Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

8-Bromo-cAMP attenuates human airway epithelial barrier disruption caused by titanium dioxide fine and nanoparticles.

Titanium dioxide fine particles (TiO2-FPs) and nanoparticles (TiO2-NPs) are the most widely used whitening pigments worldwide. Inhalation of TiO2-FPs and TiO2-NPs can be harmful as it triggers toxicity in the airway epithelial cells. The airway epithelium serves as the respiratory system's first line of defense in which airway epithelial cells are significant targets of inhaled pathogens and environmental particles. Our group previously found that TiO2-NPs lead to a disrupted barrier in the polarized airway epithelial cells. However, the effect of TiO2-FPs on the respiratory epithelial barrier has not been examined closely. In this study, we aimed to compare the effects of TiO2-FPs and TiO2-NPs on the structure and function of the airway epithelial barrier. Additionally, we hypothesized that 8-Bromo-cAMP, a cyclic adenosine monophosphate (cAMP) derivative, would alleviate the disruptive effects of both TiO2-FPs and TiO2-NPs. We observed increased epithelial membrane permeability in both TiO2-FPs and TiO2-NPs after exposure to 16HBE cells. Immunofluorescent labeling showed that both particle sizes disrupted the structural integrity of airway epithelial tight junctions and adherens junctions. TiO2-FPs had a slightly more, but insignificant impact on the epithelial barrier disruption than TiO2-NPs. Treatment with 8-Bromo-cAMP significantly attenuated the barrier-disrupting impact of both TiO2-FPs and TiO2-NPs on cell monolayers. Our study demonstrates that both TiO2-FPs and TiO2-NPs cause comparable barrier disruption and suggests a protective role for cAMP signaling. The observed effects of TiO2-FPs and TiO2-NPs provide a necessary understanding for characterizing the pathways involved in the defensive role of the cAMP pathway on TiO2-induced airway barrier disruption.

High plasma nesfatin-1 level in Chinese adolescents with depression.

Depression is a common psychiatric disorder with high prevalence and mortality rates as well as high risk of serious harm in adolescents that have significant negative impact on families and society. The feeding inhibitor Nesfatin-1 contributes to the regulation of stress and emotion. The purpose of this project was to compare the differences in the levels of Nesfatin-1 between adolescents with depression and healthy adolescents, and verify the association between the levels of Nesfatin-1 and severity of depression in adolescents. Adolescents with depression (n = 61) and healthy adolescents (n = 30) were evaluated. The Hamilton Depression Rating Scale (HAMD-17) was used to classify the adolescents with depression. Thirty-one and thirty-two was assigned to the mild-to-moderate (HAMD-17 ≤ 24) depression group and severe group (HAMD-17 > 24). Plasma Levels of Nesfatin-1 were measured by human ELISA Kit and differences among groups evaluated. Data were analyzed using the statistical software SPSS 23. HAMD-17 score was significantly higher in adolescents with depression than that in the healthy adolescents (P < 0.001). Median plasma Nesfatin-1 levels in adolescents with depression and healthy adolescents differed significantly at 37.3 pg/ml (22.1 pg/ml, 63.6 pg/ml) and 18.1 pg/ml (10.0 pg/ml, 25.7 pg/ml) (p < 0.001). A multivariate logistic regression analysis showed high plasma Nesfatin-1 concentrations were associated with increased risk of depression (OR = 0.914, 95% CI 0.87-0.96, P < 0.001). The receiver operating characteristic curve showed that the area under curve were 0.808 (95% CI 0.722-0.894, P < 0.001). Plasma Nesfatin-1 cut-off point of 32.45 pg/mL showed 59% sensitivity and 100% specificity. Median plasma Nesfatin-1 levels in the severe depression group (n = 30), mild-to-moderate depression group (n = 31), and control group (n = 30) were 53.4 pg/ml (28.2 pg/ml, 149.1 pg/ml), 29.9 pg/ml (14.5 pg/ml, 48.5 pg/ml) and 18.1 pg/ml (10.0 pg/ml, 25.7 pg/ml), and differed significantly among the three groups (P < 0.001). Median plasma level of Nesfatin-1 in males (n = 20) was 38.6 pg/ml (23.5 pg/ml, 70.1 pg/ml), while that in females (n = 41) was 37.3 pg/ml (22.0 pg/ml, 63.6 pg/ml), which was not a significant difference (P > 0.05). Plasma levels of Nesfatin-1 increased with severity of depression in adolescents and may be useful as a biomarker of depression severity. Further studies are needed in future projects.

