding meconium staining, higher percentages of piglets born without meconium staining were observed in DexaFO (54.77 ± 5.21 %; P = 0.02) compared with CON (48.58 ± 5.26 %), and no difference was observed for the DexaPF group (53.23 ± 5.21 %). In addition, a higher unbroken umbilical cord rate was observed in DexaFO (92.41 ± 1.31 %; P < 0.01) than the CON or DexaPF (86.91 ± 1.97 % and 89.31 ± 1.67 %, respectively). However, the treatments did not affect piglet performance (weight gain and survival) until 5 d of age (P ≥ 0.15). In summary, dexamethasone treatment in periparturient multiparous sows did not improve farrowing performance and key production parameters, such as the piglet weight gain and survival up to 5 d of age., Competing Interests: Declaration of competing interest No conflicts of interest to declare. The funding sponsors had no role in the design of the study, the collection, analysis, and interpretation of data, the writing of the manuscript, and the decision to publish the results., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of excessive light exposure during gestation on intrauterine development and early growth of neonates in rats., Methods: Pregnant rats were randomly allocated to three groups: the constant light exposure group, non-light exposure group and control group. Blood samples were collected from the tail vein to analyze melatonin and cortisol levels. Weight, daily food and water consumption were recorded. Uterine weight, placental weight and placental diameter were measured on gestational day 19. Natural birth and neonate growth were also monitored. The expression of NR1D1(nuclear receptor subfamily 1 group D member 1) in offspring's SCN (suprachiasmatic nuclei), liver and adipose tissue was measured. Expression of NR1D1, MT1(melatonin 1 A receptor) and 11β-HSD2 (placental 11β-hydroxysteroid dehydrogenase type 2) in placenta was also measured. Finally, the expression of MT1 and 11β-HSD2 in NR1D1 siRNA transfected JEG-3 cells was evaluated., Results: There were no significant differences in maternal weight gain, pregnancy duration, uterine weight, placental body weight, placental diameter, fetal number among three groups. There were no significant differences in weights or lengths of offspring at birth. Compared to other two groups, constant light exposure group showed significantly more rapid growth of offspring in 21st day post-birth. The expression of NR1D1 in SCN, liver and adipose tissues of offspring was not significantly different among three groups. The maternal serum melatonin and cortisol levels of the constant light exposure group were lower and higher than other two groups, respectively. The expressions of NR1D1, MT1 and 11β-HSD2 were all decreased in placenta of the constant light exposure group. The expression of MT1 and 11β-HSD2 in JEG-3 cells were decreased after NR1D1 siRNA transfection., Conclusion: Excessive light exposure during pregnancy results in elevated cortisol and reduced melatonin exposure to fetuses in uterus, potentially contributing to an accelerated early growth of offspring in rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Infant formulas (IFs), the only adequate substitute to human milk, are complex matrices that require numerous ingredients and processing steps that may impact protein digestion and subsequent amino acid (AA) absorption., Objectives: The objective was to understand the impact of the protein ingredient quality within IFs on postprandial plasma AA profiles., Methods: Four isonitrogenous and isocaloric IFs were produced at a semi-industrial scale using whey proteins from different origins (cheese compared with ideal whey) and denaturation levels (IF-A, -B, -C), and caseins with different supramolecular organizations (IF-C, -D). Ten Yucatan minipiglets (12- to 27-d-old) were used as a human infant model and received each IF for 3 d according to a Williams Latin square followed by a 2-d wash-out period. Jugular plasma was regularly sampled from 10 min preprandial to 4 h postprandial on the third day to measure free AAs, urea, insulin, and glucose concentrations. Data were statistically analyzed using a mixed linear model with diet (IFs), time, and sex as fixed factors and piglet as random factor., Results: IFs made with cheese whey (IF-A and -B) elicited significantly higher plasma total and essential AA concentrations than IFs made with ideal whey (IF-C and -D), regardless of the pre- and postprandial times. Most of the differences observed postprandially were explained by AA homeostasis modifications. IFs based on cheese whey induced an increased plasma concentration of Thr due to both a higher Thr content in these IFs and a Thr-limiting degrading capability in piglets. The use of a nonmicellar casein ingredient led to reduced plasma content of AA catabolism markers (IF-D compared with IF-C)., Conclusions: Overall, our results highlight the importance of the protein ingredient quality (composition and structure) within IFs on neonatal plasma AA profiles, which may further impact infant protein metabolism., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bronchopulmonary dysplasia (BPD) remains