NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection

Streptococcus pneumoniae is an invasive pathogen with high morbidity and mortality in the immunocompromised children and elderly. NOD-like receptor family pyrin domain containing 6 (NLRP6) plays an important role in the host innate immune response against pathogen infections. Our previous studies have shown that NLRP6 plays a negative regulatory role in host defense against S. pneumoniae, but the underlying mechanism is still unclear. The further negative regulatory role of NLRP6 in the host was investigated in this study. Our results showed that NLRP6(-/-) mice in the lung had lower bacterial burdens after S. pneumoniae infection and expressed higher level of tight junction (TJ) protein occludin compared to WT mice, indicating the detrimental role of NLRP6 in the host defense against S. pneumoniae infection. Transcriptome analysis showed that genes related to leukocytes migration and recruitment were differentially expressed between wild-type (WT) and NLRP6 knockout (NLRP6(-/-)) mice during S. pneumoniae infection. Also, NLRP6(-/-) mice showed higher expression of chemokines including C-X-C motif chemokine ligand 1 (CXCL1) and 2 (CXCL2) and lower gene expression of complement C3a receptor 1 (C3aR1) and P-selectin glycoprotein ligand-1 (PSGL-1) which are the factors that inhibit the recruitment of neutrophils. Furthermore, NLRP6(-/-) neutrophils showed increased intracellular bactericidal ability and the formation of neutrophil extracellular traps (NETs) during S. pneumoniae infection. Taken together, our study suggests that NLRP6 is a negative regulator of neutrophil recruitment and function during S. pneumoniae infection. Our study provides a new insight to develop novel strategies to treat invasive pneumococcal infection

Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss

In this study, we report the biochemical characterization of the deafness-associated mitochondrial 12S rRNA C1494T mutation using 27 cybrid cell lines constructed by transferring mitochondria from 9 lymphoblastoid cell lines derived from a Chinese family into human mitochondrial DNA (mtDNA)-less (ρ°) cells. Six cybrids derived from two asymptomatic members, and nine cybrids derived from three symptomatic members of the Chinese family carrying the C1494T mutation exhibited ∼38 and 43% decrease in the rate of mitochondrial protein labeling, respectively, compared with twelve cybrids derived from four Chinese control individuals. These defects are apparently a primary contributor to significant reductions in the rate of overall respiratory capacity or the rate of malate/glutamate promoted respiration, or succinate/G3P-promoted respiration, or TMPD/ascorbate-promoted respiration in mutant cybrid cell lines derived from either symptomatic or asymptomatic individuals. Furthermore, the very significant/nearly identical increase in the ratio of doubling times in DMDM medium in the presence/absence of high concentration of paromomycin was observed in symptomatic or asymptomatic cybrid cell lines carrying the C1494T mutation as compared with the average rate in control cell lines. These observations provide the direct biochemical evidences that the C1494T mutation is a pathogenic mtDNA mutation associated with aminoglycoside-induced and non-syndromic hearing loss. In addition, these data provide the first biochemical evidence that nuclear background plays a critical role in the phenotypic manifestation of non-syndromic hearing loss and aminoglycoside toxicity associated with the C1494T mutation

Resolving the genetic heterogeneity of prelingual hearing loss within one family: Performance comparison and application of two targeted next generation sequencing approaches.

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A Comparative Study on 5hmC Targeting Regulation of Neurons in AD Mice by Several Natural Compounds

A series of studies have confirmed that DNA methylation disorder (5mC/5hmC) is closely related to the occurrence and development of some diseases, such as Alzheimer’s disease (AD). This study aims at discovering natural compounds that could adjust and control 5-hydroxymethylcytosine (5hmC) levels and improve Alzheimer’s disease (AD) neuronal status. Cordycepin and cordycepic acid were selected as research materials, with resveratrol as positive control. The results of Dot Blot indicated that cordycepin, cordycepic acid, and resveratrol significantly increased the expression level of 5hmC. Combined with qPCR results, it was revealed that cordycepin increased the expression of ten-eleven translocation (TETs) mRNA compared with the abovementioned cordycepic acid and resveratrol. Besides, cordycepin dramatically reduced the transcription level of Apolipoprotein E (ApoE), suggesting that cordycepin might hinder the formation of NFTs (neurofibrillary tangles) and the accumulation of amyloid β-protein (Aβ) in the brain by reducing the expression of ApoE, resulting in affecting the progression of AD. Meanwhile, the immunofluorescence (IF) staining results demonstrated that the percentage of differentiation of SHSY-5Y cells reasonably increased after the treatment of cordycepin and cordycepic acid. Simultaneously, the length of axons and the number of dendritic branches in mouse primary neurons were substantially increased by cordycepin. The screening results illustrated that cordycepin had a positive influence on the level of 5hmC and the morphology of neurons, and most of the effects were better compared to the positive control (resveratrol). It indicated that cordycepin delayed the progression of neurodegenerative diseases such as AD. However, the specific mechanism of action still needs to be further investigated. Our research provided a foundation for further discussion about the influence of cordycepin on AD and a new idea for the pathological study of related diseases