Electronic cigarette exposure disrupts airway epithelial barrier function and exacerbates viral infection.

The use of electronic cigarettes (e-cigs), especially among teenagers, has reached alarming and epidemic levels, posing a significant threat to public health. However, the short- and long-term effects of vaping on the airway epithelial barrier are unclear. Airway epithelial cells are the forefront protectors from viruses and pathogens. They contain apical junctional complexes (AJCs), which include tight junctions (TJs) and adherens junctions (AJs) formed between adjacent cells. Previously, we reported respiratory syncytial virus (RSV) infection, the leading cause of acute lower respiratory infection-related hospitalization in children and high-risk adults, induces a "leaky airway" by disrupting the epithelial AJC structure and function. We hypothesized chemical components of e-cigs disrupt airway epithelial barrier and exacerbate RSV-induced airway barrier dysfunction. Using confluent human bronchial epithelial (16HBE) cells and well-differentiated normal human bronchial epithelial (NHBE) cells, we found that exposure to extract and aerosol e-cig nicotine caused a significant decrease in transepithelial electrical resistance (TEER) and the structure of the AJC even at noncytotoxic concentrations. Western blot analysis of 16HBE cells exposed to e-cig nicotine extract did not reveal significant changes in AJC proteins. Exposure to aerosolized e-cig cinnamon or menthol flavors also induced barrier disruption and aggravated nicotine-induced airway barrier dysfunction. Moreover, preexposure to nicotine aerosol increased RSV infection and the severity of RSV-induced airway barrier disruption. Our findings demonstrate that e-cig exposure disrupts the airway epithelial barrier and exacerbates RSV-induced damage. Knowledge gained from this study will provide awareness of adverse e-cig respiratory effects and positively impact the mitigation of e-cig epidemic.NEW & NOTEWORTHY Electronic cigarette (e-cig) use, especially in teens, is alarming and at epidemic proportions, threatening public health. Our study shows that e-cig nicotine exposure disrupts airway epithelial tight junctions and increases RSV-induced barrier dysfunction. Furthermore, exposure to aerosolized flavors exaggerates e-cig nicotine-induced airway barrier dysfunction. Our study confirms that individual and combined components of e-cigs deleteriously impact the airway barrier and that e-cig exposure increases susceptibility to viral infection.

Deficiency of Cullin 3, a Protein Encoded by a Schizophrenia and Autism Risk Gene, Impairs Behaviors by Enhancing the Excitability of Ventral Tegmental Area (VTA) DA Neurons.

The dopaminergic neuromodulator system is fundamental to brain functions. Abnormal dopamine (DA) pathway is implicated in psychiatric disorders, including schizophrenia (SZ) and autism spectrum disorder (ASD). Mutations in Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex, have been associated with SZ and ASD. However, little is known about the function and mechanism of CUL3 in the DA system. Here, we show that CUL3 is critical for the function of DA neurons and DA-relevant behaviors in male mice. CUL3-deficient mice exhibited hyperactive locomotion, deficits in working memory and sensorimotor gating, and increased sensitivity to psychostimulants. In addition, enhanced DA signaling and elevated excitability of the VTA DA neurons were observed in CUL3-deficient animals. Behavioral impairments were attenuated by dopamine D2 receptor antagonist haloperidol and chemogenetic inhibition of DA neurons. Furthermore, we identified HCN2, a hyperpolarization-activated and cyclic nucleotide-gated channel, as a potential target of CUL3 in DA neurons. Our study indicates that CUL3 controls DA neuronal activity by maintaining ion channel homeostasis and provides insight into the role of CUL3 in the pathogenesis of psychiatric disorders.SIGNIFICANCE STATEMENT This study provides evidence that Cullin 3 (CUL3), a core component of the Cullin-RING ubiquitin E3 ligase complex that has been associated with autism spectrum disorder and schizophrenia, controls the excitability of dopamine (DA) neurons in mice. Its DA-specific heterozygous deficiency increased spontaneous locomotion, impaired working memory and sensorimotor gating, and elevated response to psychostimulants. We showed that CUL3 deficiency increased the excitability of VTA DA neurons, and inhibiting D2 receptor or DA neuronal activity attenuated behavioral deficits of CUL3-deficient mice. We found HCN2, a hyperpolarization-activated channel, as a target of CUL3 in DA neurons. Our findings reveal CUL3's role in DA neurons and offer insights into the pathogenic mechanisms of autism spectrum disorder and schizophrenia.

