Causal relationship between inflammatory bowel disease and erythema nodosum: A two-sample bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have demonstrated the coexistence of erythema nodosum (EN) and inflammatory bowel disease (IBD), while the exact etiology of the co-occurrence of the two disorders remains uncertain. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was employed to determine the causal link between EN and IBD. Genetic variations associated with Crohn's disease (CD) and ulcerative colitis (UC) were derived from accessible genome-wide association studies pertaining to European ancestry. The FinnGen database was used to find the genetic variations containing EN. In the forward model, IBD was identified as the exposure, whereas in the reverse model, EN was identified as the exposure. The causal link between IBD and EN was examined using a range of different analysis techniques, the primary one being the inverse variance weighted (IVW) method, including inverse variance weighted-fixed effects (IVW-FE) and inverse-variance weighted-multiplicative random effects (IVW-MRE). To strengthen the results, assessments of sensitivity, heterogeneity, and pleiotropy were also conducted. RESULTS: MR results showed that IBD increased the risk of EN (IVW-MRE: OR = 1.242, 95% CI = 1.068-1.443, p = 0.005). Furthermore, there was a strong correlation found between CD and a higher risk of EN (IVW-FE: OR = 1.250, 95% CI = 1.119-1.396, p = 8.036 × 10-5 ). However, UC did not appear to be linked to EN (IVW-FE: OR = 1.104, 95% CI = 0.868-1.405, p = 0.421). The reverse MR analysis findings did not imply that EN was linked to IBD. Horizontal pleiotropy did not appear to exist, and the robustness of these findings was confirmed. CONCLUSION: The current investigation found that in European populations, IBD and its subtype CD could raise the incidence of EN.

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats.

BACKGROUND: Prenatal or postnatal lung inflammation and oxidative stress disrupt alveolo-vascular development leading to bronchopulmonary dysplasia (BPD) with and without pulmonary hypertension. L-citrulline (L-CIT), a nonessential amino acid, alleviates inflammatory and hyperoxic lung injury in preclinical models of BPD. L-CIT modulates signaling pathways mediating inflammation, oxidative stress, and mitochondrial biogenesis-processes operative in the development of BPD. We hypothesize that L-CIT will attenuate lipopolysaccharide (LPS)-induced inflammation and oxidative stress in our rat model of neonatal lung injury. METHODS: Newborn rats during the saccular stage of lung development were used to investigate the effect of L-CIT on LPS-induced lung histopathology and pathways involved in inflammatory, antioxidative processes, and mitochondrial biogenesis in lungs in vivo, and in primary culture of pulmonary artery smooth muscle cells, in vitro. RESULTS: L-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NFκB nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1ß, IL-8, MCP-1α, and TNF-α). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1α, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression. CONCLUSION: L-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD. IMPACT: The nonessential amino acid L-citrulline (L-CIT) mitigated lipopolysaccharide (LPS)-induced lung injury in the early stage of lung development in the newborn rat. This is the first study describing the effect of L-CIT on the signaling pathways operative in bronchopulmonary dysplasia (BPD) in a preclinical inflammatory model of newborn lung injury. If our findings translate to premature infants, L-CIT could decrease inflammation, oxidative stress and preserve mitochondrial health in the lung of premature infants at risk for BPD.

Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics.

The acidic extracellular microenvironment has become an effective target for diagnosing and treating tumors. A pH (low) insertion peptide (pHLIP) is a kind of peptide that can spontaneously fold into a transmembrane helix in an acidic microenvironment, and then insert into and cross the cell membrane for material transfer. The characteristics of the acidic tumor microenvironment provide a new method for pH-targeted molecular imaging and tumor-targeted therapy. As research has increased, the role of pHLIP as an imaging agent carrier in the field of tumor theranostics has become increasingly prominent. In this paper, we describe the current applications of pHLIP-anchored imaging agents for tumor diagnosis and treatment in terms of different molecular imaging methods, including magnetic resonance T1 imaging, magnetic resonance T2 imaging, SPECT/PET, fluorescence imaging, and photoacoustic imaging. Additionally, we discuss relevant challenges and future development prospects.

Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat.

BACKGROUND: Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. METHOD: We measured the acetaminophen dose-response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. RESULTS: Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with L-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone CONCLUSIONS: In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.

Enhanced quorum sensing of anode biofilm for better sensing linearity and recovery capability of microbial fuel cell toxicity sensor.

