Neoadjuvant PARPi or chemotherapy in ovarian cancer informs targeting effector Treg cells for homologous-recombination-deficient tumors.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.

The IRE1α/XBP1 signaling axis drives myoblast fusion in adult skeletal muscle.

Skeletal muscle regeneration involves a signaling network that regulates the proliferation, differentiation, and fusion of muscle precursor cells to injured myofibers. IRE1α, one of the arms of the unfolded protein response, regulates cellular proteostasis in response to ER stress. Here, we demonstrate that inducible deletion of IRE1α in satellite cells of mice impairs skeletal muscle regeneration through inhibiting myoblast fusion. Knockdown of IRE1α or its downstream target, X-box protein 1 (XBP1), also inhibits myoblast fusion during myogenesis. Transcriptome analysis revealed that knockdown of IRE1α or XBP1 dysregulates the gene expression of molecules involved in myoblast fusion. The IRE1α-XBP1 axis mediates the gene expression of multiple profusion molecules, including myomaker (Mymk). Spliced XBP1 (sXBP1) transcription factor binds to the promoter of Mymk gene during myogenesis. Overexpression of myomaker in IRE1α-knockdown cultures rescues fusion defects. Inducible deletion of IRE1α in satellite cells also inhibits myoblast fusion and myofiber hypertrophy in response to functional overload. Collectively, our study demonstrates that IRE1α promotes myoblast fusion through sXBP1-mediated up-regulation of the gene expression of multiple profusion molecules, including myomaker.

Chlamydomonas LZTFL1 mediates phototaxis via controlling BBSome recruitment to the basal body and its reassembly at the ciliary tip.

Many G protein-coupled receptors and other signaling proteins localize to the ciliary membrane for regulating diverse cellular processes. The BBSome composed of multiple Bardet-Biedl syndrome (BBS) proteins is an intraflagellar transport (IFT) cargo adaptor essential for sorting signaling proteins in and/or out of cilia via IFT. Leucine zipper transcription factor-like 1 (LZTFL1) protein mediates ciliary signaling by controlling BBSome ciliary content, reflecting how LZTFL1 mutations could cause BBS. However, the mechanistic mechanism underlying this process remains elusive thus far. Here, we show that LZTFL1 maintains BBSome ciliary dynamics by finely controlling BBSome recruitment to the basal body and its reassembly at the ciliary tip simultaneously in Chlamydomonas reinhardtii LZTFL1 directs BBSome recruitment to the basal body via promoting basal body targeting of Arf-like 6 GTPase BBS3, thus deciding the BBSome amount available for loading onto anterograde IFT trains for entering cilia. Meanwhile, LZTFL1 stabilizes the IFT25/27 component of the IFT-B1 subcomplex in the cell body so as to control its presence and amount at the basal body for entering cilia. Since IFT25/27 promotes BBSome reassembly at the ciliary tip for loading onto retrograde IFT trains, LZTFL1 thus also directs BBSome removal out of cilia. Therefore, LZTFL1 dysfunction deprives the BBSome of ciliary presence and generates Chlamydomonas cells defective in phototaxis. In summary, our data propose that LZTFL1 maintains BBSome dynamics in cilia by such a dual-mode system, providing insights into how LZTFL1 mediates ciliary signaling through maintaining BBSome ciliary dynamics and the pathogenetic mechanism of the BBS disorder as well.

Intraflagellar transport protein RABL5/IFT22 recruits the BBSome to the basal body through the GTPase ARL6/BBS3.