Iron-overload-induced ferroptosis in mouse cerebral toxoplasmosis promotes brain injury and could be inhibited by Deferiprone.

Iron is a trace metal element that is essential for the survival of cells and parasites. The role of iron in cerebral toxoplasmosis (CT) is still unclear. Deferiprone (DFP) is the orally active iron chelator that binds iron in a molar ratio of 3:1 (ligand:iron) and promotes urinary iron excretion to remove excess iron from the body. The aims of this experiment were to observe the alterations in iron in brains with Toxoplasma gondii (T. gondii) acute infections and to investigate the mechanism of ferroptosis in CT using DFP. We established a cerebral toxoplasmosis model in vivo using TgCtwh3, the dominant strains of which are prevalent in China, and treated the mice with DFP at a dose of 75 mg/kg/d. Meanwhile, we treated the HT-22 cells with 100 µM DFP for half an hour and then infected cells with TgCtwh3 in vitro. A qRT-PCR assay of TgSAG1 levels showed a response to the T. gondii burden. We used inductively coupled plasma mass spectrometry, an iron ion assay kit, Western blot analysis, glutathione and glutathione disulfide assay kits, a malonaldehyde assay kit, and immunofluorescence to detect the ferroptosis-related indexes in the mouse hippocampus and HT-22 cells. The inflammatory factors interferon-γ, tumor necrosis factor-α, transforming growth factor-ß, and arginase 1 in the hippocampus and cells were detected using the Western blot assay. Hematoxylin and eosin staining, electron microscopy, and the Morris water maze experiment were used to evaluate the brain injuries of the mice. The results showed that TgCtwh3 infection is followed by the activation of ferroptosis-related signaling pathways and hippocampal pathological damage in mice. The use of DFP led to ferroptosis resistance and attenuated pathological changes, inflammatory reactions and T. gondii burden of the mice, prolonging their survival time. The HT-22 cells with TgCtwh3 activated the ferroptosis pathway and was inhibit by DFP in vitro. In TgCtwh3-infected cells, inflammatory response and mitochondrial damage were severe, but these effects could be reduced by DFP. Our study elucidates the mechanism by which T. gondii interferes with the host's iron metabolism and activates ferroptosis, complementing the pathogenic mechanism of CT and further demonstrating the potential value of DFP for the treatment of CT.

Vitamin D3 protects against respiratory syncytial virus-induced barrier dysfunction in airway epithelial cells via PKA signaling pathway.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection in infants and young children globally and is responsible for hospitalization and mortality in the elderly population. Virus-induced airway epithelial barrier damage is a critical step during RSV infection, and emerging studies suggest that RSV disrupts the tight junctions (TJs) and adherens junctions (AJs) between epithelial cells, increasing the permeability of the airway epithelial barrier. The lack of commercially available vaccines and effective antiviral drugs for RSV emphasizes the need for new management strategies. Vitamin D3 is a promising intervention for viral infection due to its critical role in modulating innate immune responses. However, there is limited evidence on the effect of vitamin D3 on RSV pathogenies. Here, we investigated the impact of vitamin D3 on RSV-induced epithelial barrier dysfunction and the underlying mechanisms. We found that pre-incubation with 1,25(OH)2D3, the active form of vitamin D3, alleviated RSV-induced epithelial barrier disruption in a dose-dependent manner without affecting viability in 16HBE cells. 1,25(OH)2D3 induced minor changes in the protein expression level of TJ/AJ proteins in RSV-infected cells. We observed increased CREB phosphorylation at Ser133 during 1,25(OH)2D3 exposure, indicating that vitamin D3 triggered protein kinase A (PKA) activity in 16HBE. PKA inhibitors modified the restoration of barrier function by 1,25(OH)2D3 in RSV-infected cells, implying that PKA signaling is responsible for the protective effects of vitamin D3 against RSV-induced barrier dysfunction in airway epithelial cells. Our findings suggest vitamin D3 as a prophylactic intervention to protect the respiratory epithelium during RSV infections.