MFC toxicity sensor has major hindrances that limit its practical application, such as the poor concentration-response relationship and inferior recovery capability after high toxicity shock. Till now, the direct influence of intrinsic properties on the performance of MFC toxicity sensor has not been well understood. Quorum sensing (QS) is a cell-to-cell communication strategy that indirectly affects the intrinsic properties of electroactive biofilms. In this work, commercially available QS autoinducers (AHLs) were applied to MFC toxicity sensor to manipulate anode biofilm for better sensing performance. The results showed that the addition of AHLs (C6-HSL, 3-OXO-C12-HSL) led to higher sensing linearity to a wider range of Pb2+. The voltage of MFC sensors with AHLs addition fully recovered even after 10 mg/L Cu2+ shock, indicating an enhanced recovery capability of MFC toxicity sensor. It was found that higher live/dead cells ratio and increased exoelectrogen Geobacter abundance were responsible for the superior sensing linearity and recovery capability of MFC toxicity sensor. Our work presented a novel and effective way to advance the process of MFC toxicity sensor application from the perspective of EABs.

The effect of a single anti-Vascular Endothelial Growth Factor injection on neonatal growth and organ development: In-vivo study.

Retinopathy of prematurity (ROP) is one of the leading causes of blindness in preterm Infants. Anti-vascular endothelial growth factor (VEGF) is emerging as a promising treatment, but there is insufficient evidence on their safety. We investigate the effect of systemic anti-VEGF in rat pups with equivalent maturity to a 32 week neonate. A single dose of either anti-VEGF antibody (n = 7) or saline (control group; n = 6) was administered to newborn rats intra-peritoneally on the first day of life. 14 days' post treatment, the serum concentration of anti-VEGF was measured and the brain, lung, heart, kidney and liver were harvested and weighed. The heart was processed to measure the Fulton index (a surrogate for pulmonary hypertension). All other organs were processed for mRNA expression of VEGF and VEGF-receptors (R1&R2). No group differences in body and organ weights were noted. The anti-VEGF was still detected in serum 14 days post Injection and resulted in increase in lung (p < 0.002) and kidney (p < 0.01) VEGF mRNA expressions and the lung (p < 0.02) VEGF-R1 and kidney (P < 0.001) VEGF-R2 mRNA expressions. The treated pups exhibited increased total heart weight (p < 0.01) and Fulton Index (p < 0.05). No changes were seen in the liver and brain. Anti-VEGF antibody did not affect mortality, total body and organ weights, but was associated with pulmonary hypertension. Expression of lung and kidney VEGF and its receptors was increased, whilst the brain and liver did not show changes. Dosing experiments can now be targeted to assess safety threshold and at anti-VEGF dose used in human ROP treatment.

Human milk H2O2 content: does it benefit preterm infants?

BackgroundHuman milk has a high content of the antimicrobial compound hydrogen peroxide (H2O2). As opposed to healthy full-term infants, preterm neonates are fed previously expressed and stored maternal milk. These practices may favor H2O2 decomposition, thus limiting its potential benefit to preterm infants. The goal of this study was to evaluate the factors responsible for H2O2 generation and degradation in breastmilk.MethodsHuman donors' and rats' milk, along with rat mammary tissue were evaluated. The role of oxytocin and xanthine oxidase on H2O2 generation, its pH-dependent stability, as well as its degradation via lactoperoxidase and catalase was measured in milk.ResultsBreast tissue xanthine oxidase is responsible for the H2O2 generation and its milk content is dependent on oxytocin stimulation. Stability of the human milk H2O2 content is pH-dependent and greatest in the acidic range. Complete H2O2 degradation occurs when human milk is maintained, longer than 10 min, at room temperature and this process is suppressed by lactoperoxidase and catalase inhibition.ConclusionFresh breastmilk H2O2 content is labile and quickly degrades at room temperature. Further investigation on breastmilk handling techniques to preserve its H2O2 content, when gavage-fed to preterm infants is warranted.

Hydrogen peroxide promotes gastric motility in the newborn rat.

