Regulation of axon repulsion by MAX-1 SUMOylation and AP-3.

During neural development, growing axons express specific surface receptors in response to various environmental guidance cues. These axon guidance receptors are regulated through intracellular trafficking and degradation to enable navigating axons to reach their targets. In Caenorhabditis elegans, the UNC-5 receptor is necessary for dorsal migration of developing motor axons. We previously found that MAX-1 is required for UNC-5-mediated axon repulsion, but its mechanism of action remained unclear. Here, we demonstrate that UNC-5-mediated axon repulsion in C. elegans motor axons requires both max-1 SUMOylation and the AP-3 complex β subunit gene, apb-3 Genetic interaction studies show that max-1 is SUMOylated by gei-17/PIAS1 and acts upstream of apb-3 Biochemical analysis suggests that constitutive interaction of MAX-1 and UNC-5 receptor is weakened by MAX-1 SUMOylation and by the presence of APB-3, a competitive interactor with UNC-5. Overexpression of APB-3 reroutes the trafficking of UNC-5 receptor into the lysosome for protein degradation. In vivo fluorescence recovery after photobleaching experiments shows that MAX-1 SUMOylation and APB-3 are required for proper trafficking of UNC-5 receptor in the axon. Our results demonstrate that SUMOylation of MAX-1 plays an important role in regulating AP-3-mediated trafficking and degradation of UNC-5 receptors during axon guidance

Factors for poor prognosis of neonatal bacterial meningitis in a medical center in Northern Taiwan

BackgroundBacterial meningitis has long been a severe infectious disease in neonates, as well as a leading cause of adverse outcomes. We designed this study to know the factors for poor prognosis in neonatal bacterial meningitis.MethodsWe enrolled children aged less than 1 month who were admitted to Mackay Memorial Hospital from 1984 to 2008 and had culture-proven bacterial meningitis. The laboratory data and children’s clinical features were recorded. The patients’ outcomes were divided into four groups: death, having sequelae, complete recovery, and loss to follow-up. Patients with the outcomes of death and having sequelae were regarded as having a poor prognosis. Those who were lost to follow-up were excluded from the analysis of outcome. Multivariate analyses were performed to find the risk factors for poor prognosis.ResultsOne hundred fifty-six neonates fulfilled the inclusion criteria. Among these, 96 were boys (61.5%) and 102 (65.4%) had concomitant bacteremia. Group B streptococci (39.1%) and Escherichia coli (20.1%) were the two leading pathogens. Excluding those who were lost to follow-up (4.5%), 22 of 149 patients (14.8%) died, 36 (24.2%) had sequelae, and 91 (61.1%) recovered completely. Cerebrospinal fluid (CSF) protein more than 500 mg/dL at admission {odds ratio (OR): 171.18 [95% confidence interval (CI): 25.6–1000]}, predisposition to congenital heart disease [OR: 48.96 (95% CI: 6.06–395.64)], hearing impairment found during hospitalization [OR: 23.40 (95% CI: 3.62–151.25)], and seizure at admission or during hospitalization [OR: 10.10 (95% CI: 2.11–48.32)] were the factors predicting poor prognosis.ConclusionIn this 25-year study of newborns with bacterial meningitis, approximately one-seventh of the patients died, while two-fifths had sequelae. Nearly two-thirds of these had concomitant bacteremia. Group B streptococci and E. coli remained the two leading pathogens throughout the study period. Several factors for poor prognosis in newborns with culture-proven bacterial meningitis were found: high CSF protein concentration, congenital heart disease, hearing impairment, and seizure

Topographic Study of Extracted Molars with Advanced Furcation Involvement: Furcation Entrance Dimension and Molar Type

This study investigated the topography of the furcation entrance dimension (FED) on molars with advanced furcation involvement (FI). The sample pool consisted of 169 maxillary and mandibular molars from a group of 165 individuals with severely advanced periodontal destruction. The subjects included men and women aged 24 to 84 years (mean, 47.8 ± 7.2 years). The FEDs of the maxillary buccal, mesial, and distal surfaces as well as the mandibular buccal and lingual surfaces were measured under a stereomicroscope and clarified into grades I (FED < 0.55 mm), II (0.55-0.75 mm), and III (> 0.75 mm) using automatic grading system software designed by our research associates. The differences and relationships among molar location, furcation site, and FED grade were analyzed using the chi-square test. There was a significant difference among buccal (BFED), mesial (MFED), and distal (DFED) FEDs in both the maxillary first (χ24 = 58.915, p < 0.001) and second (χ24 = 66.839, p < 0.001) molars. The relationship between molar type and FED grade was statistically significant for both the BFED (p < 0.001) and the DFED (p < 0.001) of maxillary molars, as well as for both the BFED (p < 0.0001) and LFED (p < 0.0001). The difference in FED grade between the first and second molars was statistically significant in both maxillary (p < 0.001) and mandibular (p < 0.0001) molars. There was a significant relationship between FED grade and tooth location at molars with advanced FI

Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

<p>Abstract</p> <p>Background</p> <p>Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3) in both carrageenan- and complete Freund's adjuvant (CFA)-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation.</p> <p>Methods</p> <p>Here we used mechanical stimuli to assess behavioral responses in paw and muscle inflammation induced by carrageenan or CFA. We also used immunohistochemistry staining and western blot methodology to evaluate the expression of ASIC3 in dorsal root ganglion (DRG) neurons.</p> <p>Results</p> <p>In comparison with the control, the inflammation group showed significant mechanical hyperalgesia with both intraplantar carrageenan and CFA-induced inflammation. Interestingly, both carrageenan- and CFA-induced hyperalgesia were accompanied by ASIC3 up-regulation in DRG neurons. Furthermore, electroacupuncture (EA) at the ST36 rescued mechanical hyperalgesia through down-regulation of ASIC3 overexpression in both carrageenan- and CFA-induced inflammation.</p> <p>Conclusions</p> <p>In addition, electrical stimulation at the ST36 acupoint can relieve mechanical hyperalgesia by attenuating ASIC3 overexpression.</p

Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation.