Bardet-Biedl syndrome (BBS) is a ciliopathy caused by defects in the assembly or distribution of the BBSome, a conserved protein complex. The BBSome cycles via intraflagellar transport (IFT) through cilia to transport signaling proteins. How the BBSome is recruited to the basal body for binding to IFT trains for ciliary entry remains unknown. Here, we show that the Rab-like 5 GTPase IFT22 regulates basal body targeting of the BBSome in Chlamydomonas reinhardtii Our functional, biochemical and single particle in vivo imaging assays show that IFT22 is an active GTPase with low intrinsic GTPase activity. IFT22 is part of the IFT-B1 subcomplex but is not required for ciliary assembly. Independent of its association to IFT-B1, IFT22 binds and stabilizes the Arf-like 6 GTPase BBS3, a BBS protein that is not part of the BBSome. IFT22/BBS3 associates with the BBSome through an interaction between BBS3 and the BBSome. When both IFT22 and BBS3 are in their guanosine triphosphate (GTP)-bound states they recruit the BBSome to the basal body for coupling with the IFT-B1 subcomplex. The GTP-bound BBS3 likely remains to be associated with the BBSome upon ciliary entry. In contrast, IFT22 is not required for the transport of BBSomes in cilia, indicating that the BBSome is transferred from IFT22 to the IFT trains at the ciliary base. In summary, our data propose that nucleotide-dependent recruitment of the BBSome to the basal body by IFT22 regulates BBSome entry into cilia.

Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead.

Hypoplastic left heart syndrome (HLHS) is a lethal congenital heart disease (CHD) affecting 8-25 per 100,000 neonates globally. Clinical interventions, primarily surgical, have improved the life expectancy of the affected subjects substantially over the years. However, the etiological basis of HLHS remains fundamentally unclear to this day. Based upon the existing paradigm of studies, HLHS exhibits a multifactorial mode of etiology mediated by a complicated course of genetic and signaling cascade. This review presents a detailed outline of the HLHS phenotype, the prenatal and postnatal risks, and the signaling and molecular mechanisms driving HLHS pathogenesis. The review discusses the potential limitations and future perspectives of studies that can be undertaken to address the existing scientific gap. Mechanistic studies to explain HLHS etiology will potentially elucidate novel druggable targets and empower the development of therapeutic regimens against HLHS in the future.

Role of the Nrf2 Signaling Pathway in Ovarian Aging: Potential Mechanism and Protective Strategies.

The ovary holds a significant role as a reproductive endocrine organ in women, and its aging process bears implications such as menopause, decreased fertility, and long-term health risks including osteoporosis, cardiovascular disorders, and cognitive decline. The phenomenon of oxidative stress is tightly linked to the aging metabolic processes. More and more studies have demonstrated that oxidative stress impacts both physiologic and pathologic ovarian aging, and the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a crucial role in regulating the antioxidant response. Furthermore, various therapeutic approaches have been identified to ameliorate ovarian aging by modulating the Nrf2 pathway. This review summarizes the important role of the Nrf2/ Kelch-like ECH-associated protein 1 (Keap1) signaling pathway in regulating oxidative stress and influencing ovarian aging. Additionally, it highlights the therapeutic strategies aimed at targeting the Nrf2/Keap1 pathway.

Increased circulating innate lymphoid cell (ILC)1 and decreased circulating ILC3 are involved in the pathogenesis of Henoch-Schonlein purpura.

BACKGROUND: Innate lymphoid cell (ILC) dysfunction is involved in numerous immune diseases, but this has not been demonstrated in Henoch-Schonlein purpura (HSP). This study aimed to investigate whether ILC dysfunction or imbalance participate in the pathogenesis of HSP. METHODS: This was a prospective study in patients with HSP who were hospitalized at the Children's Hospital of Soochow University from June to December 2019. Age- and sex-matched controls were also enrolled. ILC subsets and lymphocyte subpopulations were determined by flow cytometry. The transmission immune turbidimetric method also facilitated the exploration of correlations between ILC subset frequency and lymphocyte subpopulation, as well as serum IgA in HSP patients. RESULTS: Fifty-one patients with HSP and 22 control patients were included. There were no differences in age and sex between the two groups. Compared with controls, patients with HSP had higher ILCs in relation to lymphocytes (P = 0.036), higher ILCs in relation to PBMCs (P = 0.026), higher ILC1s (P < 0.001), lower ILC3s (P < 0.05), and higher ILC1/ILC3 ratio (P < 0.001). Sixteen patients underwent routine therapy combined with methylprednisolone for 7-10 days; ILC1s were significantly decreased (P < 0.001) and ILC3s were increased (P = 0.033), and ILC1/ILC3 was significantly decreased (P < 0.001). Compared with the controls, the ratios of ILCs/lymphocytes and ILCs/PBMC were higher in patients in the arthritis and mixed groups (all P < 0.05). ILC1 were elevated in the purpura, arthritis, abdominal, and mixed groups (P = 0.027, P = 0.007, P < 0.001, and P < 0.001, respectively). ILC1/ILCs were positively correlated with CD3 + CD8 + T lymphocytes (r = 0.3701, P = 0.0075). The level of IgA did not correlate with ILCs. CONCLUSIONS: Higher circulating ILC1s and lower circulating ILC3s appear to be involved in the pathogenesis of HSP.

