Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?1? and P = 4.1 × 10??, respectively).     

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin^?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.     

Systems thinking,systems practice,and practical philosophy: A program of research

IfSystems Practice is to serve the cause of socially rational decision making, its understanding of systems approach must open itself up to the communicative dimension of rational practice uncovered by contemporary practical philosophy. This programmatic paper argues that building the bridge between the two traditions of systems thinking and practical philosophy is a key challenge to be faced by the systems community. A three-level framework of rational systems practice is suggested as a point of departure for a program of research.     

Ecology: a niche for cyanobacteria containing chlorophyll d

The cyanobacterium known as Acaryochloris marina is a unique phototroph that uses chlorophyll d as its principal light-harvesting pigment instead of chlorophyll a, the form commonly found in plants, algae and other cyanobacteria; this means that it depends on far-red light for photosynthesis. Here we demonstrate photosynthetic activity in Acaryochloris-like phototrophs that live underneath minute coral-reef invertebrates (didemnid ascidians) in a shaded niche enriched in near-infrared light. This discovery clarifies how these cyanobacteria are able to thrive as free-living organisms in their natural habitat.     

Recruitment of entomopathogenic nematodes by insect-damaged maize roots

Plants under attack by arthropod herbivores often emit volatile compounds from their leaves that attract natural enemies of the herbivores. Here we report the first identification of an insect-induced belowground plant signal, (E)-beta-caryophyllene, which strongly attracts an entomopathogenic nematode. Maize roots release this sesquiterpene in response to feeding by larvae of the beetle Diabrotica virgifera virgifera, a maize pest that is currently invading Europe. Most North American maize lines do not release (E)-beta-caryophyllene, whereas European lines and the wild maize ancestor, teosinte, readily do so in response to D. v. virgifera attack. This difference was consistent with striking differences in the attractiveness of representative lines in the laboratory. Field experiments showed a fivefold higher nematode infection rate of D. v. virgifera larvae on a maize variety that produces the signal than on a variety that does not, whereas spiking the soil near the latter variety with authentic (E)-beta-caryophyllene decreased the emergence of adult D. v. virgifera to less than half. North American maize lines must have lost the signal during the breeding process. Development of new varieties that release the attractant in adequate amounts should help enhance the efficacy of nematodes as biological control agents against root pests like D. v. virgifera.     

Effects of Gd solutes on hardness and yield strength of Mg alloys

Relative contribution of individual strengthening mechanisms to the yield strength of Mg–0–15 wt%Gd alloys were investigated.Alloys with different grain size were prepared by adding Zr and hot extrusion.Hardness and tensile/compression yield strength were tested on the alloys after solid solution treatment and extrusion.HallPetch constants were calculated with hardness and tensile/compressive data.The results showed that the hardness of Mg–Gd alloys with similar Gd content and different grain size were almost the same,which indicates that grain size had little effect on hardness.The hardness linearly increased with rising Gd content(d H_v/dc≈25 kg mm~(-2)/at%Gd).The tensile and compressive yield strengths enhanced with the increase of Gd content for all alloys in different conditions.In addition,the tensile/compressive(t/c)yield asymmetry of extruded alloys decreased with increasing Gd content.Large t/c yield asymmetry ratio(1.77)was observed for pure Mg,and with increasing Gd content this value decreased to 1.With the increasing of tensile strength,the stress intensity factor,k_y,decreased from 0.27 MPa m~(1/2)for Mg–2 wt%Gd alloy to 0.19 MPa m~(1/2) for Mg–5 wt%Gd alloy,then increased to 0.29 MPa m~(1/2) for Mg–15 wt%Gd alloy.However,k_yincreased linearly form 0.16–0.31 MPa for compression test.The influence of grain size strengthening was eliminated,and the yield strength of tension and compression both linearly increased with c~n,where c is the atom concentration of Gd,and n=1/2 or 2/3.     

双束电子束焊接温度场的数值模拟

结合数值模拟和实验,研究了双束电子束焊接过程的温度场.根据对电子束的能量分布的测试数据,考虑电子束焊接的小孔效应和电子的散射和反射,得到了电子束焊接过程真实的能量输入.将该能量输入通过有限元软件的子程序实现加载,得到双移动热源,同时考虑到焊接材料的非线性,得到有限元数值模型,进行了数值模拟,并在相同条件下进行了多组实验.数值模拟和实验表明: 焊缝特征和温度场都与2个热输入的比例有关, 2个温度场是相互影响的;在小热源的焊接路径上,会出现2个热循环峰值.