QoS-enabled voice support in the next-generation internet: Issues, existing approaches and challenges

The Internet is under rapid growth and continuous evolution in order to accommodate an increasingly large number of applications with diverse service requirements. In particular, Internet telephony, or voice over IP is one of the most promising services currently being deployed. Besides the potentially significant cost reduction, Internet telephony can offer many new features and easier integration with widely adopted Web-based services. Despite these advantages, there still exist a number of barriers to the widespread deployment of Internet telephony such as the lack of control architectures and associated protocols for managing calls, a security mechanism for user authentication, and proper charging schemes. The most prominent one, however, is how to ensure the QoS needed for voice conversation. The purpose of this article is to survey the state-of-the-art technologies in enabling the QoS support for voice communications in the next-generation Internet. In this article. we first review the existing technologies in supporting voice over If networks. including the basic mechanisms in the IETF Internet telephony architecture and ITU-T H.323-related Recommendations, We then discuss the IETF QoS framework. specifically the Intserv and Diffserv framework. Finally, we present two leading companies' (Cisco and Lucent) solutions to offering if telephony services as examples to illustrate how real systems are implemented

Case Report: Active tuberculosis infection in CAR T-cell recipients post CAR T-cell therapy: a retrospective case series

High response rates in B-cell malignancies have been achieved with chimeric antigen receptor (CAR) T-cell therapy. Emerging reports indicate a risk of active tuberculosis (TB) with novel immunotherapy for tumors. However, studies of TB in patients post CAR T-cell therapy are limited. In this case series study, we describe five patients with active TB post CD19/CD22 target CAR T-cell therapy alone or following autologous stem cell transplantation (ASCT). One of the patients developed active TB within the first 30 days post CAR T-cell therapy, and fever was the dominant presenting symptom; extrapulmonary manifestations of active TB were common in the other four patients and manifested after the first 30 days of CAR T-cell therapy. Four of the five patients improved with anti-TB treatment, but one patient with isoniazid resistance died of central nervous system TB infection. Our study provides the first series report of active TB following CD19/CD22 target CAR T-cell therapy

FLOT Neoadjuvant Chemotherapy Followed by Laparoscopic D2 Gastrectomy in the Treatment of Locally Resectable Advanced Gastric Cancer

Background. The prognosis of patients with advanced gastric cancer remains unsatisfactory, highlighting the need for improved therapeutic strategies. We analyzed 23 resectable advanced gastric cancer patients who received FLOT followed by laparoscopic gastrectomy with D2 lymphadenectomy to evaluate the efficacy and safety. Methods. Patients aged 18–75 years with gastric adenocarcinoma (stage cT3–4 and/or N + M0) underwent neoadjuvant FLOT therapy (four preoperative and four postoperative 2-week cycles) at Shanghai East Hospital. Laparoscopic gastrectomy was scheduled 3-4 weeks after completion of the last cycle of preoperative chemotherapy. The type of surgical procedure was determined by the location and extent of the primary tumor. Results. 23 patients were reviewed in the study. 20 patients (81.2%) received four courses of FOLT therapy, while 3 patients (18.8%) received three courses of treatment. There were 3 (13.0%) complete responses, 13 (56.5%) partial responses, 4 (26.1%) of stable disease, and 1 (4.3%) of progressive disease. The clinical efficacy response rate was 69.6%. The R0 resection rate was 91.3%. Only one patient exhibited grade III postoperative complications. The pathologic complete remission was 13%. The common grade 3/4 adverse events from chemotherapy were leucopenia (17.4%), neutropenia (30.4%), anemia (13%), anorexia (13%), and nausea (17.4%). Postoperative complications occurred in 5 patients (26.1%). There was no treatment-related mortality or reoperation. The most reason for not completing chemotherapy was the patient’s request. Conclusions. These findings suggest that FLOT neoadjuvant chemotherapy, followed by laparoscopic D2 gastrectomy, is effective and safe in advanced, resectable advanced gastric cancer