BACKGROUND: When compared with infant formula, human milk enhances gastric emptying in preterm infants. Hydrogen peroxide (H2O2) is present in large quantities in human milk that has an antimicrobial role for the mother and infant. In vitro adult rat studies suggest that H2O2 facilitates gastric motor contraction. Hypothesizing that H2O2 enhances gastric motility, we investigated its effects on the newborn rat stomach tissue. METHODS: Rat newborn and adult gastric fundic segments, or their smooth muscle cells, were used to evaluate the muscle response to H2O2 exposure. Tissue expression of Rho kinase 2 (ROCK-2; Western blot), its catalase activity, and H2O2 content (Amplex Red) were measured. H2O2 gastric mucosal diffusion was evaluated with Ussing chambers. RESULTS: In both newborn and adult rats, H2O2 induced gastric muscle contraction and this response was attenuated by pre-incubation with the antioxidant melatonin. H2O2 passively diffused across the gastric mucosa. Its effect on the muscle was modulated via ROCK-2 activation and inhibited by melatonin. CONCLUSION: H2O2, at a concentration similar to that of human milk, promotes gastric motility in the rat. To the extent that the present findings can be clinically extrapolated, the human milk H2O2 content may enhance gastric emptying in neonates.

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina.

BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor in multiple metabolic processes and plays an essential role in maintaining the inflammatory and neurovascular homeostasis. In this study, we have investigated the deleterious effects of BH4 deficiency on retinal vasculature during development. METHODS: hph-1 mice, which display deficiency in BH4 synthesis, were used to characterize the inflammatory effects and the integrity of retinal microvasculature. BH4 levels in retinas from hph-1 and wild type (WT) mice were measured by LC-MS/MS. Retinal microvascular area and microglial cells number were quantified in hph-1 and WT mice at different ages. Retinal expression of pro-inflammatory, anti-angiogenic, and neuronal-derived factors was analyzed by qPCR. BH4 supplementation was evaluated in vitro, ex-vivo, and in vivo models. RESULTS: Our findings demonstrated that BH4 levels in the retina from hph-1 mice were significantly lower by ~ 90% at all ages analyzed compared to WT mice. Juvenile hph-1 mice showed iris atrophy, persistent fetal vasculature, significant increase in the number of microglial cells (p < 0.01), as well as a marked degeneration of the retinal microvasculature. Retinal microvascular alterations in juvenile hph-1 mice were associated with a decreased expression in Norrin (0.2-fold) and its receptor Frizzled-4 (FZD4; 0.51-fold), as well as with an augmented expression of pro-inflammatory factors such as IL-6 (3.2-fold), NRLP-3 (4.4-fold), IL-1ß (8.6-fold), and the anti-angiogenic factor thrombospondin-1 (TSP-1; 17.5-fold). We found that TSP-1 derived from activated microglial cells is a factor responsible of inducing microvascular degeneration, but BH4 supplementation markedly prevented hyperoxia-induced microglial activation in vitro and microvascular injury in an ex-vivo model of microvascular angiogenesis and an in vivo model of oxygen-induced retinopathy (OIR). CONCLUSION: Our findings reveal that BH4 is a key cofactor in regulating the expression of inflammatory and anti-angiogenic factors that play an important function in the maintenance of retinal microvasculature.

Gastric and pyloric sphincter muscle function and the developmental-dependent regulation of gastric content emptying in the rat.

Feeding intolerance is a common issue in the care of preterm neonates. The condition manifests as delayed emptying of gastric contents and represents a therapeutic challenge, since the factors accounting for its manifestations are unknown. The main goal of this study was to comparatively investigate the age-related function of rat gastric and pyloric smooth muscle and their putative regulators. We hypothesized that a reduced gastric muscle contraction potential early in life contributes to the delayed gastric emptying of the newborn. Newborn and adult rat gastric (fundus) and pyloric sphincter tissues were comparatively studied in vitro. Shortening of the tissue-specific dissociated smooth muscle cell was evaluated, and expression of the key regulatory proteins Rho-associated kinase 2 and myosin light chain kinase was determined. Gastric and pyloric smooth muscle cell shortening was significantly greater in the adult than the respective newborn counterpart. Expression of myosin light chain kinase and Rho-associated kinase 2 was developmentally regulated and increased with age. Pyloric sphincter muscle expresses a higher neuronal nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein content in newborn than adult tissue. Compared with later in life, the newborn rat gastropyloric muscle has a Ca(2+)-related reduced potential for contraction and the pyloric sphincter relaxation-dependent modulators are overexpressed. To the extent that these rodent data can be extrapolated to humans, the delayed gastric emptying in the newborn reflects reduced stomach muscle contraction potential, as opposed to increased pyloric sphincter tone.

