Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial

Background

Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).

Methods and Findings

An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥5,000/µl, was 2.88 (95% confidence interval [CI] 2.70–3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78–0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%–74%) (p<0.001). There was a 69% (95% CI 6%–90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%–69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%–77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65–1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72–0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.

Conclusions

IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00738946","term_id":"NCT00738946"}}NCT00738946 Please see later in the article for the Editors'' Summary     

C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1

Neutrophils are significant compositions of solid tumors and exert distinct functions in different types of tumors. However, the precise role of neutrophils in the progression of breast cancer (BC) is presently unclear. In this study, by investigating the single-cell RNA sequencing data, we identify a new neutrophil subset, C5aR1-positive neutrophils, that correlates with tumor progression and poor survival for BC patients. Furthermore, it is discovered that C5aR1-positive neutrophils enhance BC cell glycolysis via upregulating ENO1 expression. Mechanically, C5aR1-positive neutrophil-secreted IL1β and TNFα cooperatively activate ERK1/2 signaling, which phosphorylates WTAP at serine341 and thereby stabilizes WTAP protein. The stabilization of WTAP further promotes RNA m6A methylation of ENO1, impacting the glycolytic activity of BC cells. Importantly, C5aR1-positive neutrophils also promote breast cancer growth in vivo, and this effect is abolished by WTAP silencing. In clinical BC samples, increased C5aR1-positive neutrophils correlate with elevated IL1β, TNFα, and ENO1 expression. A high co-expression of C5aR1-positive neutrophil gene signature and ENO1 predicts worse prognosis of BC patients compared with a low co-expression. Collectively, our study reveals a novel subset of C5aR1-positive neutrophils that induces breast cancer glycolysis via increasing ERK1/2-WTAP-dependent m6A methylation of ENO1. These findings support the potential for exploration of C5aR1-positive neutrophils as a therapeutic target in breast cancer.Subject terms: Cancer microenvironment, Breast cancer, Oncogenesis     

内含子源性microRNA对内皮型一氧化氮合酶表达及血管内皮细胞增殖的作用

前期工作表明,内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)第4内含子中的27碱基 (nucleotide,nt)重复序列是27-nt microRNA的来源,并对eNOS具有重要的调节作用．为进一步探讨该内含子源性27-nt microRNA参与调节eNOS表达的分子机制及其在内皮细胞增殖中的可能作用,通过构建27-nt microRNA高表达质粒,用脂质体将该质粒转染人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVEC),Western blot和RT-PCR检测该细胞系中eNOS蛋白和mRNA表达情况以及胞核转录因子的表达改变,并观察HUVEC增殖的变化情况．结果发现：27-nt microRNA 高表达能降低eNOSmRNA的水平和蛋白质表达;同时对转录因子Sp1、Ap1的蛋白质表达也产生了不同程度的抑制作用;转染后细胞的生长速度比未转染的细胞明显减慢,尤其转染了27-nt microRNA的双倍长度突变体(pEGP-mut-54nt-mi)质粒的HUVEC,其生长倍增时间比正常对照组明显延长达49.4%．结果表明,27-nt microRNA明显抑制eNOS蛋白及其mRNA表达,同时 HUVEC增殖受到明显抑制,转录因子Sp1 和Ap1 在27-nt microRNA对eNOS的表达调节中起重要作用．实验提示,内含子源性microRNA与转录因子共同参与对内皮细胞增殖及其相关性基因的表达调节,可能是众多真核细胞中某些疾病相关性基因表达自我调节的重要机制之一．     

Impacts of recreational trampling on sub-alpine vegetation and soils in Northwest Yunnan, China

Controlled trampling experiments were undertaken to assess impacts of recreation in a sub-alpine environment in an upper-Mekong mountainous protected area in China. Hiking and recreational horse-riding were applied at different trampling intensity to two typical, widespread vegetation types (Carex grassland and low Rhododendron shrubland) and trampling effects were assessed to study vegetation resistance and soil compaction. The results indicate: (1) low shrub vegetation is highly vulnerable to trampling damage while the graminoids-dominated grassland is more resistant; (2) dry soil with low organic matter, which often is found in the shrubland, is more susceptible to compaction than wet soil and (3) horses cause substantially more damage than hikers at equivalent trampling levels. These data are useful to develop a visitor’s management strategy that allows to minimize the impact from recreation on the vegetation.     

Purification and characterization of a processing protease from rat liver mitochondria.