Cardiomyocyte orientation modulated by the Numb family proteins-N-cadherin axis is essential for ventricular wall morphogenesis.

The roles of cellular orientation during trabecular and ventricular wall morphogenesis are unknown, and so are the underlying mechanisms that regulate cellular orientation. Myocardial-specific Numb and Numblike double-knockout (MDKO) hearts display a variety of defects, including in cellular orientation, patterns of mitotic spindle orientation, trabeculation, and ventricular compaction. Furthermore, Numb- and Numblike-null cardiomyocytes exhibit cellular behaviors distinct from those of control cells during trabecular morphogenesis based on single-cell lineage tracing. We investigated how Numb regulates cellular orientation and behaviors and determined that N-cadherin levels and membrane localization are reduced in MDKO hearts. To determine how Numb regulates N-cadherin membrane localization, we generated an mCherry:Numb knockin line and found that Numb localized to diverse endocytic organelles but mainly to the recycling endosome. Consistent with this localization, cardiomyocytes in MDKO did not display defects in N-cadherin internalization but rather in postendocytic recycling to the plasma membrane. Furthermore, N-cadherin overexpression via a mosaic model partially rescued the defects in cellular orientation and trabeculation of MDKO hearts. Our study unravels a phenomenon that cardiomyocytes display spatiotemporal cellular orientation during ventricular wall morphogenesis, and its disruption leads to abnormal trabecular and ventricular wall morphogenesis. Furthermore, we established a mechanism by which Numb modulates cellular orientation and consequently trabecular and ventricular wall morphogenesis by regulating N-cadherin recycling to the plasma membrane.

Carbon tetrachloride exposure induces ovarian damage through oxidative stress and inflammatory mediated ovarian fibrosis.

Carbon tetrachloride (CCL4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17ß-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1ß, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL4 group. In the CCL4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.

[Preadmission follow-up condition of neonates hospitalized due to severe hyperbilirubinemia after discharge from the department of obstetrics and influencing factors for follow-up compliance: a multicenter investigation]. / äº§ç§‘å‡ºé™¢åŽå› ä¸¥é‡é«˜èƒ†çº¢ç´ è¡€ç—‡ä½é™¢æ–°ç”Ÿå„¿å ¥é™¢å‰éšè®¿æƒ å†µåŠéšè®¿ä¾ä»Žæ€§å½±å“å› ç´ çš„å¤šä¸­å¿ƒè°ƒæŸ¥.

OBJECTIVES: To investigate the preadmission follow-up condition of neonates hospitalized due to severe hyperbilirubinemia after discharge from the department of obstetrics and the influencing factors for follow-up compliance. METHODS: A multicenter retrospective case-control study was performed for the cases from the multicenter clinical database of 12 units in the Quality Improvement Clinical Research Cooperative Group of Neonatal Severe Hyperbilirubinemia in Jiangsu Province of China from January 2019 to April 2021. According to whether the follow-up of neonatal jaundice was conducted on time after discharge from the department of obstetrics, the neonates were divided into two groups: good follow-up compliance and poor follow-up compliance. The multivariate logistic regression model was used to identify the influencing factors for follow-up compliance of the neonates before admission. RESULTS: A total of 545 neonates with severe hyperbilirubinemia were included in the study, with 156 neonates (28.6%) in the good follow-up compliance group and 389 (71.4%) in the poor follow-up compliance group. The multivariate logistic regression analysis showed that low gestational age at birth, ≥10% reduction in body weight on admission compared with birth weight, history of phototherapy of siblings, history of exchange transfusion of siblings, Rh(-) blood type of the mother, a higher educational level of the mother, the use of WeChat official account by medical staff to remind of follow-up before discharge from the department of obstetrics, and the method of telephone notification to remind of follow-up after discharge were associated with the increase in follow-up compliance (P<0.05). CONCLUSIONS: Poor follow-up compliance is observed for the neonates with severe hyperbilirubinemia after discharge from the department of obstetrics, which suggests that it is necessary to further strengthen the education of jaundice to parents before discharge and improve the awareness of jaundice follow-up. It is recommended to remind parents to follow up on time by phone or WeChat official account.