a significant challenge in neonatal care, the pathogenesis of which potentially involves altered lipid metabolism. Given the critical role of lipids in lung development and the injury response, we hypothesized that specific lipid species could serve as therapeutic agents in BPD. This study aimed to investigate the role of the lipid Phosphatidylcholine (PC) (16:0/14:0) in modulating BPD pathology and to elucidate its underlying mechanisms of action. Our approach integrated in vitro and in vivo methodologies to assess the effects of PC (16:0/14:0) on the histopathology, cellular proliferation, apoptosis, and molecular markers in lung tissue. In a hyperoxia-induced BPD rat model, we observed a reduction in alveolar number and an enlargement in alveolar size, which were ameliorated by PC (16:0/14:0) treatment. Correspondingly, in BPD cell models, PC (16:0/14:0) intervention led to increased cell viability, enhanced proliferation, reduced apoptosis, and elevated surfactant protein C (SPC) expression. RNA sequencing revealed significant gene expression differences between BPD and PC (16:0/14:0) treated groups, with a particular focus on Cldn1 (encoding claudin 1), which was significantly enriched in our analysis. Our findings suggest that PC (16:0/14:0) might protect against hyperoxia-induced alveolar type II cell damage by upregulating CLDN1 expression, potentially serving as a novel therapeutic target for BPD. This study not only advances our understanding of the role of lipids in BPD pathogenesis, but also highlights the significance of PC (16:0/14:0) in the prevention and treatment of BPD, offering new avenues for future research and therapeutic development., Competing Interests: Declaration of Competing Interest All authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The motor development of 14 healthy foals was observed using continuous video-recording from birth to 24 h of age. An ethogram was made of behaviours of interest with behaviour quantification using CowLog software. Behaviours were divided into six main classes: main activities, attempts to get up or lie down, nursing, playing and other skills, being helped by a human, and the foal not being visible. First-time behaviours (mean, range) of early motor development after birth included going into sternal position (5.4 min, 0-34.5 min), attempting to get up (7.6 min, 0.5-34.6 min), successfully getting up (56.4 min, 27.7 min - 1 h 43.3 min), walking (1 h 1.9 min, 28.1 min - 1 h 43.4 min), nursing (1 h 49.1 min, 1 h 10.3 min - 2 h 29.7 min), shaking (31.9 min, 0.2 min - 2 h 32.7 min), running (2 h 55.6 min, 1h 33.2 min - 6 h 12.1 min), walking backwards (4 h 12.8 min, 56.9 min - 12 h 50.6 min), frolicking (4 h 52.5 min, 2 h 3 min - 15 h 18.8 min), and autogrooming (7 h 30.3 min, 43.3 min - 14 h 40.1 min). All foals made several attempts before they were able to get up for the first time (61.9, 14-103). During the first 24 h the overall duration of lying down was highest, followed by standing and walking. This information adds to the basic information for assessing normal motor development in these animals, with the potential to identify delayed development., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Newborns exposed to birth asphyxia transiently experience deficient blood flow and a lack of oxygen, potentially inducing hypoxic-ischaemic encephalopathy and subsequent neurological damage. Immunomodulatory components in plasma may dampen these responses. Using caesarean-delivered pigs as a model, we hypothesized that dietary plasma supplementation improves brain outcomes in pigs exposed to birth asphyxia. Mild birth asphyxia was induced by temporary occlusion of the umbilical cord prior to caesarean delivery. Motor development was assessed in asphyxiated (ASP) and control (CON) piglets using neonatal arousal, physical activity and gait test parameters before euthanasia on Day 4. The ASP pigs exhibited increased plasma lactate at birth, deficient motor skills and increased glial fibrillary acidic protein levels in CSF and astrogliosis in the putamen. The expression of genes related to oxidative stress, inflammation and synaptic functions was transiently altered in the motor cortex and caudate nucleus. The number of apoptotic cells among CTIP2-positive neurons in the motor cortex and striatal medium spiny neurons was increased, and maturation of preoligodendrocytes in the internal capsule was delayed. Plasma supplementation improved gait performance in the beam test, attenuated neuronal apoptosis and affected gene expression related to neuroinflammation, neurotransmission and antioxidants (motor cortex, caudate). We present a new clinically relevant animal model of moderate birth asphyxia inducing structural and functional brain damage. The components in plasma that support brain repair remain to be identified but may represent a therapeutic potential for infants and animals after birth asphyxia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cold exposure is a common stressor for newborn goats. Skeletal muscle plays an important role in maintaining whole-body homeostasis of glucose and lipid