Maternal-pup interaction disturbances induce long-lasting changes in the newborn rat pulmonary vasculature.

The factors accounting for the pathological maintenance of a high pulmonary vascular (PV) resistance postnatally remain elusive, but neonatal stressors may play a role in this process. Cross-fostering in the immediate neonatal period is associated with adult-onset vascular and behavioral changes, likely triggered by early-in-life stressors. In hypothesizing that fostering newborn rats induces long-lasting PV changes, we evaluated them at 14 days of age during adulthood and compared the findings with animals raised by their biological mothers. Fostering resulted in reduced maternal-pup contact time when compared with control newborns. At 2 wk of age, fostered rats exhibited reduced pulmonary arterial endothelium-dependent relaxation secondary to downregulation of tissue endothelial nitric oxide synthase expression and tetrahydrobiopterin deficiency-induced uncoupling. These changes were associated with neonatal onset-increased ANG II receptor type 1 expression, PV remodeling, and right ventricular hypertrophy that persisted into adulthood. The pulmonary arteries of adult-fostered rats exhibited a higher contraction dose response to ANG II and thromboxane A2, the latter of which was abrogated by the oxidant scavenger Tempol. In conclusion, fostering-induced neonatal stress induces long-standing PV changes modulated via the renin-angiotensin system.

Caffeine impairs gastrointestinal function in newborn rats.

BACKGROUND: Feeding intolerance is commonly documented in premature infants. Caffeine is routinely utilized for apnea of prematurity treatment and known to reduce the lower esophageal sphincter (LES) muscle tone, but the caffeine effect on the newborn gastrointestinal function is unknown. We hypothesized that caffeine impairs esophageal and gastrointestinal motor function. As such, we investigated the drug effect on the tissue's mechanical properties and the newborn rat's in vivo gastric emptying rate. METHODS: The effects of caffeine on LES, gastric fundal and antrum, as well as ileal and colonic muscle force potential and relaxation response, were measured in newborn and adult rats. The caffeine-induced (10 mg/kg i.p.) newborn gastric emptying rate changes were evaluated following 3 h of fasting. RESULTS: Caffeine relaxed the precontracted LES and fundal muscle (P < 0.01), reduced the gastric and intestinal muscle contraction (P < 0.01), and delayed the pups' gastric emptying time (P < 0.01). The caffeine-induced muscle relaxant effect was independent of age and mediated via ryanodine receptors. CONCLUSION: Caffeine administration to newborn rats at a dose comparable to the one therapeutically used for preterm neonates impairs LES and gastrointestinal motor function. Further clinical investigation on the possible contribution of caffeine to neonatal feeding intolerance is warranted.

Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators.

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso-N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41-2272 (10(-9) M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Infantile hypertrophic pyloric stenosis (IHPS): a study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease.

Infantile hypertrophic pyloric stenosis (IHPS) is a common disease of unknown etiology. The tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia-1 (hph-1) newborn mouse has a similar phenotype to the human condition. For hph-1 and wild-type control animals, pyloric tissue agonist-induced contractile properties, reactive oxygen species (ROS) generation, cGMP, neuronal nitric oxide synthase (nNOS) content, and Rho-associated protein kinase 2 (ROCK-2) expression and activity were evaluated. Primary pyloric smooth muscle cells from wild-type newborn animals were utilized to evaluate the effect of BH4 deficiency. One-week-old hph-1 mice exhibited a fourfold increase (P < 0.01) in the pyloric sphincter muscle contraction magnitude but similar relaxation values when compared with wild-type animals. The pyloric tissue nNOS expression and cGMP content were decreased, whereas the rate of nNOS uncoupling increased (P < 0.01) in 1-wk-old hph-1 mice when compared with wild-type animals. These changes were associated with increased pyloric tissue ROS generation and elevated ROCK-2 expression/activity (P < 0.05). At 1-3 days of age and during adulthood, the gastric emptying rate of the hph-1 mice was not altered, and there were no genotype differences in pyloric tissue ROS generation, nNOS expression, or ROCK-2 activity. BH4 inhibition in pyloric smooth muscle cells resulted in increased ROS generation (P < 0.01) and ROCK-2 activity (P < 0.05). Oxidative stress upregulated ROCK-2 activity in pyloric tissue, but no changes were observed in newborn fundal tissue in vitro. We conclude that ROS-induced upregulation of ROCK-2 expression accounts for the increased pyloric sphincter tone and nNOS downregulation in the newborn hph-1 mice. The role of ROCK-2 activation in the pathogenesis of IHPS warrants further study.

