Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.     

Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret

Almost 1% of human infants are born with urogenital abnormalities, many of which are linked to irregular connections between the distal ureters and the bladder. During development, ureters migrate by an unknown mechanism from their initial integration site in the Wolffian ducts up to the base of the bladder in a process that we call ureter maturation. Rara(-/-) Rarb2(-/-) mice display impaired vitamin A signaling and develop syndromic urogenital malformations similar to those that occur in humans, including renal hypoplasia, hydronephrosis and mega-ureter, abnormalities also seen in mice with mutations in the proto-oncogene Ret. Here we show that ureter maturation depends on formation of the 'trigonal wedge', a newly identified epithelial outgrowth from the base of the Wolffian ducts, and that the distal ureter abnormalities seen in Rara(-/-) Rarb2(-/-) and Ret(-/-) mutant mice are probably caused by a failure of this process. Our studies indicate that formation of the trigonal wedge may be essential for correct insertion of the distal ureters into the bladder, and that these events are mediated by the vitamin A and Ret signaling pathways.     

Plasmodium, human and Anopheles genomics and malaria

The Plasmodium spp. parasites that cause malaria are transmitted to humans by Anopheles spp. mosquitoes. Scientists have now amassed a great body of knowledge about the parasite, its mosquito vector and human host. Yet this year there will be 300-500 million new malaria infections and 1-3 million deaths caused by the disease. We believe that integrated analyses of genome sequence, DNA polymorphisms, and messenger RNA and protein expression profiles will lead to greater understanding of the molecular basis of vector-human and host-parasite interactions and provide strategies to build upon these insights to develop interventions to mitigate human morbidity and mortality from malaria.     

A candidate prostate cancer susceptibility gene at chromosome 17p

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).     

Experimental study on dehydration melting of natural biotite-plagioclase gneiss from High Himalayas and implications for Himalayan crust anatexis

Here we present the results of dehydration melting, melt morphology and fluid migration based on the dehydration melting experiments on natural biotite-plagioclase gneiss performed at the pressure of 1.0—1.4 GPa, and at the temperature of 770—1028℃. Experimental results demonstrate that: (ⅰ) most of melt tends to be distributed along mineral boundaries forming “melt film” even the amount of melt is less than 5 vol%; melt connectivity is controlled not only by melt topology but also by melt fraction; (ⅱ) dehydration melting involves a series of subprocesses including subsolidus dehydration reaction, fluid migration, vapor-present melting and vapor-absent melting; (ⅲ) experiments produce peraluminous granitic melt whose composition is similar to that of High Himalayan leucogranites (HHLG) and the residual phase assemblage is Pl+Qz+ Gat+Bio+Opx± Cpx+Ilm/Rut± Kfs and can be comparable with granulites observed in Himalayas. The experiments provide the evidence that biotite-plagioclase gneiss is one of source rocks of HHLG and dehydration melting is an important way to form HHLG and the granulites. Additionally, experimental results provide constraints on determining the P-T conditions of Himalayan crustal anatexis.     

What is the environment in environmental health research? Perspectives from the ethics of science

Environmental health research produces scientific knowledge about environmental hazards crucial for public health and environmental justice movements that seek to prevent or reduce exposure to these hazards. The environment in environmental health research is conceptualized as the range of possible social, biological, chemical, and/or physical hazards or risks to human health, some of which merit study due to factors such as their probability and severity, the feasibility of their remediation, and injustice in their distribution. This paper explores the ethics of identifying the relevant environment for environmental health research, as judgments involved in defining an environmental hazard or risk, judgments of that hazard or risk's probability, severity, and/or injustice, as well as the feasibility of its remediation, all ought to appeal to non-epistemic as well as epistemic values. I illustrate by discussing the case of environmental lead, a housing-related hazard that remains unjustly distributed by race and class and is particularly dangerous to children. Examining a controversy in environmental health research ethics where researchers tested multiple levels of lead abatement in lead-contaminated households, I argue that the broader perspective on the ethics of environmental health research provided in the first part of this paper may have helped prevent this controversy.     

Prevention of graft-versus-host-disease with preserved graft-versus-leukemia-effect by ex vivo and in vivo modulation of CD4+ T-cells

This is the first report showing that an epitope-specific ex vivo modulation of an allogeneic hematopoietic stem cell graft by the anti-human CD4 antibody MAX.16H5 IgG₁ simultaneously facilitates the anti-tumor capacity of the graft (Graft-versus-leukemia effect, GvL) and the long-term suppression of the deleterious side effect Graft-versus-host-disease (GvHD). To distinguish and consolidate GvL from GvHD, the anti-human CD4 antibody MAX16.H5 IgG₁ was tested in murine GvHD and tumor models. The survival rate was significantly increased in recipients receiving a MAX.16H5 IgG₁ short-term (2 h) pre-incubated graft even when tumor cells were co-transplanted or when recipient mice were treated by MAX.16H5 IgG₁ before transplantation. After engraftment, regulatory T-cells are generated only supporting the GvL effect. It was also possible to transfer the immune tolerance from GvHD-free recipient chimeras into third party recipient mice without the need of reapplication of MAX.16H5 IgG₁ anti-human CD4 antibodies. These findings are also benefical for patients with leukemia when no matched related or unrelated donor is available and provides a safer allogeneic HSCT, which is more effective against leukemia. It also facilitates allogeneic (stem) cell transplantations for other indications (e.g., autoimmune-disorders).     

Gap analysis of the vegetation of the Intermountain Semi-Desert ecoregion

A conservation gap analysis was conducted for the Intermountain Semi-Desert ecoregion to assess the representation of land-cover types within areas managed primarily for biodiversity objectives. Mapped distributions of plant communities were summarized by land-management status categories. The total amount of land permanently protected in the ecoregion is < 4%, and most types that are characteristic of the region have < 10%. Of 48 land-cover types, 20 were found to be particularly vulnerable to potential loss or degradation because of low level of representation in biodiversity management areas and the impact of expected land-use activities. Gap analysis data and findings will be useful in providing a regional perspective in project impact assessment and future conservation planning within this ecoregion.