metabolism. However, the molecular mechanisms underlying regulation of skeletal muscle of newborn goats by cold exposure remains unclear. In this study, we found a significant increase (P < 0.01) in serum glucagon levels after 24 h of cold exposure (COLD, 6°C), while glucose and insulin concentrations were significantly decreased (P < 0.01) compared to room temperature (RT, 25°C). Additionally, we found that cold exposure reduced glycogen content (P < 0.01) in skeletal muscle. Pathway enrichment analysis revealed that cold exposure activated skeletal muscle glucose metabolism pathways (including insulin resistance and the insulin signaling pathway) and mitophagy-related pathways. Cold exposure up-regulated the expression of genes involved in fatty acid and triglyceride synthesis, promoting skeletal muscle lipid deposition. Notably, cold exposure induced mitophagy in skeletal muscle., Competing Interests: Declaration of competing interest All authors have declared no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: β-casein is the main casein constituent in human milk (HM) and a source of bioactive peptides for the developing gastrointestinal tract and immune system. Infant formulas contain less β-casein than HM, but whether different concentrations of β-casein affect tolerability and gut and immune maturation in newborns is unknown., Objectives: Using near-term piglets as a model for newborn infants, we investigated whether increasing the β-casein fraction in bovine-based formula is clinically safe and may improve gut and immune maturation., Methods: Three groups of near-term pigs (96% gestation) were fed formula with bovine casein and whey protein (ratio 40:60): 1) standard skim milk casein (BCN-standard, 35% β-casein of total casein, n = 18); 2) β-casein enrichment to HM concentrations (BCN-medium, 65%, n = 19); and 3) high β-casein enrichment (BCN-high, 91%, n = 19). A reference group was fed 100% whey protein concentrate (WPC) as protein (WPC, n = 18). Intestinal and immune parameters were assessed before and after euthanasia on day 5., Results: Clinical variables (mortality, activity, body growth, and diarrhea) were similar among the groups, and no differences in intestinal or biochemical parameters were observed between BCN-standard and BCN-medium pigs. However, pigs receiving high amounts of β-casein (BCN-high) had lower small intestine weight and tended to have more intestinal complications (highest gut pathology score, permeability, and interleukin-8) than the other groups, particularly those receiving no casein (WPC pigs). Blood lymphocyte, thrombocyte, and reticulocyte counts were increased with higher β-casein, whereas eosinophil counts were reduced. In vitro blood immune cell responses were similar among groups., Conclusions: β-casein enrichment of bovine-based formula to HM concentrations is clinically safe, as judged from newborn, near-term pigs, whereas no additional benefits to gut maturation were observed. However, excessive β-casein supplementation, beyond concentrations in HM, may potentially induce gut inflammation together with increased blood cell populations relative to natural β-casein concentrations or pure whey-based formula., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Iron is crucial for growth and development, but excess iron is harmful. Neonatal mice have elevated concentrations of circulating iron, but the source of this iron is unclear. This lack of understanding makes it difficult to optimize early life iron balance., Objectives: Identify the origins of neonatal tissue-specific iron pools using dietary manipulation and cross-fostering murine models., Methods: To determine whether tissue-specific neonatal iron was primarily acquired during gestation or after birth, pups born to iron-sufficient or iron-deficient dams were cross-fostered, and tissues were harvested at postnatal days 3-5 to measure iron content. A separate set of female mice were fed a diet enriched with the stable iron isotope 57 ( 57 Fe) for 4 generations to replace naturally abundant liver iron isotope 56 ( 56 Fe) stores with 57 Fe. To quantify the proportions of neonatal iron acquired during gestation, pups born to dams with 56 Fe or 57 Fe stores were cross-fostered, and tissues were harvested at postnatal day 3-5 to determine 56 Fe: 57 Fe ratios by inductively coupled plasma mass spectrometry. Finally, to quantify the proportion of neonatal iron acquired from the maternal diet, female mice with 56 Fe or 57 Fe stores switched diets upon mating, and pup tissues were harvested on P0 to determine 56 Fe: 57 Fe ratios by inductively coupled plasma mass spectrometry., Results: Perinatal iron deficiency resulted in smaller pups, and gestational iron deficiency resulted in lower neonatal serum and liver iron. Cross-fostering between dams with 56 Fe and 57 Fe stores demonstrated that ≤70% of neonatal serum, liver, and brain iron were acquired during gestation. Dietary manipulation experiments using dams with 56 Fe and 57 Fe stores showed that over half of neonatal serum, liver, and brain iron were from the dam's gestational diet rather than preconception iron stores., Conclusions: This study provides quantitative values for the sources of neonatal iron, which may inform approaches to optimize neonatal iron status., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