Metoclopramide does not increase gastric muscle contractility in newborn rats.

Feeding intolerance resulting from delayed gastric emptying is common in premature neonates. Metoclopramide (MCP), the most frequently used prokinetic drug in neonates, enhances gastric muscle contractility through inhibition of dopamine receptors. Although its therapeutic benefit is established in adults, limited data are available to support its clinical use in infants. Hypothesizing that developmentally dependent differences are present, we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn, juvenile, and adult rats. The muscle strips were either contracted with electrical field stimulation (EFS) to induce cholinergic nerve-mediated acetylcholine release or carbachol, a cholinergic agonist acting directly on the muscarinic receptor. Although in adult rats MCP increased EFS-induced contraction by 294 ± 122% of control (P < 0.01), no significant effect was observed in newborn fundic muscle. MCP had no effect on the magnitude of the carbachol-induced and/or bethanechol-induced gastric muscle contraction at any age. In response to dopamine, an 80.7 ± 5.3% relaxation of adult fundic muscle was observed, compared with only a 8.4 ± 8.7% response in newborn tissue (P < 0.01). Dopamine D2 receptor expression was scant in neonates and significantly increased in adult gastric tissue (P < 0.01). In conclusion, the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression. To the extent that these novel data can be extrapolated to neonates, the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation.

Pantoprazole decreases gastroesophageal muscle tone in newborn rats via rho-kinase inhibition.

Proton pump inhibitors reduce gastric acid secretion and are commonly utilized in the management of gastroesophageal reflux disease across all ages. Yet a decrease in lower esophageal sphincter tone has been reported in vitro in rats through an unknown mechanism; however, their effect on the gastroesophageal muscle tone early in life was never studied. Hypothesizing that proton pump inhibitors also reduce gastroesophageal muscle contraction in newborn and juvenile rats, we evaluated the in vitro effect of pantoprazole on gastric and lower esophageal sphincter muscle tissue. Electrical field stimulation and carbachol-induced force were significantly (P < 0.01) reduced in the presence of pantoprazole, whereas the drug had no effect on the neuromuscular-dependent relaxation. When administered in vivo, pantoprazole (9 mg/kg) significantly (P < 0.01) reduced gastric emptying time at both ages. To ascertain the signal transduction pathway responsible for the reduction in muscle contraction, we evaluated the tissue ROCK-2 and CPI-17 activity. Pantoprazole reduced myosin light chain phosphatase MYPT-1, but not CPI-17 phosphorylation of gastric and lower esophageal sphincter tissue, strongly suggesting that it is a ROCK-2 inhibitor. To the extent that these findings can be extrapolated to human neonates, the use of pantoprazole may impair gastric and lower sphincter muscle tone and thus paradoxically exacerbate esophageal reflux. Further studies addressing the effect of proton pump inhibitors on gastroesophageal muscle contraction are warranted to justify its therapeutic use in gastroesophageal reflux disease.

Age dependency of vasopressin pulmonary vasodilatory effect in rats.

BACKGROUND: Vasopressin is a systemic vasoconstrictor. Its pulmonary vasodilatory effect is controversial, and limited data are available on its use in neonates with pulmonary hypertension. Hypothesizing that the vasopressin-induced pulmonary vasodilation is developmentally regulated, we evaluated its pulmonary and systemic arterial response in newborn and adult rats. METHODS: Vessels were mounted on a wire myograph, and the vasopressin-induced changes in vasomotor tone measured. The vessel- and age-dependent differences in vasopressin V1a and V2 receptors' expression were evaluated by western blotting. RESULTS: Vasopressin induced a dose-dependent increase in mesenteric arterial tone at both ages, but of greater magnitude in adult vessels (P < 0.01). At lower concentrations, vasopressin induced pulmonary vasodilation in adult vessels and vasoconstriction in newborn arteries. The adult vasopressin-induced pulmonary vasodilation was inhibited by ibuprofen, suggesting that the response is prostaglandin mediated. Pulmonary tissue V1a receptor protein expression was higher in adult, when compared with newborn arteries (P < 0.01). The adult vessels V1a expression predominated in the pulmonary arteries, and V2 was only detected in mesenteric arteries. CONCLUSION: The vasopressin-induced pulmonary vasodilation is absent in newborn rats likely due to the lower tissue V1a expression early in life. These animal data challenge the therapeutic use of vasopressin in neonatal pulmonary hypertension.

