High-energy colliders and the rise of the standard model

Over the past quarter of a century, experiments at high-energy particle colliders have established the standard model as the precise theory of particle interactions up to the 100 GeV scale. A series of important experimental discoveries and measurements have filled in most of the missing pieces and tested the predictions of the standard model with great precision.     

Discretionary databases in forecasting

Information for forecasting databases is often initially under the control of individuals who have no compelling reason to contribute, and who face various significant costs if they do. Such discretionary databases are subject to public goods problems, and are likely to be undersupplied, even when all participants agree that the overall benefits outweigh the overall costs. This paper explores the implications of this incentive structure for the existence, completeness and accuracy of forecasting databases. It also offers some hypotheses as to when the difficulties will be more and less severe, and outlines some directions for possible remedial strategies.     

In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment

The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells.     

疟疾疫苗的研究策略

从疟原虫的不同发育时期、不同的疫苗成份和宿主的遗传基因限制性等方面，深入研究抗疟疾疫苗。作用于红细胞前期的疟疾疫苗主要是抑制疟疾的临床发作，控制疟疾的传播；作用于红细胞期的疟疾疫苗诱导宿主体液免疫系统，产生特异性抗体，抑制疟原虫侵入和感染红细胞，达到减少疟原虫虫荷，降低疟疾的发病率和死亡率。作用于疟原虫有性生殖时期，控制疟疾传播的疟疾疫苗，其在于控制一个地区疟原虫的感染率和疟疾发病率，但对已感染疟原虫个体的免疫保护作用意义不大。在设计疟疾疫苗的过程中，必须克服不同个体的遗传基因限制性问题。由于疟原虫生活史的复杂性，同时也必须考虑到疟原虫不同发育阶段抗原成份的复杂性。     

Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells

Myeloid cells are a feature of most tissues. Here we show that during development, retinal myeloid cells (RMCs) produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in RMCs of the Wnt ligand transporter Wntless results in increased angiogenesis in the deeper layers. We also show that mutation of Wnt5a and Wnt11 results in increased angiogenesis and that these ligands elicit RMC responses via a non-canonical Wnt pathway. Using cultured myeloid-like cells and RMC somatic deletion of Flt1, we show that an effector of Wnt-dependent suppression of angiogenesis by RMCs is Flt1, a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). These findings indicate that resident myeloid cells can use a non-canonical, Wnt-Flt1 pathway to suppress angiogenic branching.     

In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche

Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30?days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.