The characteristics of HIV-1 subtype B on phylogenetic dynamic and molecular transmission network in Fuyang City, China, 2011 to 2019.

Introduction: HIV-1 subtype B, as once one of the earliest strains introduced into mainland China rapidly spread in commercial plasma donors and heterosexuals in 1990s. Here, we aim to investigate the origin and evolutionary history of HIV-1 subtype B in Fuyang city, China. Methods: We collected sequences tested from Fuyang in the east of China where higher prevalence of HIV-1 among commercial plasma donors and heterosexuals to construct a phylogenetic tree using the Markov chain Monte Carlo (MCMC) algorithm, infer molecular transmission network using TN93 model and visualize it with Cytoscape software. Results and discussion: Our results showed that >99% of subtype B sequences belonged to Thai B. The sequences from Fuyang often cluster closer to those from other its adjacent cities, which clustered together and formed a monophyletic cluster. HIV-1 B circulating in Fuyang dates back to approximately 1990. Among the 1,437 sequences, 166 clustered at a genetic distance of ≤1.2%, resulting in 73 clusters. The degree of clustering with at least one other person was 11.55%. Among the transmission clusters, 50 (80.65%) comprised two individuals. Most clusters consisted of both heterosexual transmission routes and men who have sex with men. Phylogenetic and molecular network analyses revealed a common origin with neighboring regions in mainland China, local onwards transmission after its introduction, and a limited clustering degree. However, at least two co-existing transmission routes in most transmission clusters imply a greater challenge in controlling the spread of HIV-1. Our findings highlight the value on tailoring prevention interventions by combination of molecular surveillance and epidemiology.

The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

Transforming growth factor-ß and bone morphogenetic protein signaling pathways in pathological cardiac hypertrophy.

Pathological cardiac hypertrophy (referred to as cardiac hypertrophy) is a maladaptive response of the heart to a variety of pathological stimuli, and cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Currently, the treatments for cardiac hypertrophy are limited to improving symptoms and have little effect. Elucidation of the developmental process of cardiac hypertrophy at the molecular level and the identification of new targets for the treatment of cardiac hypertrophy are crucial. In this review, we summarize the research on multiple active substances related to the pathogenesis of cardiac hypertrophy and the signaling pathways involved and focus on the role of transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling in the development of cardiac hypertrophy and the identification of potential targets for molecular intervention. We aim to identify important signaling molecules with clinical value and hope to help promote the precise treatment of cardiac hypertrophy and thus improve patient outcomes.

Airway Epithelial Cell Junctions as Targets for Pathogens and Antimicrobial Therapy.

Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build epithelial barriers to pathogens, inhaled allergens, and environmental particles in the respiratory tract. AJCs consist of tight junctions (TJs) and adherens junctions (AJs), which play a key role in maintaining the integrity of the airway barrier. Emerging evidence has shown that different microorganisms cause airway barrier dysfunction by targeting TJ and AJ proteins. This review discusses the pathophysiologic mechanisms by which several microorganisms (bacteria and viruses) lead to the disruption of AJCs in airway epithelial cells. We present recent progress in understanding signaling pathways involved in the formation and regulation of cell junctions. We also summarize the potential chemical inhibitors and pharmacological approaches to restore the integrity of the airway epithelial barrier. Understanding the AJCs-pathogen interactions and mechanisms by which microorganisms target the AJC and impair barrier function may further help design therapeutic innovations to treat these infections.

LFA-1/ ICAM-1 promotes NK cell cytotoxicity associated with the pathogenesis of ocular toxoplasmosis in murine model.

Ocular toxoplasmosis (OT) is one of the most common causes of posterior uveitis. However, the pathogenic mechanisms of OT have not been well elucidated. Here, we used C57BL/6 (B6) mice to establish OT by peroral infection with 20 cysts of the TgCtWh6 strain, and severe ocular damage was observed by histopathological analysis in the eyes of infected mice. RNA-sequencing results showed that infection with T. gondii increased the expression of the NK-mediated cytotoxicity gene pathway at Day 30 after ocular T. gondii infection. Both NK-cell and CD49a+ NK-cell subsets are increased in ocular tissues, and the expression levels of LFA-1 in NK cells and ICAM-1 in the OT murine model were upregulated upon infection. Furthermore, inhibition of the interaction between LFA-1 and ICAM-1 with lifitegrast, a novel small molecule integrin antagonist, inhibited the protein expression of LFA-1 and ICAM-1 in murine OT and NK cells, improved the pathology of murine OT and influenced the secretion of cytokines in the OT murine model. In conclusion, the interaction between LFA-1 and ICAM-1 plays a role in the early regulation of the CD49a+ NK-cell proportion in an OT murine model. LFA-1/ ICAM-1 may be a key molecule in the pathogenesis of OT, and may provide new insights for potential immunotherapy.