[Antibiotic use in very low birth weight/extremely low birth weight infants in 15 hospitals in Jiangsu Province of China: a multicenter survey]. / 江苏省15家医院极低/è¶ ä½Žå‡ºç”Ÿä½“é‡å„¿æŠ—ç”Ÿç´ ä½¿ç”¨çŽ°çŠ¶è°ƒæŸ¥.

OBJECTIVES: To investigate the current status of antibiotic use in very low birth weight/extremely low birth weight infants in Jiangsu Province of China, and to provide a clinical basis for the quality and improvement of antibiotic management in the neonatal intensive care unit (NICU). METHODS: A retrospective analysis was performed on the data on general conditions and antibiotic use in the very low birth weight/extremely low birth weight infants who were admitted to 15 hospitals of Jiangsu Province from January 1, 2019 to December 31, 2020. A questionnaire containing 10 measures to reduce antibiotic use was designed to investigate the implementation of these intervention measures. RESULTS: A total of 1 920 very low birth weight/extremely low birth weight infants were enrolled, among whom 1 846 (96.15%) were treated with antibiotic, and the median antibiotic use rate (AUR) was 50/100 patient-days. The AUR ranged from 24/100 to 100/100 patient-days in the 15 hospitals. After adjustment for the confounding factors including gestational age, birth weight, and neonatal critical score, the Poisson regression analysis showed that there was a significant difference in the adjusted AUR (aAUR) among the hospitals (P<0.01). The investigation results showed that among the 10 measures to reduce antibiotic use, 8 measures were implemented in less than 50% of these hospitals, and the number of intervention measures implemented was negatively correlated with aAUR (rs=-0.564, P=0.029). CONCLUSIONS: There is a high AUR among the very low birth weight/extremely low birth weight infants in the 15 hospitals of Jiangsu Province, with a significant difference among hospitals. The hospitals implementing a relatively few measures to reduce antibiotic use tend to have a high AUR. It is expected to reduce AUR in very low birth weight/extremely low birth weight infants by promoting the quality improvement of antibiotic use management in the NICU.

IFI27 may predict and evaluate the severity of respiratory syncytial virus infection in preterm infants.

BACKGROUND: Preterm infants are a special population that vulnerable to respiratory syncytial virus (RSV) infection and the lower respiratory tract infections (LRTIs) caused by RSV could be severe and even life-threating. The purpose of the present study was to identify candidate genes of preterm infants who are susceptible to RSV infection and provide a new insight into the pathogenesis of RSV infection. METHODS: Three datasets (GSE77087, GSE69606 and GSE41374) containing 183 blood samples of RSV infected patients and 33 blood samples of healthy controls from Gene Expression Omnibus (GEO) database were downloaded and the differentially expressed genes (DEGs) were screened out. The function and pathway enrichments were analyzed through Database for Annotation, Visualization and Integrated Discovery (DAVID) website. The protein-protein interaction (PPI) network for DEGs was constructed through Search Tool for the Retrieval of Interacting Genes (STRING). The module analysis was performed by Cytoscape software and hub genes were identified. Clinical verification was employed to verify the expression level of top five hub genes among 72 infants including 50 RSV infected patients and 22 non-RSV-infected patients hospitalized in our center. Further, the RSV infected infants with high-expression IFI27 and those with low-expression IFI27 were compared (defined as higher or lower than the median mRNA level). Finally, the gene set enrichment analysis (GSEA) focusing on IFI27 was carried out. RESULTS: Totally, 4028 DEGs were screened out and among which, 131 most significant DEGs were selected. Subsequently, 13 hub genes were identified, and function and pathway enrichments of hub genes mainly were: response to virus, defense response to virus, regulation of viral genome replication and regulation of viral life cycle. Furthermore, IFI27 was confirmed to be the most significantly expressed in clinical verification. Gene sets associated with calcium signaling pathway, arachidonic acid metabolism, extracellular matrix receptor interaction and so on were significantly enriched when IFI27 was highly expressed. Moreover, high-expression IFI27 was associated with more severe cases (p = 0.041), more requirements of mechanical ventilation (p = 0.034), more frequent hospitalization (p < 0.001) and longer cumulative hospital stay (p = 0.012). CONCLUSION: IFI27 might serve to predict RSV infection and evaluate the severity of RSV infection in preterm infants.

