Cell circuits and niches controlling B cell development

Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B cell progenitors. HSC and lymphoid niches are predominantly composed by mesenchymal progenitor cells (MPCs) and by a small subset of endothelial cells. Niche cells create specialized microenvironments through the concomitant production of short‐range acting cell‐fate determining cytokines such as interleukin (IL)‐7 and stem cell factor and the potent chemoattractant C‐X‐C motif chemokine ligand 12. This type of cellular organization allows for the cross‐talk between hematopoietic stem and progenitor cells with niche cells, such that niche cell activity can be regulated by the quality and quantity of hematopoietic progenitors being produced. For example, preleukemic B cell progenitors and preB acute lymphoblastic leukemias interact directly with MPCs, and downregulate IL‐7 expression and the production of non‐leukemic lymphoid cells. In this review, we discuss a novel model of B cell development that is centered on cellular circuits formed between B cell progenitors and lymphopoietic niches.     

Cdk13表达对神经元轴突伸长的影响

目的探讨智力障碍相关基因Cdk13对神经轴突伸长的影响。方法通过基因敲除模型、质粒细胞转染等方法,荧光共聚焦显微镜成像技术检测神经元轴突的形态,观察轴突伸长的变化。结果 Cdk12和Cdk13在神经系统中有表达,在敲除Cdk12和Cdk13后轴突长度比对照组减少,两者比较有统计学差异(P0.05),敲除Cdk12和Cdk13基因后Cdk5 mRNA水平降低。结论 Cdk13和Cdk12的表达对神经元轴突的生长至关重要,其失活会引起神经元轴突形态异常,可能是导致智力障碍的病理机制。     

Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line

Background

In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex – brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions.

Switching biologics in psoriasis - practical guidance and evidence to support

ABSTRACT

Introduction

Advances of biologic agents have changed the treatment paradigm of psoriasis to higher efficacy and better quality of life. However, the demand for biologic switch is increasing due to patient’s greater expectation and decreasing efficacy in long-term use. Also, biologic-induced adverse effects necessitate the switching of biologics.     

NLRP12 negatively regulates EtOH-induced liver macrophage activation via NF-κB pathway and mediates hepatocyte apoptosis in alcoholic liver injury

Alcohol-induced liver injury is characterized by abnormal liver dysfunction and excessive inflammation response. Recent years a wealth of data have been yielded indicating that EtOH (ethyl alcohol)-induced macrophage activation along with liver inflammation plays a dominating role in the progression of alcohol-induced liver injury. Here we found high expression of NLRP12 (Nucleotide-binding oligomerization domain protein 12, which is generally considered to be a negative regulator of inflammatory response) in EtOH-fed mouse liver tissue, primary Kupffer cells and EtOH-induced RAW264.7 cells. Additionally, overexpression of NLRP12 following Ad (adenovirus)-NLRP12-EGFP contributed to the attenuation of steatosis and inflammation in EtOH-fed mice model and EtOH-primed RAW264.7 cells. In parallel, Knockdown of NLRP12 aggravated the inflammatory response in RAW264.7 cells triggered by EtOH. Meanwhile, after administration of overexpression or inhibition of NLRP12 expression in vitro, the expression of phosphorylated protein of NF-kB signaling pathway was significantly affected. After increasing or decreasing the expression of NLRP12 in RAW264.7 cells, AML-12 cells were cultured with the supernatant of RAW264.7 cells stimulated by EtOH, and the percent of apoptosis ratio of AML-12 cells was remarkably altered. The study suggested that reduced inflammatory response induced by NLRP12-mediated inhibition of NF-kB pathway participated in the decrease of hepatocyte apoptosis in alcohol-induced liver injury. Collectively, these findings suggested the significance of NLRP12-mediated macrophage activation in alcohol-induced liver injury.     

An evaluation of rectal artesunate for the pre-hospital management of severe malaria

ABSTRACT

Introduction

Severe falciparum malaria stills accounts for around half a million childhood deaths per year in sub-Saharan Africa. Prompt treatment of sick children close to home starting with artesunate given rectally by appropriately trained people can be lifesaving.     

Novel antibodies that selectively block mouse IL-12 enable the re-evaluation of the role of IL-12 in immune protection and pathology

The dimeric cytokine IL-12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL-23 and p35 in IL-35. This has led to erroneous conclusions like the alleged implication of IL-12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti-mouse IL-12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL-35) but specifically recognize and functionally inhibit the IL-12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN-γ production and LPS-induced septic shock after viral infection, we demonstrate the critical role played by IL-12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG-induced EAE, which was clearly prevented by anti-p40 mAb C17.8. Given this selective inhibition of IL-12, these mAbs provide new options for reassessing IL-12 function in vivo.     

A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases

BackgroundOur aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature.MethodsWe performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature.ResultsOur patient is a six‐year‐old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non‐classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat‐soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0‐54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity.ConclusionThe first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.