Protective effects of ZIP8 on Toxoplasma gondii-induced acute hepatocyte injury in mice.

Toxoplasma gondii (T. gondii), as an intracellular protozoan parasite, has the potential to disturb the homeostasis of trace metal elements in host cells. Zinc (Zn) is one of those essential metals that is required for combating infection. Zinc cellular homeostasis is controlled by zinc membrane transporters, including efflux and influx transporters. One of the Zrt-Irt-like protein (ZIP) transporters, ZIP8, facilitates zinc influx into the cytosol. It was recently reported to play significant roles in facilitating Zn uptakes during infection. Here, we investigated the function of ZIP8 in host defense against T. gondii infection in cultured alpha mouse liver 12 (AML12) hepatocytes and mice, with loss of ZIP8 function. Herein, C57BL/6 J female wild-type (WT) and ZIP8-KD mice (Slc39a8 knockdown mice), that were infected with tachyzoites of ToxoDB#9(TgCtwh3), were used as a model of acute toxoplasmosis. AML12 hepatocytes were transfected with lentivirus (LV), with silenced ZIP8 expression. Finally, we observed the function of hepatocytes pretreated with ZnCl2 before TgCtwh3 infection in vivo and in vitro. In vivo, the levels of zinc ions and ZIP8 protein were upregulated after TgCtwh3 infection. ZIP8 knockdown exacerbated liver damage, further decreased antioxidant enzyme activity, promoted inflammatory mediator expression, and upregulated the rate of apoptosis. ZnCl2 pretreatment before TgCtwh3 infection improved liver injury, increased antioxidant enzyme activity, restrained the expression of inflammatory mediators, and decreased the rate of apoptosis. The results in vitro were almost the same as those in vivo. This study defines the function of ZIP8-dependent zinc in hepatocyte damage during intracellular pathogen infection. Reagents that regulate ZIP8 activity might be developed as therapeutics to protect the liver function of toxoplasmosis.

Respiratory syncytial virus disrupts the airway epithelial barrier by decreasing cortactin and destabilizing F-actin.

Respiratory syncytial virus (RSV) infection is the leading cause of acute lower respiratory tract infection in young children worldwide. Our group recently revealed that RSV infection disrupts the airway epithelial barrier in vitro and in vivo. However, the underlying molecular pathways were still elusive. Here, we report the critical roles of the filamentous actin (F-actin) network and actin-binding protein cortactin in RSV infection. We found that RSV infection causes F-actin depolymerization in 16HBE cells, and that stabilizing the F-actin network in infected cells reverses the epithelial barrier disruption. RSV infection also leads to significantly decreased cortactin in vitro and in vivo. Cortactin-knockout 16HBE cells presented barrier dysfunction, whereas overexpression of cortactin protected the epithelial barrier against RSV. The activity of Rap1 (which has Rap1A and Rap1B forms), one downstream target of cortactin, declined after RSV infection as well as in cortactin-knockout cells. Moreover, activating Rap1 attenuated RSV-induced epithelial barrier disruption. Our study proposes a key mechanism in which RSV disrupts the airway epithelial barrier via attenuating cortactin expression and destabilizing the F-actin network. The identified pathways will provide new targets for therapeutic intervention toward RSV-related disease. This article has an associated First Person interview with the first author of the paper.

NCX1 coupled with TRPC1 to promote gastric cancer via Ca2+/AKT/ß-catenin pathway.

