DC-SIGN increases the affinity of HIV-1 envelope glycoprotein interaction with CD4

Mannose-binding C-type lectin receptors, expressed on Langerhans cells and subepithelial dendritic cells (DCs) of cervico-vaginal tissues, play an important role in HIV-1 capture and subsequent dissemination to lymph nodes. DC-SIGN has been implicated in both productive infection of DCs and the DC-mediated trans infection of CD4(+) T cells that occurs in the absence of replication. However, the molecular events that underlie this efficient transmission have not been fully defined. In this study, we have examined the effect of the extracellular domains of DC-SIGN and Langerin on the stability of the interaction of the HIV-1 envelope glycoprotein with CD4 and also on replication in permissive cells. Surface plasmon resonance analysis showed that DC-SIGN increases the binding affinity of trimeric gp140 envelope glycoproteins to CD4. In contrast, Langerin had no effect on the stability of the gp140:CD4 complex. In vitro infection experiments to compare DC-SIGN enhancement of CD4-dependent and CD4-independent strains demonstrated significantly lower enhancement of the CD4-independent strain. In addition DC-SIGN increased the relative rate of infection of the CD4-dependent strain but had no effect on the CD4-independent strain. DC-SIGN binding to the HIV envelope protein effectively increases exposure of the CD4 binding site, which in turn contributes to enhancement of infection.

The community-level effect of light on germination timing in relation to seed mass: a source of regeneration niche differentiation

Within a community, species may germinate at different times so as to mitigate competition and to take advantage of different aspects of the seasonal environment (temporal niche differentiation). We illustrated a hypothesis of the combined effects of abiotic and biotic competitive factors on germination timing and the subsequent upscale effects on community assembly. We estimated the germination timing (GT) for 476 angiosperm species of the eastern Tibetan Plateau grasslands under two light treatments in the field: high (i.e. natural) light and low light. We also measured the shift in germination timing (SGT) across treatments for all species. Furthermore, we used phylogenetic comparative methods to test if GT and SGT were associated with seed mass, an important factor in competitive interactions. We found a significant positive correlation between GT and seed mass in both light treatments. Additionally, small seeds (early germinating seeds) tended to germinate later and large seeds (late germinating seeds) tended to germinate earlier under low light vs high light conditions. Low light availability can reduce temporal niche differentiation by increasing the overlap in germination time between small and large seeds. In turn, reduced temporal niche differentiation may increase competition in the process of community assembly.

Taking account of dependent species in management of the Southern Ocean krill fishery: estimating crabeater seal abundance off east Antarctica

1. The crabeater seal Lobodon carcinophaga is considered to be a key species in the krill-based food web of the Southern Ocean. Reliable estimates of the abundance of this species are necessary to allow the development of multispecies, predator–prey models as a basis for management of the krill fishery in the Southern Ocean. 2. A survey of crabeater seal abundance was undertaken in 1500 000 km2 of pack-ice off east Antarctica between longitudes 64–150° E during the austral summer of 1999/2000. Sighting surveys, using double observer line transect methods, were conducted from an icebreaker and two helicopters to estimate the density of seals hauled out on the ice in survey strips. Satellite-linked dive recorders were deployed on a sample of seals to estimate the probability of seals being hauled out on the ice at the times of day when sighting surveys were conducted. Model-based inference, involving fitting a density surface, was used to infer densities in the entire survey region from estimates in the surveyed areas. 3. Crabeater seal abundance was estimated to be between 0.7 and 1.4 million animals (with 95% confidence), with the most likely estimate slightly less than 1 million. 4. Synthesis and applications. The estimation of crabeater seal abundance in Convention for the Conservation of Antarctic Marine Living Resources (CCAMLR) management areas off east Antarctic where krill biomass has also been estimated recently provides the data necessary to begin extending from single-species to multispecies management of the krill fishery. Incorporation of all major sources of uncertainty allows a precautionary interpretation of crabeater abundance and demand for krill in keeping with CCAMLR’s precautionary approach to management. While this study focuses on the crabeater seal and management of living resources in the Southern Ocean, it has also led to technical and theoretical developments in survey methodology that have widespread potential application in ecological and resource management studies, and will contribute to a more fundamental understanding of the structure and function of the Southern Ocean ecosystem.