Intrinsic cellular chirality regulates left-right symmetry breaking during cardiac looping.

The vertebrate body plan is overall symmetrical but left-right (LR) asymmetric in the shape and positioning of internal organs. Although several theories have been proposed, the biophysical mechanisms underlying LR asymmetry are still unclear, especially the role of cell chirality, the LR asymmetry at the cellular level, on organ asymmetry. Here with developing chicken embryos, we examine whether intrinsic cell chirality or handedness regulates cardiac C looping. Using a recently established biomaterial-based 3D culture platform, we demonstrate that chick cardiac cells before and during C looping are intrinsically chiral and exhibit dominant clockwise rotation in vitro. We further show that cells in the developing myocardium are chiral as evident by a rightward bias of cell alignment and a rightward polarization of the Golgi complex, correlating with the direction of cardiac tube rotation. In addition, there is an LR polarized distribution of N-cadherin and myosin II in the myocardium before the onset of cardiac looping. More interestingly, the reversal of cell chirality via activation of the protein kinase C signaling pathway reverses the directionality of cardiac looping, accompanied by a reversal in cellular biases on the cardiac tube. Our results suggest that myocardial cell chirality regulates cellular LR symmetry breaking in the heart tube and the resultant directionality of cardiac looping. Our study provides evidence of an intrinsic cellular chiral bias leading to LR symmetry breaking during directional tissue rotation in vertebrate development.

[Clinical features of preterm infants with a birth weight less than 1 500 g undergoing different intensities of resuscitation: a multicenter retrospective analysis].

OBJECTIVE: To evaluate the clinical features of preterm infants with a birth weight less than 1 500 g undergoing different intensities of resuscitation. METHODS: A retrospective analysis was performed for the preterm infants with a birth weight less than 1 500 g and a gestational age less than 32 weeks who were treated in the neonatal intensive care unit of 20 hospitals in Jiangsu, China from January 2018 to December 2019. According to the intensity of resuscitation in the delivery room, the infants were divided into three groups:non-tracheal intubation (n=1 184), tracheal intubation (n=166), and extensive cardiopulmonary resuscitation (ECPR; n=116). The three groups were compared in terms of general information and clinical outcomes. RESULTS: Compared with the non-tracheal intubation group, the tracheal intubation and ECPR groups had significantly lower rates of cesarean section and use of antenatal corticosteroid (P < 0.05). As the intensity of resuscitation increased, the Apgar scores at 1 minute and 5 minutes gradually decreased (P < 0.05), and the proportion of infants with Apgar scores of 0 to 3 at 1 minute and 5 minutes gradually increased (P < 0.05). Compared with the non-tracheal intubation group, the tracheal intubation and ECPR groups had significantly higher mortality rate and incidence rates of moderate-severe bronchopulmonary dysplasia and serious complications (P < 0.05). The incidence rates of grade Ⅲ-Ⅳ intracranial hemorrhage and retinopathy of prematurity (stage Ⅲ or above) in the tracheal intubation group were significantly higher than those in the non-tracheal intubation group (P < 0.05). CONCLUSIONS: For preterm infants with a birth weight less than 1 500 g, the higher intensity of resuscitation in the delivery room is related to lower rate of antenatal corticosteroid therapy, lower gestational age, and lower birth weight. The infants undergoing tracheal intubation or ECRP in the delivery room have an increased incidence rate of adverse clinical outcomes. This suggests that it is important to improve the quality of perinatal management and delivery room resuscitation to improve the prognosis of the infants.

