Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.     

The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.     

A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac

With the availability of complete genome sequence for Drosophila melanogaster, one of the next strategic goals for fly researchers is a complete gene knockout collection. The P-element transposon, the workhorse of D. melanogaster molecular genetics, has a pronounced nonrandom insertion spectrum. It has been estimated that 87% saturation of the approximately 13,500-gene complement of D. melanogaster might require generating and analyzing up to 150,000 insertions. We describe specific improvements to the lepidopteran transposon piggyBac and the P element that enabled us to tag and disrupt genes in D. melanogaster more efficiently. We generated over 29,000 inserts resulting in 53% gene saturation and a more diverse collection of phenotypically stronger insertional alleles. We found that piggyBac has distinct global and local gene-tagging behavior from that of P elements. Notably, piggyBac excisions from the germ line are nearly always precise, piggyBac does not share chromosomal hotspots associated with P and piggyBac is more effective at gene disruption because it lacks the P bias for insertion in 5' regulatory sequences.     

Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.     

The central dusty torus in the active nucleus of NGC 1068

Active galactic nuclei (AGNs) display many energetic phenomena--broad emission lines, X-rays, relativistic jets, radio lobes--originating from matter falling onto a supermassive black hole. It is widely accepted that orientation effects play a major role in explaining the observational appearance of AGNs. Seen from certain directions, circum-nuclear dust clouds would block our view of the central powerhouse. Indirect evidence suggests that the dust clouds form a parsec-sized torus-shaped distribution. This explanation, however, remains unproved, as even the largest telescopes have not been able to resolve the dust structures. Here we report interferometric mid-infrared observations that spatially resolve these structures in the galaxy NGC 1068. The observations reveal warm (320 K) dust in a structure 2.1 parsec thick and 3.4 parsec in diameter, surrounding a smaller hot structure. As such a configuration of dust clouds would collapse in a time much shorter than the active phase of the AGN, this observation requires a continual input of kinetic energy to the cloud system from a source coexistent with the AGN.     

Coherent spin manipulation without magnetic fields in strained semiconductors

A consequence of relativity is that in the presence of an electric field, the spin and momentum states of an electron can be coupled; this is known as spin-orbit coupling. Such an interaction opens a pathway to the manipulation of electron spins within non-magnetic semiconductors, in the absence of applied magnetic fields. This interaction has implications for spin-based quantum information processing and spintronics, forming the basis of various device proposals. For example, the concept of spin field-effect transistors is based on spin precession due to the spin-orbit coupling. Most studies, however, focus on non-spin-selective electrical measurements in quantum structures. Here we report the direct measurement of coherent electron spin precession in zero magnetic field as the electrons drift in response to an applied electric field. We use ultrafast optical techniques to spatiotemporally resolve spin dynamics in strained gallium arsenide and indium gallium arsenide epitaxial layers. Unexpectedly, we observe spin splitting in these simple structures arising from strain in the semiconductor films. The observed effect provides a flexible approach for enabling electrical control over electron spins using strain engineering. Moreover, we exploit this strain-induced field to electrically drive spin resonance with Rabi frequencies of up to approximately 30 MHz.     

The transulfuration of sulfinates by polysulfides

Riassunto È stato dimostrato che la transulfurazione che consegue alla incubazione dei solfinati con zolfo ed un composto tiolico è dovuta in parte alla produzione di un polisolfuro organico, formato dal tiolo e zolfo, ed in parte al polisolfuro inorganico, formato dalla decomposizione di quello organico. L'entità della transulfurazione prodotta direttamente dal polisolfuro organico varia con il tipo di polisolfuro e dipende dalla sua stabilità nelle condizioni usate.