In this study the efficacy of an intramuscular formulation of toltrazuril combined with gleptoferron for the control of porcine cystoisosporosis caused by Cystoisospora suis was investigated. The study was carried out on three Belgian farms with a confirmed history of C. suis infections. As none of the farms implemented a standardized toltrazuril treatment regimen for their piglets, the presence of resistant C. suis strains seems improbable. In total 90 litters, representing 1249 piglets, were included in the study and randomly allocated to either the treatment or control group. Piglets in the treatment group received a single intramuscular injection, containing 45 mg toltrazuril and 200 mg gleptoferron, between 1 and 3 days of age. Piglets in the control group received a single injection with only 200 mg gleptoferron. The effect of treatment on oocyst excretion, expressed in oocysts per gram of feces (OPG), average daily weight gain (ADG) and mortality was determined both pre- and post-weaning. A significant decrease in OPG as well as a decrease in the number of litters (pre-weaning) and pens (post-weaning) that tested positive for cystoisosporosis, was observed in the treated animals compared to the controls. Furthermore, treatment resulted in an increased ADG during the period from day 1 to day 21 (p-value: 0.03881). There was no significant difference in mortality observed between the treatment group to the control group (p-value: 0.2167). To our knowledge, this is the first report on the effect of toltrazuril on oocyst excretion after weaning. This finding highlights the potential long-term benefits of the treatment beyond the initial administration., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Bregt Decorte reports financial support was provided by CEVA Animal Health. Daniel Sperling reports a relationship with CEVA Animal Health that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aim: Neonatal intensive care treatment, including frequently performed painful procedures and administration of analgesic drugs, can have different effects on the neurodevelopment. This systematic review and meta-analysis aimed to investigate the influence of pain, opiate administration, and pre-emptive opiate administration on pain threshold in animal studies in rodents, which had a brain development corresponding to preterm and term infants., Methods: A systematic literature search of electronic data bases including CENTRAL (OVID), CINAHL (EBSCO), Embase.com, Medline (OVID), Web of Science, and PsycInfo (OVID) was conducted. A total of 42 studies examining the effect of pain (n = 38), opiate administration (n = 9), and opiate administration prior to a painful event (n = 5) in rodents were included in this analysis., Results: The results revealed that pain (g = 0.42, 95%CI 0.16-0.67, p = 0.001) increased pain threshold leading to hypoalgesia. Pre-emptive opiate administration had the opposite effect, lowering pain threshold, when compared to pain without prior treatment (g = -1.79, 95%CI -2.71-0.86, p = 0.0001). Differences were found in the meta regression for type of stimulus (thermal: g = 0.66, 95%CI 0.26-1.07, p = 0.001; vs. mechanical: g = 0.13, 95%CI -0.98-1.25, p = 0.81) and gestational age (b = -1.85, SE = 0.82, p = 0.027). In addition, meta regression indicated an association between higher pain thresholds and the amount of cumulative pain events (b = 0.06, SE = 0.03, p = 0.05) as well as severity of pain events (b = 0.94, SE = 0.28, p = 0.001)., Conclusion: Neonatal exposure to pain results in higher pain thresholds. However, caution is warranted in extrapolating these findings directly to premature infants. Further research is warranted to validate similar effects in clinical contexts and inform evidence-based practices in neonatal care., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Several single-cell RNA studies of developing mouse skin have elucidated the molecular and cellular processes involved in skin development. However, they have primarily focused on either the fetal or early postnatal period, leaving a gap in our understanding of skin development. In this study, we conducted a comprehensive time-series analysis by combining single-cell RNA-sequencing datasets collected at different stages of development (embryonic days 13.5, 14.5, and 16.5 and postnatal days 0, 2, and 4) and validated our findings through multipanel in situ spatial transcriptomics. Our analysis indicated that embryonic fibroblasts exhibit heterogeneity from a very early stage and that the rapid determination of each lineage occurs within days after birth. The expression of putative key driver genes, including Hey1, Ebf1, Runx3, and Sox11 for the dermal papilla trajectory; Lrrc15 for the dermal sheath trajectory; Zfp536 and Nrn1 for the papillary fibroblast trajectory; and Lrrn4cl and Mfap5 for the fascia fibroblast trajectory, was detected in the corresponding, spatially identified cell types. Finally, cell-to-cell