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

Extraocular Muscles in Patients With Infantile Nystagmus Adaptations at the Effector Level

Objective: To test the hypothesis that the extraocular muscles (EOMs) of patients with infantile nystagmus have muscular and innervational adaptations that may have a role in the involuntary oscillations of the eyes. Methods: Specimens of EOMs from 10 patients with infantile nystagmus and postmortem specimens from 10 control subjects were prepared for histologic examination. The following variables were quantified: mean myofiber cross-sectional area, myofiber central nucleation, myelinated nerve density, nerve fiber density, and neuromuscular junction density. Results: In contrast to control EOMs, infantile nystagmus EOMs had significantly more centrally nucleated myofibers, consistent with cycles of degeneration and regeneration. The EOMs of patients with nystagmus also had a greater degree of heterogeneity in myofiber size than did those of controls, with no difference in mean myofiber cross-sectional area. Mean myelinated nerve density, nerve fiber density, and neuromuscular junction density were also significantly decreased in infantile nystagmus EOMs. Conclusions: The EOMs of patients with infantile nystagmus displayed a distinct hypoinnervated phenotype. This represents the first quantification of changes in central nucleation and myofiber size heterogeneity, as well as decreased myelinated nerve, nerve fiber, and neuromuscular junction density. These results suggest that deficits in motor innervation are a potential basis for the primary loss of motor control.

Back related outcome assessment instruments

A literature review of the most widely used condition specific, self administered assessment questionnaires for low back pain had been undertaken. General and historic aspects, reliability, responsiveness and minimum clinically important difference, external validity, floor and ceiling effects, and available languages were analysed. These criteria, however, are only part of the consideration. Of similar importance are the content, wording of questions and answers in each of the six questionnaires and an analysis of the different score results. The issue of score bias is discussed and suggestions are given in order to increase the construct validity in the practical use of the individual questionnaires.

RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells

BACKGROUND: With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to cause anaplasia and correlate with unfavorable prognosis. METHODS: To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425). RESULTS: siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector. CONCLUSION: In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly.

Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation.

Medulloblastoma, one of the most malignant brain tumors in children, is thought to arise from undifferentiated neural stem/progenitor cells (NSCs) present in the external granule layer of the cerebellum. However, the mechanism of tumorigenesis remains unknown for the majority of medulloblastomas. In this study, we found that many human medulloblastomas express significantly elevated levels of both myc oncogenes, regulators of neural progenitor proliferation, and REST/NRSF, a transcriptional repressor of neuronal differentiation genes. Previous studies have shown that neither c-Myc nor REST/NRSF alone could cause tumor formation. To determine whether c-Myc and REST/NRSF act together to cause medulloblastomas, we used a previously established cell line derived from external granule layer stem cells transduced with activated c-myc (NSC-M). These immortalized NSCs were able to differentiate into neurons in vitro. In contrast, when the cells were engineered to express a doxycycline-regulated REST/NRSF transgene (NSC-M-R), they no longer underwent terminal neuronal differentiation in vitro. When injected into intracranial locations in mice, the NSC-M cells did not form tumors either in the cerebellum or in the cerebral cortex. In contrast, the NSC-M-R cells did produce tumors in the cerebellum, the site of human medulloblastoma formation, but not when injected into the cerebral cortex. Furthermore, the NSC-M-R tumors were blocked from terminal neuronal differentiation. In addition, countering REST/NRSF function blocked the tumorigenic potential of NSC-M-R cells. To our knowledge, this is the first study in which abnormal expression of a sequence-specific DNA-binding transcriptional repressor has been shown to contribute directly to brain tumor formation. Our findings indicate that abnormal expression of REST/NRSF and Myc in NSCs causes cerebellum-specific tumors by blocking neuronal differentiation and thus maintaining the "stemness" of these cells. Furthermore, these results suggest that such a mechanism plays a role in the formation of human medulloblastoma.