A processing protease has been purified from the matrix fraction of rat liver mitochondria. The purified protease contained two protein subunits of 55 kd (P-55) and 52 kd (P-52) as determined by SDS-PAGE. The processing protease was estimated to be 105 kd in gel filtration, indicating that the two protein subunits form a heterodimeric complex. At high ionic conditions, the two subunits dissociated. The purified processing protease cleaved several mitochondrial protein precursors destined to different mitochondrial compartments, including adrenodoxin, malate dehydrogenase, P-450(SCC) and P-450(11 beta), but the processing efficiencies were different each other. The endoprotease nature of the processing protease was confirmed with the purified enzyme using adrenodoxin precursor as the substrate; both the mature form and the extension peptide were detected after the processing. The processing activity of the protease was inhibited by metal chelators, and reactivated by Mn2+, indicating that the protease is a metalloprotease.     

SSR alpha and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membrane

GTP phosphorylation of rough microsomes in vitro is limited to four integral membrane proteins. Two of these, a phosphoprotein (pp90) and a phosphoglycoprotein (pgp35) were purified as a complex with two nonphosphorylated membrane glycoproteins, gp25H and gp25L. The authenticity of this complex was confirmed using two different purification procedures and by coimmunoprecipitation. By immunofluorescence a reticulated cytoplasmic network was revealed for the proteins which was similar to that for Louvard et al. (Louvard, D., Reggio, H., and Warren, G. (1982) J. Cell Biol. 92, 92-107) marker antisera which also recognized purified pp90 on immunoblots. Amino acid sequencing of peptides derived from pgp35 identified this protein as SSR alpha, an endoplasmic reticulum constituent as identified by cross-linking of translocating nascent chains (G?rlich, D, Prehn, S., Hartmann, E., Herz, J., Otto, A., Kraft, R., Wiedmann, M., Knespel, S., Dobberstein, B., and Rapoport, T. A. (1990) J. Cell Biol. 111, 2283-2294). The sequence of gp25H was determined from cDNA clones and was identical with SSR beta identified by G?rlich et al. (1990) as being tightly bound to SSR alpha. Sequencing of gp25L revealed no similarity of the deduced sequence with other proteins. However, pp90 revealed a high degree of sequence identity with the Ca(2+)-binding protein, calreticulin. 45Ca2+ overlay studies indicated that pp90 bound Ca2+ and the name calnexin is proposed. Surprisingly, pgp25 (SSR alpha) also bound Ca2+ although gp25H (SSR beta) and gp25L did not. Triton X-114 partitioning of the integral membrane proteins of rough microsomes suggested that pgp35 (SSR alpha) and calnexin were major Ca(2+)-binding proteins of the endoplasmic reticulum membrane. We propose that the function of the complex is to regulate Ca(2+)-dependent retention mechanisms for luminal proteins of the endoplasmic reticulum.     

Transpositional activation of <Emphasis Type="Italic">mPing</Emphasis> in an asymmetric nuclear somatic cell hybrid of rice and <Emphasis Type="Italic">Zizania latifolia</Emphasis> was accompanied by massive element loss

We have reported previously that the most active miniature inverted terminal repeat transposable element (MITE) of rice, mPing, was transpositionally mobilized in several rice recombinant inbred lines (RILs) derived from an introgressive hybridization between rice and wild rice (Zizania latifolia Griseb.). To further study the phenomenon of hybridization-induced mPing activity, we undertook the present study to investigate the element’s behavior in a highly asymmetric somatic nuclear hybrid (SH6) of rice and Z. latifolia, which is similar in genomic composition to that of the RILs, though probably contains more introgressed alien chromatins from the donor species than the RILs. We found that mPing, together with its transposase-donor, Pong, underwent rampant transpositional activation in the somatic hybrid (SH6). Because possible effects of protoplast isolation and cell culture can be ruled out, we attribute the transpositional activation of mPing and Pong in SH6 to the process of asymmetric somatic hybridization, namely, one-step introgression of multiple chromatin segments of the donor species Z. latifolia into the recipient rice genome. A salient feature of mPing transposition in the somatic hybrid is that the element’s activation was accompanied by massive loss of its original copies, i.e., abortive transpositions, which was not observed in previously reported cases of mPing activity. These data not only corroborated our earlier finding that wide hybridization and introgression may trigger transpositional activation of otherwise quiescent transposable elements, but also suggest that transpositional mobilization of a MITE like mPing can be accompanied by dramatic reduction of its original copy numbers under certain conditions, thus provide novel insights into the dynamics of MITEs in the course of genome evolution.