Transcriptional control of a novel long noncoding RNA Mymsl in smooth muscle cells by a single Cis-element and its initial functional characterization in vessels.

Differentiated vascular smooth muscle cells (VSMCs) are crucial in maintaining vascular homeostasis. While the coding transcriptome of the differentiated VSMC phenotype has been defined, we know little about its noncoding signature. Herein, we identified a Myocardin-induced muscle specific long noncoding RNA (lncRNA) (Mymsl) downregulated upon VSMC phenotypic modulation. We demonstrated an essential role of a proximal consensus CArG element in response to MYOCD/SRF in vitro. To validate the in vivo role of this CArG element, we generated CArG mutant mice via CRISPR-Cas9 genome editing. While the CArG mutation had no impact on the expression of surrounding genes, it abolished Mymsl expression in SMCs, but not skeletal and cardiac muscle. Chromatin immunoprecipitation assays (ChIPs) showed decreased SRF binding to CArG region in mutants whereas the enrichment of H3K79Me2 remained the same. RNA-seq analysis showed a downregulation of matrix genes in aortas from Mymsl knockout mice, which was further validated in injured carotid arteries. Our study defined the transcriptional control of a novel lncRNA in SMCs via a single transcription factor binding site, which may offer a new strategy for generating SMC-specific knockout mouse models. We also provided in vivo evidence supporting the potential importance of Mymsl in vascular pathophysiology.

CDC42 is required for epicardial and pro-epicardial development by mediating FGF receptor trafficking to the plasma membrane.

The epicardium contributes to multiple cardiac lineages and is essential for cardiac development and regeneration. However, the mechanism of epicardium formation is unclear. This study aimed to establish the cellular and molecular mechanisms underlying the dissociation of pro-epicardial cells (PECs) from the pro-epicardium (PE) and their subsequent translocation to the heart to form the epicardium. We used lineage tracing, conditional deletion, mosaic analysis and ligand stimulation in mice to determine that both villous protrusions and floating cysts contribute to PEC translocation to myocardium in a CDC42-dependent manner. We resolved a controversy by demonstrating that physical contact of the PE with the myocardium constitutes a third mechanism for PEC translocation to myocardium, and observed a fourth mechanism in which PECs migrate along the surface of the inflow tract to reach the ventricles. Epicardial-specific Cdc42 deletion disrupted epicardium formation, and Cdc42 null PECs proliferated less, lost polarity and failed to form villous protrusions and floating cysts. FGF signaling promotes epicardium formation in vivo, and biochemical studies demonstrated that CDC42 is involved in the trafficking of FGF receptors to the cell membrane to regulate epicardium formation.

Epidemiological and clinical course of 483 patients with COVID-19 in Wuhan, China: a single-center, retrospective study from the mobile cabin hospital.

During the COVID-19 outbreak, the mobile cabin hospital has effectively isolated and treated patients diagnosed as mild-moderate disease. However, a detailed clinical course has not been well described. We included 483 patients who were isolated and treated from Feb 6, 2020, to Feb 15, 2020, including definite outcome (discharge or deterioration). Sixty-two patients were transferred to severe cases, of whom were trasfered to designated hospital for intensive care. By March 9, 2020, all patients were discharged without dead. The mobile cabin hospital provides feasible strategy of isolation of mild-moderate cases and timely intervention during the virus outbreak.

Update on recommendations for the diagnosis and treatment of SARS-CoV-2 infection in children.

Since the outbreak of novel coronavirus infection pneumonia in Wuhan City, China, in late 2019, such cases have been gradually reported in other parts of China and abroad. Children have become susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of their immature immune function. As the outbreak has progressed, more cases of novel coronavirus infection/pneumonia in children have been reported. Compared with adults, the impact of SARS-CoV-2 infection in children is less severe, with a lower incidence and susceptibility in children, which results in fewer children being tested, thereby underestimating the actual number of infections. Therefore, strengthening the diagnosis of the disease is particularly important for children, and early and clear diagnosis can determine treatment strategies and reduce the harm caused by the disease to children. According to the Novel Coronavirus Infection Pneumonia Diagnosis and Treatment Standards (trial version 7) issued by National Health Committee and the latest diagnosis and treatment strategies for novel coronavirus infection pneumonia in children, this review summarizes current strategies on diagnosis and treatment of SARS-CoV-2 infection in children.