Na 1 Nachlass Max Horkheimer, 19 - Korrespondenzen u.a. mit Alfred Haas (p. I 10, 1-250)

20 Briefe zwischen Alfred Haas und Max Horkheimer, 1935-1941; 2 Briefe von Willy Haas an Max Horkheimer, 1938; 3 Briefe zwischen Virginia Haber und Max Horkheimer, 12.09.1945, August 1945; 7 Briefe zwischen Hugo Hahn und Max Horkheimer, 1942-1946; 1 Brief von Max Horkheimer an Charles G. Haines, 23.10.1940; 1 Brief von Max Horkheimer an Hall, 02.07.1939; 2 Briefe zwischen H. Duncan Hall und Max Horkheimer, 04.08.1939, 24.07.1939; 2 Briefe zwsichen Herbert Berkerath und Max Horkheimer, 10.10.1939, 09.10.1939; 23 Briefe zwischen Wolfgang Hallgarten und Max Horkheimer, 1937-1941; 1 Brief von Max Horkheimer an die American Philosophic Society Philadelphia, 15.04.1940; 2 Briefe zwischen Betty Drury und Max Horkheimer, 29.02.1940, 20.02.1940; 6 Briefe zwischen Nina Almond und Max Horkheimer, 1939; 1 Brief von Ruth E. Hollander an Max Horkheimer, 08.09.1938; 1 Brief von dem Brooklyn College an Wolfgang Hallgarten, 29.04.1938; 4 briefe zwischen dem Brooklyn College und Max Horkheimer, 18.05.1938, 17.05.1938; 2 Briefe zwischen Robert Maynard Hutchins und Max Horkheimer, 02.11.1937, 28.10.1937; 2 Briefe zwsichen Hardt und Max Horkheimer, 01.10.1943; 4 Briefe zwischen Gertrude Hardt und Max Horkheimer, 1947-1948; 4 Briefe zwischen den Harper & Brothers New York und Max Horkheimer, 24.10.1950, 1950; 1 Brief von Friedrich Pollock an Margot von Mendelssohn, 13.09.1950; 1 Brief von Hartoch an Max Horkheimer, 09.06.1937; 4 Briefe zwischen dem Harvard College Cambridge Massachusetts und Max Horkheimer, 1939-1940; 3 Briefe zwischen Felix Hase und Max Horkheimer, 1936, 13.03.1936; 1 Brief von Freda E. Hecht an Max Horkheimer, 01.03.1947; 1 Brief von Ernest S. Hediger an Max Horkheimer, 02.09.1940; 2 Briefe zwischen Agnes Heilbut und Max Horkheimer, 18.07.1938,; 7 Briefe zwischen Eduard Heimann und Max Horkheimer, 1936-1939; 1 Brief von Fritz Hein an Max Horkheimer, 14.06.1949; 2 Briefe zwischen Walter Heinemann und Max Horkheimer, 15.02.1945, 12.03.1945; 2 Briefe zwischen Philipp Heller und Max Horkheimer, 16.09.1944, 09.10.1944; 1 Brief von Max Horkheimer an Hellmann, 23.03.1939; 4 Briefe zwischen L. E. Hellmann und Max Horkheimer, 1939; 4 Briefe zwischen P. A. Hemerijk und Max Horkheimer, 1936-1937, 03.02.1936; 5 Briefe zwischen Carl G. Hempel und Max Horkheimer, 1939-1941; 1 Lebenslauf von Hans Henning; 1 Brief von Else Henschke an Max Horkheimer, 24.07.1940; 1 Briefe von Isi Hepner an Max Horkheimer, 23.01.1941; 1 Brief von Leo Löwenthal an Isi Hepner, 03.02.1941; 1 Brief von Gertrude E. Herman anMax Horkheimer, 10.12.1949; 1 Brief von Wilhelm G. Hertz an Max Horkheimer, 29.09.1938; 2 Briefe zwischen Wieland Herzfelde und der National City Bank of New York, 28.11.1939, 30.11.1939; 2 Briefe zwischen Karl Hess und Max Horkheimer, 14.08.1935, 25.10.1934; 4 Briefe zwischen Karl Heymann und Max Horkheimer, 1947, 1949; 19 Briefe zwischen Robert Hilb und Max Horkheimer, 1937-1941; 2 Briefe zwischen Joseph Rosenthal und Max Horkheimer, 12.11.1940, 25.10.1940; 2 Briefe zwischen Henry Church und Max Horkheimer, 14.12.1940, 18.12.1940; 1 Brief von Ellen Hilb an Max Horkheimer, 11.03.1938; 1 Brief von Emil Hilb an Max Horkheimer, 15.04.1939; 2 Briefe zwischen Yoshitaro Hirano und Max Horkheimer, 1936, 23.01.1936; 2 Briefe von Max Horkheimer an Hirsch, 1938; 1 Brief von Arnold Hirsch an Max Horkheimer, 14.07.1949; 4 Briefe zwischen Charles Hirsch und Max Horkheimer, 1937, 1938; 2 Briefe von Max Horkheimer an Ernst Hirsch, Oktober 1938; 1 Brief von Max Horkheimer an Julius Hirsch, 24.02.1942;