DeepIMAGER: Deeply Analyzing Gene Regulatory Networks from scRNA-seq Data.

Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often result in high rates of false positives and low precision. Here, we introduce an advanced computational tool, DeepIMAGER, for inferring cell-specific GRNs through deep learning and data integration. DeepIMAGER employs a supervised approach that transforms the co-expression patterns of gene pairs into image-like representations and leverages transcription factor (TF) binding information for model training. It is trained using comprehensive datasets that encompass scRNA-seq profiles and ChIP-seq data, capturing TF-gene pair information across various cell types. Comprehensive validations on six cell lines show DeepIMAGER exhibits superior performance in ten popular GRN inference tools and has remarkable robustness against dropout-zero events. DeepIMAGER was applied to scRNA-seq datasets of multiple myeloma (MM) and detected potential GRNs for TFs of RORC, MITF, and FOXD2 in MM dendritic cells. This technical innovation, combined with its capability to accurately decode GRNs from scRNA-seq, establishes DeepIMAGER as a valuable tool for unraveling complex regulatory networks in various cell types.

Effect of CNT Oxidation on the Processing and Properties of Superacid-Spun CNT Fibers.

Spinning fibers from carbon nanotube (CNT)/superacid dispersions has emerged as a promising strategy for industrial-scale production of high-performance CNT fibers (CNTFs). The oxygen content and types of functional groups on CNT surfaces significantly influence dispersion, assembly processes, and fiber properties. In this study, Tuball-SWCNTs were purified and oxidized at varying levels. The dispersion behavior of CNTs with different oxidation levels in chlorosulfonic acid was systematically observed, and the mechanical properties of fibers spun from these dispersions were compared. By adjusting the dispersion concentration, highly oriented CNTFs were produced with a specific strength of 1.03 N/tex, a tensile strength of 1.59 GPa, and an electrical conductivity of 3.58 MS/m. Further investigations indicated that oxygen-containing functional groups decrease the coagulation rate, increasing the maximum draw ratio during spinning and improving CNT alignment in the fibers. Molecular dynamics simulations demonstrated that these functional groups (-OH, -COOH) enhance load transfer between CNTs through hydrogen bonding. This specific strength is the highest achieved using Tuball-SWCNTs for superacid-spun fibers, surpassing previous works due to the oxidation-controlled coagulation rate, enhanced fiber orientation, and improved load transfer via hydrogen bonding. This study provides insights for designing and optimizing high-performance CNTFs.

Tetrahydrobiopterin deficiency induces gastroparesis in newborn mice.

Pyloric stenosis, the most common infant gastrointestinal disease, has no known etiology and clinically presents as abnormal gastric emptying with evidence of pyloric muscle hypertrophy. Whether abnormalities in gastric muscle contraction and/or relaxation have a role in this condition is poorly known, but gastroparesis is commonly observed in association with delayed gastric emptying in adults. Therefore, we evaluated the tetrahydrobiopterin (BH4)-deficient newborn mouse model of this disease (hph-1) and hypothesized that their gastric muscle properties are impaired, when compared with wild-type control animals. In vitro studies evaluating the age-dependent gastric fundus muscle contraction and relaxation potential were conducted. Compared with wild-type mice, the hph-1 stomach content/body weight ratio was significantly increased in newborn but not juvenile or adult animals, confirming abnormal gastric emptying. Gastric tissue neuronal nitric oxide synthase (nNOS) protein expression was upregulated in both newborn and adult hph-1 mice, but in the former there was evidence of enzyme uncoupling and higher tissue superoxide generation when compared with same age-matched animals. As opposed to the lack of strain differences in the U46619-induced force, the newborn hph-1 gastric muscle carbachol-induced contraction and nNOS-dependent relaxation were significantly reduced (P < 0.01). These group differences were not present in juvenile or adult mice. Preincubation with BH4 significantly enhanced the newborn hph-1, but not wild-type, gastric muscle contraction. In conclusion, changes compatible with gastroparesis are present in the newborn mouse model of pyloric stenosis. The role of BH4 deficiency and possibly associated gastroparesis in the pathogenesis of infantile pyloric stenosis warrants further investigation.