Long non-coding RNA Snhg3 protects against hypoxia/ischemia-induced neonatal brain injury.

Hypoxic-ischemic brain damage (HIBD) is a major cause of morbidity and mortality in the preterm and term infant. However, the precise mechanism of HIBD remains largely elusive. As a newly discovered long non-coding RNA, small nucleolar RNA host gene 3 (Snhg3) has shown its important roles in cell apoptosis, proliferation, and disease development. In this study, we determined the role of Snhg3 in the pathogenesis of HIBD. Snhg3 expression was significantly down-regulated in the neonatal brain and primary hippocampal cells response to hypoxic/ischemic stress. Snhg3 overexpression protected against hypoxic/ischemic-induced brain injury in vivo and hippocampal cell injury in vitro. Snhg3 acted as the sponge of miR-196 in the hippocampal cells by regulating the expression of miR-196 target genes, XIAP and CAAP1. Moreover, Snhg3 overexpression decreased brain infarct size and ameliorated hypoxic-ischemic neonatal brain damage. This study suggests that Snhg3 is a potential target for the treatment of HIBD.

Dose-dependent effect of human milk on Bronchopulmonary dysplasia in very low birth weight infants.

BACKGROUND AND AIM: Human milk has potential protective effects against bronchopulmonary dysplasia (BPD). However, studies on the association between the dose of human milk and BPD in China are limited. This study aimed to evaluate the dose-dependent effects of human milk on BPD and other neonatal morbidities in very low birth weight (VLBW) infants. METHODS: This retrospective cohort study of preterm infants was conducted on preterm infants of gestational age ≤ 34 weeks and birth weight < 1500 g admitted to the multicenter clinical research database for breastfeeding quality improvement in Jiangsu province. The multivariate analysis was performed to compare the effect outcomes of daily graded doses [1-24 mL/(kg · day), 25-49 mL/(kg · day), and ≥ 50 mL/(kg · day) of body weight] of human milk on neonatal outcomes throughout the first 4 weeks of life versus a reference group receiving no human milk. The models were adjusted for potential confounding variables. RESULTS: Of 964 included infants, 279 (28.9%) received exclusive preterm formula, 128 (13.3%) received 1-24 ml/(kg · day), 139 (14.4%) received 25-49 ml/(kg · day), and 418 (43.4%) received ≥50 ml/(kg · day) human milk for the first 4 weeks of life. Compared with infants receiving exclusive formula, those receiving the highest volume of human milk daily [≥50 mL/(kg · day)] had lower incidences of BPD [27.5% in ≥50 mL/(kg · day) vs 40.1% in 0 mL/(kg · day) human milk, P = 0.001)], moderate and severe BPD [8.9% in ≥50 mL/(kg · day) vs 16.1% in 0 mL/(kg · day), P = 0.004], necrotizing enterocolitis [NEC; 3.8% in ≥50 mL/(kg · day) vs 10.8% in 0 mL/(kg · day), P = 0.001], late-onset sepsis [LOS; 9.3% in ≥50 mL/(kg · day) vs 19.7% in 0 mL/(kg · day), P <0.01], and extrauterine growth retardation [EUGR; 38.5% in ≥50 mL/(kg · day) vs 57.6% in 0 mL/(kg · day), P <0.01)]. The logistic regression indicated that those receiving ≥50 ml/kg · day human milk had lower odds of BPD [adjusted odds ratio (AOR) 0.453; 95% confidence interval (CI): 0.309, 0.666], moderate and severe BPD (AOR 0.430; 95% CI: 0.249, 0.742), NEC (AOR 0.314; 95% CI: 0.162, 0. 607), LOS (AOR 0.420; 95% CI: 0.263, 0.673), and EUGR (AOR 0.685; 95% CI: 0.479, 0.979). CONCLUSIONS: A daily threshold amount of ≥50 ml/(kg · day) human milk in the first 4 weeks of life was associated with lower incidence of BPD as well as NEC, LOS, and EUGR in VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03453502 . Registration date: March 5, 2018. This study was retrospectively registered.