Reorganization of an arid ecosystem in response to recent climate change

Natural ecosystems contain many individuals and species interacting with each other and with their abiotic environment. Such systems can be expected to exhibit complex dynamics in which small perturbations can be amplified to cause large changes. Here, we document the reorganization of an arid ecosystem that has occurred since the late 1970s. The density of woody shrubs increased 3-fold. Several previously common animal species went locally extinct, while other previously rare species increased. While these changes are symptomatic of desertification, they were not caused by livestock grazing or drought, the principal causes of historical desertification. The changes apparently were caused by a shift in regional climate: since 1977 winter precipitation throughout the region was substantially higher than average for this century. These changes illustrate the kinds of large, unexpected responses of complex natural ecosystems that can occur in response to both natural perturbations and human activities.

Effect of genetic background on the contribution of New Zealand Black loci to autoimmune lupus nephritis

Autoimmune diseases such as systemic lupus erythematosus are complex genetic traits with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes. Studies of animal models of lupus have provided important insight into the immunopathogenesis of disease, and genetic analyses of these models overcome certain obstacles encountered when studying human patients. Genome-wide scans of different genetic crosses have been used to map several disease-linked loci in New Zealand hybrid mice. Although some consensus exists among studies mapping the New Zealand Black (NZB) and New Zealand White (NZW) loci that contribute to lupus-like disease, considerable variability is also apparent. A variable in these studies is the genetic background of the non-autoimmune strain, which could influence genetic contributions from the affected strain. A direct examination of this question was undertaken in the present study by mapping NZB nephritis-linked loci in backcrosses involving different non-autoimmune backgrounds. In a backcross with MHC-congenic C57BL/6J mice, H2z appeared to be the strongest genetic determinant of severe lupus nephritis, whereas in a backcross with congenic BALB/cJ mice, H2z showed no influence on disease expression. NZB loci on chromosomes 1, 4, 11, and 14 appeared to segregate with disease in the BALB/cJ cross, but only the influence of the chromosome 1 locus spanned both crosses and showed linkage with disease when all mice were considered. Thus, the results indicate that contributions from disease-susceptibility loci, including MHC, may vary markedly depending on the non-autoimmune strain used in a backcross analysis. These studies provide insight into variables that affect genetic heterogeneity and add an important dimension of complexity for linkage analyses of human autoimmune disease.

Cost effectiveness of community leg ulcer clinics: randomised controlled trial

Objectives: To establish the relative cost effectiveness of community leg ulcer clinics that use four layer compression bandaging versus usual care provided by district nurses.

Elongation factor 1 alpha concentration is highly correlated with the lysine content of maize endosperm.

Lysine is the most limiting essential amino acid in cereals, and for many years plant breeders have attempted to increase its concentration to improve the nutritional quality of these grains. The opaque2 mutation in maize doubles the lysine content in the endosperm, but the mechanism by which this occurs is unknown. We show that elongation factor 1 alpha (EF-1 alpha) is overexpressed in opaque2 endosperm compared with its normal counterpart and that there is a highly significant correlation between EF-1 alpha concentration and the total lysine content of the endosperm. This relationship is also true for two other cereals, sorghum and barley. It appears that genetic selection for genotypes with a high concentration of EF-1 alpha can significantly improve the nutritional quality of maize and other cereals.

1883 University of Michigan Baseball Team

Top Row: Charles A. Huber, Henry Ernest Montgomery, mngr, Metcalfe, Albert Miller, Lincoln McMillan

Front Row: William D. Condon,. Charles G. Allmendinger, Weldy W. Walker, Arthur P. Packard, Charles H. Blackburn