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications

Case report: Presentations and cytokine profiles of inflammatory non-pulmonary COVID-19 and related diseases in children

The coronavirus disease 2019 (COVID-19) pandemic has evolved to dynamic waves of different SARS-CoV-2 variants. Initially, children diagnosed with COVID-19 presented pulmonary involvement characterized by mild diseases. In the later waves of the COVID-19 pandemic, life-threatening non-pulmonary inflammatory diseases such as (1) aseptic meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) multisystem inflammatory syndrome in children (MIS-C) have been reported, affecting the pediatric population. To alert timely identification and prevention of the life-threatening non-pulmonary COVID-19, we present the cases of ME, ANE, and MIS-C in terms of clinical manifestation, cytokine profile, and follow-up consequences. Based on the immunopathogenesis and risk factors associated with non-pulmonary COVID-19, we delineate strategies for an early diagnosis and treatment to reduce morbidity and mortality in children

Seismic Stratigraphic Features of the Late Miocene-Present Unconformities and Related Seismic Units, Northern Offshore Taiwan

We investigate the seismic stratigraphic features offshore northern Taiwan by using newly collected multichannel seismic data. Two significant regional unconformities U1 and U2 have been identified, which further subdivide the sedimentary sequence into three seismic units as SU I, SU II, and SU III. The lowermost seismic unit SU I is a pre-late Miocene sequence, while the middle and upper seismic unit SU II and SU III result from the interactions between the rapid fault-controlled subsidence and the stable thermal-controlled subsidence. We consider that the present-day offshore northern Taiwan is under a post-collisional state and the unconformities U1 and U2 represent a response to the mountain collapse and to the cessation of the regional volcano-tectonic activities. It is not until 1.5 Ma that northern offshore Taiwan became a post-collisional basin and started to receive sediments, with a rapid fault-controlled subsidence. Afterward, the basin became dominated by a stable thermal-controlled subsidence at 0.2 Ma. Although the main volcano-tectonic activities in the northern offshore Taiwan are ceased, modern geophysical and geochemical investigations have suggested that the tectonism and the volcanism are still active and represent potential threatening geohazard

Afatinib Exerts Immunomodulatory Effects by Targeting the Pyrimidine Biosynthesis Enzyme CAD

13 páginas, 7 figurasCurrent clinical trials of combined EGFR-tyrosine kinase inhibitors (TKI) and immune checkpoint blockade (ICB) therapies show no additional effect. This raises questions regarding whether EGFR-TKIs attenuate ICB-enhanced CD8+ T lymphocyte function. Here we show that the EGFR-TKI afatinib suppresses CD8+ T lymphocyte proliferation, and we identify CAD, a key enzyme of de novo pyrimidine biosynthesis, to be a novel afatinib target. Afatinib reduced tumor-infiltrating lymphocyte numbers in Lewis lung carcinoma (LLC)-bearing mice. Early afatinib treatment inhibited CD8+ T lymphocyte proliferation in patients with non-small cell lung cancer, but their proliferation unexpectedly rebounded following long-term treatment. This suggests a transient immunomodulatory effect of afatinib on CD8+ T lymphocytes. Sequential treatment of afatinib with anti-PD1 immunotherapy substantially enhanced therapeutic efficacy in MC38 and LLC-bearing mice, while simultaneous combination therapy showed only marginal improvement over each single treatment. These results suggest that afatinib can suppress CD8+ T lymphocyte proliferation by targeting CAD, proposing a timing window for combined therapy that may prevent the dampening of ICB efficacy by EGFR-TKIs. SIGNIFICANCE: This study elucidates a mechanism of afatinib-mediated immunosuppression and provides new insights into treatment timing for combined targeted therapy and immunotherapy. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3270/F1.large.jpg.This study was supported by Taiwan Ministry of Science and Technology grants MOST 104-2320-B-002-044-MY3, MOST 106-2320-B-002-046-MY3, and MOST 108-2320-B-002-024-MY3, National Health Research Institutes grants NHRI-EX106-10401BI and NHRI-EX109-10725BI, National Taiwan University grants NTU107L890504 and NTU110L893503 to M.-S. Lee, and National Taiwan University Hospital grants 106-003451, 107-003849, 108-004269, and 109-004720 to C.-C. Ho. This work was also supported by MINECO grants BFU2016-80570-R and RTI2018-098084-B-I00 (AEI/FEDER, UE). The authors would like to thank the Laboratory Animal Core Facility at the College of Medicine, National Taiwan University for their servicesPeer reviewe