interaction analysis indicated that the dermal papilla lineage is the primary source of the noncanonical Wnt pathway during skin development. Together, our study provides a transcriptomic reference for future research in the field of skin development and regeneration., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1 -/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8 + T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8 + T cells had reduced interferon-gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1 -/- neonatal CD8 + T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1 -/- neonates had increased acute pathology with HMPV or influenza. Pdcd1 -/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8 + T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8 + T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8 + T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D 2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia., Objective: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use., Methods: Neonatal treatment of animals with the dopamine D 2 -like receptor agonist quinpirole (NQ) from postnatal day (P)1-21 produces a lifelong increase in D 2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13)., Results: Pretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals., Conclusion: In conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

pathological pain and Attention-deficit/hyperactivity disorder (ADHD) are two complex multifactorial syndromes. The comorbidity of ADHD and altered pain perception is well documented in children, adolescents, and adults. According to pathophysiological investigations, the dopaminergic system's dysfunction provides a common basis for ADHD and comorbid pain. Growing evidence suggests that oxidative stress may be crucial in both pathologies. Recent studies revealed that a small peptide encompassing the redox-active site of selenoprotein T (PSELT), protects dopaminergic neurons and fibers as well as lesioned nerves in animal models. The current study aims to examine the effects of PSELT treatment on ADHD-like symptoms and pain sensitivity, as well as the role of catecholaminergic systems in these effects. Our results demonstrated that intranasal administration of PSELT reduced the hyperactivity in the open field, decreased the impulsivity displayed by 6-OHDA-lesioned male mice in the 5-choice serial reaction time task test and improved attentional performance. In addition, PSELT treatment significantly increased the nociception threshold in both normal and inflammatory conditions. Furthermore, anti-hyperalgesic activity was antagonized with sulpiride pre-treatment, but not by phentolamine, or propranolol pre-treatments. The present study suggests that PSELT reduces the severity of ADHD symptoms in mice and possesses potent antinociceptive effects which could be related to the involvement of D2/D3 dopaminergic receptors., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study was conducted to examine how colostrum pasteurization affects resistance genes and microbial communities in calf feces. Forty female Holstein calves were randomly assigned to either the control (CON) group, which received unheated colostrum, or the pasteurized colostrum (PAT) group. The calves body weight was measured weekly before morning feeding. Calf starter intake were measured and recorded daily before morning feeding. Samples of colostrum were collected before feeding. Blood was collected on d 1 and 70 before morning feeding. Ten calves were randomly selected from each group (n = 20 calves total) for fecal sampling on d 3, 28, 56 and 70 for subsequent DNA extraction and metagenomic sequencing. Total bacterial counts in the colostrum were markedly higher in the CON group than in the PAT group. Pasteurized colostrum administration substantially reduced the ARO diversity and diminishes the abundance of Enterobacteriaceae, thereby decreasing their contribution to resistance genes. Pasteurization also reduced glucoside hydrolase-66 activity in 3-day-old calves which led to an increase in the activity of aminoglycoside antibiotics, resulting in 52.63 % of PAT-enriched bacteria acquiring aminoglycoside resistance genes. However, from the perspective of overall microbial community, the proportion of aminoglycoside, beta-lactam and tetracycline resistance genes carried by microbial community in PAT group was lower than CON group (P < 0.05). Fecal samples from the PAT group contained greater abundances of Subdoligranulum (P < 0.05) and Lachnospiraceae&#95;NK4A136&#95;group (P < 0.05) on days 28 and 70 compared to CON. Network analysis and abundance variations of the different bacteria obtained by linear discriminant analysis effect size analysis showed that pasteurized colostrum feeding reduced the interactions among related bacteria and maintained stability of the hind-gut microbiome. In conclusion, these findings underscore the intricate interactions between early diet, calf resistance-gene transmission and microbial dynamics, which should be carefully considered in calf-rearing practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)