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Weekly Reports (100)on International Trends of Cutting –edge Life Science Development
Add Time:2013/9/26 17:16:18

1. Richness of human gut microbiome correlates with metabolic markers
【Text abstracts】Nature, Vol. 500, 541-546. doi:10.1038/nature12506

Richness of human gut microbiome correlates with metabolic markers
Emmanuelle Le Chatelier, Trine Nielsen, Junjie Qin,et al.

We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.

我们正面临着由肥胖流行病激发的全球代谢问题危机。 在此,我们报告了123位非肥胖和169位肥胖的丹麦人的肠道菌群组成。我们发现这两组人群的肠道菌群的基因及菌群的多样性是有差异的。他们包括的已知的和未知细菌种类的比例是不同的, 与菌群丰富的群体相比,菌群不丰富的群体(总人数的23%)都明显更肥胖,有胰岛素耐性,脂肪代谢紊乱及更显著地炎症表型。菌群种类少的肥胖者更易增重。胖瘦对象的菌群种类的差异紧紧在于几种物种。我们的分类是基于肠道微生物群的变异,这种分类发现了一个导致成年白人群体增加肥胖合并症风险的子菌群。

2. Bacteria activate sensory neurons that modulate pain and inflammation
【Text abstracts】Nature. 501, 52–57. doi:10.1038

Bacteria activate sensory neurons that modulate pain and inflammation
Isaac M. Chiu, Balthasar A. Heesters, Nader Ghasemlou, et al

Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviours. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed to be secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils and monocytes is not necessary for Staphylococcus aureus-induced pain in mice. Mechanical and thermal hyperalgesia in mice is correlated with live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin α-haemolysin, through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host–pathogen interactions.

伤害感受器是专门用于探测潜在危害性刺激的感觉神经元,它通过产生疼痛感诱导防御行为来保护生物。细菌感染能通过一种未知的分子机制产生疼痛,虽然这种机制被认为是次于免疫激活机制的。在此,我们表明细菌是可以直接激活伤害感受器的,由 TLR2, MyD88, T 细胞, B 细胞,中性白细胞和单核细胞调节的免疫反应在金黄葡萄球菌导致的小鼠疼痛是没有必要的。小鼠的机械和热力导致的痛觉过敏与活细菌的量有关而不是组织水肿或者免疫激活。细菌在伤害感受器神经元上产生钙运转及动作电位,这一过程一方面是通过细菌N甲酰化肽和钻孔毒素α-溶血素及独特的机理。 具体的对Nav1.8系神经元的消融,包括伤害感受器,细菌感染事疼痛的消除,并发的局部的免疫渗透和引流淋巴结的淋巴结疾病。 因此,细菌性病原体是通过直接激活调节炎症的感受神经元来产生疼痛的,这是一个从未料想过的宿主与病原体相互作用中神经系统的作用.

3. Induction of mouse germ-cell fate by transcription factors in vitro
【Text abstracts】Nature. 501, 222-226. doi:10.1038

Induction of mouse germ-cell fate by transcription factors in vitro
Fumio Nakaki, Katsuhiko Hayashi, Hiroshi Ohta, et al. Nature

The germ-cell lineage ensures the continuity of life through the generation of male and female gametes, which unite to form a totipotent zygote. We have previously demonstrated that, by using cytokines, embryonic stem cells and induced pluripotent stem cells can be induced into epiblast-like cells (EpiLCs) and then into primordial germ cell (PGC)-like cells with the capacity for both spermatogenesis and oogenesis1, 2, creating an opportunity for understanding and regulating mammalian germ-cell development in both ***es in vitro. Here we show that, without cytokines, simultaneous overexpression of three transcription factors, Blimp1 (also known as Prdm1), Prdm14 and Tfap2c (also known as AP2γ), directs EpiLCs, but not embryonic stem cells, swiftly and efficiently into a PGC state. Notably, Prdm14 alone, but not Blimp1 or Tfap2c, suffices for the induction of the PGC state in EpiLCs. The transcription-factor-induced PGC state, irrespective of the transcription factors used, reconstitutes key transcriptome and epigenetic reprogramming in PGCs, but bypasses a mesodermal program that accompanies PGC or PGC-like-cell specification by cytokines including bone morphogenetic protein 4. Notably, the transcription-factor-induced PGC-like cells contribute to spermatogenesis and fertile offspring. Our findings provide a new insight into the transcriptional logic for PGC specification, and create a foundation for the transcription-factor-based reconstitution and regulation of mammalian gametogenesis.