Plasma membrane Na+/Ca2+ exchanger 1 (NCX1) is a bidirectional ion transporter to operate in Ca2+ entry or exit modes, and TRPC1 is Ca2+-permeable channel. Both NCX1 and TRPC1 play critical roles in maintaining cytosolic free Ca2+ ([Ca2+]cyt) homeostasis in mammalian cells. Although either TRPC1 channel or Ca2+ entry mode of NCX1 is implicated in some tumorigenesis, it has not been explored if a coordination of NCX1 and TRPC1 involves in the pathogenesis of H. pylori-associated human gastric cancer (GC). Here we found the protein expression of NCX1 was significantly enhanced in human GC specimens, which correlated with tumor progression and poor survival in GC patients. TRPC1 and NCX1 were parallelly enhanced, co-localized and bound in human GC cells. By a functional coupling, TRPC1 drives NCX1 to the Ca2+ entry mode, raising [Ca2+]cyt in GC cells. Moreover, CaCl2, H. pylori and their virulence factors all enhanced expressions and activities of NCX1 and TRPC1, and evoked aberrant Ca2+ entry to promote proliferation, migration, and invasion of GC cells through AKT/ß-catenin pathway. Tumor growth and metastasis also depended on the enhanced expression of NCX1 in subcutaneously xenografted GC mouse model. Overall, our findings indicate that TRPC1/NCX1 coupling may promote H. pylori-associated GC through the Ca2+/AKT/ß-catenin pathway. Since the Ca2+ exit mode and the Ca2+ entry mode of NCX1 play different roles under mostly physiological and pathological conditions respectively, targeting TRPC1/NCX1 coupling could be a novel strategy for selectively blocking Ca2+ entry mode to potentially treat digestive cancer with less side effect.

Differences in Postnatal Growth of Preterm Infants in Northern China Compared to the INTERGROWTH-21st Preterm Postnatal Growth Standards: A Retrospective Cohort Study.

Background: The INTERGROWTH-21st preterm postnatal growth standards (IPPGS) have increasingly been used to evaluate the growth of preterm infants worldwide. However, the validity of IPPGS's application to specific preterm populations remains controversial. This retrospective cohort study aimed to formulate reference growth charts for a preterm cohort in northern China and compare them to the IPPGS. Methods: A total of 1,827 healthy preterm infants with follow-up visits before 70 weeks of postmenstrual age (PMA) were retrospectively sampled from a preterm cohort (N = 2,011) born between 1 January 2011 and 28 February 2021, at the First Affiliated Hospital of Shandong First Medical University. Using the Generalized Additive Models for Location, Scale, and Shape method, 5,539 sets of longitudinal data were used to construct percentile and Z-score charts of length, weight, and head circumference (HC) at 40-64 weeks of PMA. Z-scores of length, weight, and HC (LAZ, WAZ, and HCZ) before 64 weeks were calculated using the IPPGS. Differences in the 50th percentile values between preterm infants and IPPGS (dLength, dWeight, and dHC) were calculated. Z-scores were assigned to six PMA clusters: 40-44, 44-48, 48-52, 52-56, 56-60, and 60-64 weeks for comparison between sexes. Results: For eligible infants, the mean PMA and weight at birth were 33.93 weeks and 2.3 kg, respectively. Boys, late preterm infants, twins, and infants with exclusively breastfeeding accounted for 55.8, 70.6, 27.8, and 45.9%, respectively. Compared to IPPGS, preterm infants were longer and heavier, especially for dLength in girls (range, 2.19-2.97 cm), which almost spanned the 50th and 90th percentiles of IPPGS. The dHC tended to narrow with PMA for both sexes. The mean LAZ, WAZ, and HCZ of both sexes at all PMA clusters were >0, especially for LAZ and WAZ (about 1.0 relative to IPPGS), indicating higher levels than the IPPGS at 40-64 weeks. Girls had larger LAZ at each PMA cluster, larger WAZ at 40-44 weeks, and lower HCZ after 56 weeks than boys. HCZ declined with PMA for both sexes. Conclusion: Postnatal growth of this preterm cohort was considerably higher than that of the IPPGS at 40-64 weeks of PMA with sex differences.

A novel spinal neuron connection for heat sensation.

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.

A New Birthweight Reference by Gestational Age: A Population Study Based on the Generalized Additive Model for Location, Scale, and Shape Method.

