Complex zeolite structure solved by combining powder diffraction and electron microscopy

Many industrially important materials, ranging from ceramics to catalysts to pharmaceuticals, are polycrystalline and cannot be grown as single crystals. This means that non-conventional methods of structure analysis must be applied to obtain the structural information that is fundamental to the understanding of the properties of these materials. Electron microscopy might appear to be a natural approach, but only relatively simple structures have been solved by this route. Powder diffraction is another obvious option, but the overlap of reflections with similar diffraction angles causes an ambiguity in the relative intensities of those reflections. Various ways of overcoming or circumventing this problem have been developed, and several of these involve incorporating chemical information into the structure determination process. For complex zeolite structures, the FOCUS algorithm has proved to be effective. Because it operates in both real and reciprocal space, phase information obtained from high-resolution transmission electron microscopy images can be incorporated directly into this algorithm in a simple way. Here we show that by doing so, the complexity limit can be extended much further. The power of this approach has been demonstrated with the solution of the structure of the zeolite TNU-9 (|H9.3|[Al9.3Si182.7O384]; ref. 10) with 24 topologically distinct (Si,Al) atoms and 52 such O atoms. For comparison, ITQ-22 (ref. 11), the most complex zeolite known to date, has 16 topologically distinct (Si,Ge) atoms.     

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.     

John Machin and Robert Simson on inverse-tangent series for π

Communicated by D. T. Whiteside     

Cognitive change and the APOE epsilon 4 allele

There is a marked variation in whether people retain sufficient cognitive function to maintain their quality of life and independence in old age, even among those without dementia, so it would be valuable to identify the determinants of normal age-related cognitive change. We have retested non-demented 80-year-olds who were participants in the Scottish Mental Survey of 1932, and find that the variation in their non-pathological cognitive change from age 11 to 80 is related to their apolipoprotein E (APOE) genotype. This effect of the APOE epsilon 4 allele on normal cognitive ageing may be mediated by a mechanism that is at least partly independent of its predisposing effect towards Alzheimer's disease.     

Sleeping sickness and the brain

Recent progress in understanding the neuro-pathological mechanisms of sleeping sickness reveals a complex relationship between the trypanosome parasite that causes this disease and the host nervous system. The pathology of late-stage sleeping sickness, in which the central nervous system is involved, is complicated and is associated with disturbances in the circadian rhythm of sleep. The blood-brain barrier, which separates circulating blood from the central nervous system, regulates the flow of materials to and from the brain. During the course of disease, the integrity of the blood-brain barrier is compromised. Dysfunction of the nervous system may be exacerbated by factors of trypanosomal origin or by host responses to parasites. Microscopic examination of cerebrospinal fluid remains the best way to confirm late-stage sleeping sickness, but this necessitates a risky lumbar puncture. Most drugs, including many trypanocides, do not cross the blood-brain barrier efficiently. Improved diagnostic and therapeutic approaches are thus urgently required. The latter might benefit from approaches which manipulate the blood-brain barrier to enhance permeability or to limit drug efflux. This review summarizes our current understanding of the neurological aspects of sleeping sickness, and envisages new research into blood-brain barrier models that are necessary to understand the interactions between trypanosomes and drugs active against them within the host nervous system. Received 10 October 2001; received after revision 29 November 2001; accepted 5 December 2001     

Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.