胚细胞谱系通过产生雌雄配子保证生命的延续,这些雌雄配子结合形成全能的接合子。我们之前已经证明通过使用细胞因子,胚胎干细胞和诱导的多能干细胞可以被诱导成外胚层样的细胞(EpiLCs)然后变成原始胚细胞(PGC)样的细胞,这种细胞有能力实现精子发生及卵子发生,创造机会理解并调节两性哺乳类胚细胞的体外发育。 在此,我们证明,没有细胞因子,3个转录因子,Blimp1,Prdm14 和Tfap2c的同时过度表达,指示着外胚层样的细胞而非胚胎干细胞的快速有效的进入原始胚细胞状态。值得注意的是,仅仅Prdm14,而不是Blimp1 或 Tfap2c, 就足以诱导PGC 到 EpiLCs 状态。不管使用的是哪个转录因子,转录因子诱导的PGC状态,重组PGCs中关键的转录组和表观遗传的重编,但是避开了伴随PGC或PGC样细胞中胚层的编译要求包括骨形成蛋白4。值得注意的是,转录因子诱导的PGC样细胞有助于精子发生及后代繁殖。我们的发现为PGC规格的转录逻辑提供了一个新的见解,为以转录因子为基础的重组和哺乳类配子发生创造了基础。

4. Forging New Approaches to Stem Cell Tracking
Sci. Transl. Med. Vol. 5, Issue 203, p. 203ec153 DOI: 10.1126/scitranslmed.3007554

Forging New Approaches to Stem Cell Tracking
Edward Kai-Hua Chow

Tracking stem cells in the brain will be an important component of cell therapy clinical trials. Traditional approaches to cell labeling, such as fluorophores, are not ideal for use in the human brain because the light cannot penetrate the thickness of the tissues. In response, Gutova and colleagues describe ultrasmall super paramagnetic iron oxide nano particles (USPIOs) for tagging and tracking neural stem cells (NSCs) by means of magnetic resonance imaging (MRI). Translation of this approach would allow clinicians to see how stem cells home to glioma tumors through serial MRI scans.

To make USPIOs such as ferumoxytol more biocompatible with NSCs, the researchers optimized the ratios for the formation of heparin, protamine sulfate, and ferumoxytol (HPF) particles. MRI studies in orthotopic glioma tumor mouse models revealed that both intracerebrally and intravenously delivered NSCs loaded with HPFs could be seen homing near and within brain tumors. On the basis of these studies, Gutova et al. were able to determine the amount of iron needed to successfully and safely image NSCs clinically. At doses higher than expected for use in humans, no iron-associated toxicity was seen at 4 and 12 weeks after SPIO administration, and any immune cell infiltration eventually resolved over the 12-week study period.

Ferumoxytol is currently approved for the treatment of iron-deficiency anemia and is also being evaluated for MRI in many cancer clinical trials. Both NSC tumor-targeting therapy and the use of SPIO nanoparticles to track them will require continued optimization and evaluation. However, the work described in this study laid the preclinical groundwork that has already contributed to the translation of ferumoxytol-based nanoparticles into clinical use as agents for labeling human NSCs.
追踪大脑里的干细胞将是细胞疗法临床试验的重要部分。细胞标记的传统方法,如荧光素,不适宜用于人脑,因为光不足以穿透此组织的厚度。因此,Gutova 和他的同事们描述了超小型超级顺磁氧化铁纳米粒子(USPIOs)以用来标记追踪神经干细胞(NSCs),此方法需借助磁共振成像来实现。这种方式的转译将使临床专家通过系列的磁共振扫描看到干细胞如何朝着胶质瘤发展。

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