Background: It is important to choose a suitable birthweight reference to assess newborns, especially those that are small for gestational age (SGA). Currently, there is no regional standard reference for the north of China or for Shandong province. Methods: A total of 130,911 data records of singleton, live neonates born at 24-42 weeks of gestation were collected from 2016 to 2018 in Shandong province. A new birthweight-for-gestational age percentile reference was constructed based on the Generalized Additive Model for Location, Scale and Shape (GAMLSS) package in R version 3.5. The established gestational age weight curve was compared separately with the Fenton curve, INTERGROWTH-21st curve, and the Chinese Neonatal Network Standard curve of 2015. Results: We established the reference values of birthweight by gestational age at the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles. Newborns had much heavier birthweights than those in the INTERGROWTH-21st and Fenton curves at most gestational ages. Although the newborns' birthweight references were closer to the Chinese Neonatal Network Standard except a few for gestational age, this study and INTERGROWTH-21st had similar birthweight curve shapes. Conclusions: There are obvious differences among the criteria for newborn birthweights. Therefore, it is more accurate to assess newborns using the local birthweight reference.

Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 delays early Wallerian degeneration after sciatic nerve injury.

Wallerian degeneration is a complex biological process that occurs after nerve injury, and involves nerve degeneration and regeneration. Schwann cells play a crucial role in the cellular and molecular events of Wallerian degeneration of the peripheral nervous system. However, Wallerian degeneration regulating nerve injury and repair remains largely unknown, especially the early response. We have previously reported some key regulators of Wallerian degeneration after sciatic nerve injury. Baculoviral inhibitor of apoptosis protein repeat-containing protein 3 (BIRC3) is an important factor that regulates apoptosis-inhibiting protein. In this study, we established rat models of right sciatic nerve injury. In vitro Schwann cell models were also established and subjected to gene transfection to inhibit and overexpress BIRC3. The data indicated that BIRC3 expression was significantly up-regulated after sciatic nerve injury. Both BIRC3 upregulation and downregulation affected the migration, proliferation and apoptosis of Schwan cells and affected the expression of related factors through activating c-fos and ERK signal pathway. Inhibition of BIRC3 delayed early Wallerian degeneration through inhibiting the apoptosis of Schwann cells after sciatic nerve injury. These findings suggest that BIRC3 plays an important role in peripheral nerve injury repair and regeneration. The study was approved by the Institutional Animal Care and Use Committee of Nantong University, China (approval No. 2019-nsfc004) on March 1, 2019.

A reassortant G3P[12] rotavirus A strain associated with severe enteritis in donkeys (Equus asinus).

BACKGROUND: In contrast to horses, the only evidence suggesting gastrointestinal disease in neonatal donkeys is associated with Group A rotaviruses (RVAs) is the detection of viral antigens by ELISA in just 1 of 82 symptomatic donkey foals. No additional, more comprehensive investigations have been conducted, and RVAs if circulating in donkey populations have not been molecularly characterised. OBJECTIVES: To investigate if RVAs are associated with an outbreak of severe enteritis in neonatal donkeys and if associated determine the genotype(s) along with the phylogenetic relationship to RVA strains circulating in horses. STUDY DESIGN: Cross-sectional. METHODS: RT-PCR-based techniques were used for RVA diagnosis and gene amplification. Statistical significance was determined by Chi-square and Fisher's exact two-sided tests. Genotyping was performed by RotaC and phylogenetic analysis by neighbour joining. RESULTS: In 2019, acute enteritis occurred in 119 of 206 donkey foals (≤4 months) at two intensive donkey farms in the Shandong province of China. The highest morbidity (68.1%), mortality (29.5%) and fatality levels (45.5%) occurred in foals in the 30-89 day, 30-59 day and 0-29 day age groups respectively. RVA gene sequences were detected in 107 (89.9%) of the symptomatic individuals while further analysis demonstrated the outbreak was associated with the same G3P[12] RVA strain designated RVA/Donkey-wt/CHN/Don01/2019/G3P[12]. Although the VP4 gene of Don01 exhibited close phylogenetic relationships with equivalent RVA sequences commonly circulating in horses, encoding VP7 was more closely associated with sequences isolated from bats suggesting this new donkey strain arose via an intergenogroup reassortment event. MAIN LIMITATIONS: Actual prevalence not determined because <7% of asymptomatic donkey foals were included in this study. The complete genomic sequence of RVA/Donkey-wt/CHN/Don01/2019/G3P[12] remains to be determined. CONCLUSIONS: Valuable new information about the molecular epidemiology of rotaviruses in different equid species is provided by isolation and molecular characterisation of a novel RVA strain from neonatal donkeys.