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Long sediment cores recovered from the deep portions of Lake Titicaca are used to reconstruct the precipitation history of tropical South America for the past 25,000 years. Lake Titicaca was a deep, fresh, and continuously overflowing lake during the last glacial stage, from before 25,000 to 15,000 calibrated years before the present (cal yr B.P.), signifying that during the last glacial maximum (LGM), the Altiplano of Bolivia and Peru and much of the Amazon basin were wetter than today. The LGM in this part of the Andes is dated at 21,000 cal yr B.P., approximately coincident with the global LGM. Maximum aridity and lowest lake level occurred in the early and middle Holocene (8000 to 5500 cal yr B.P.) during a time of low summer insolation. Today, rising levels of Lake Titicaca and wet conditions in Amazonia are correlated with anomalously cold sea-surface temperatures in the northern equatorial Atlantic. Likewise, during the deglacial and Holocene periods, there were several millennial-scale wet phases on the Altiplano and in Amazonia that coincided with anomalously cold periods in the equatorial and high-latitude North Atlantic, such as the Younger Dryas.

Background Myosin heavy chain 7 ( MYH7 )-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7 . Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion This work adds to the genotype-phenotype correlation of MYH7 -relatedmyopathies confirming the complexity of the disorder.

Caveolin-3, a muscle specific caveolin-related protein, is the principal structural protein of caveolar membranes. We have recently identified an autosomal dominant form of limb girdle muscular dystrophy (LGMD-1C) that is due to caveolin-3 deficiency and caveolin-3 gene mutations. Here, we studied by electron microscopy, including freeze-fracture and lanthanum staining, the distribution of caveolae and the organization of the T-tubule system in caveolin-3 deficient human muscle fibers. We found a severe impairment of caveolae formation at the muscle cell surface, demonstrating that caveolin-3 is essential for the formation and organization of caveolae in muscle fibers. In addition, we also detected a striking disorganization of the T-system openings at the sub-sarcolemmal level in LGMD-1C muscle fibers. These observations provide new perspectives in our understanding of the role of caveolin-3 in muscle and of the pathogenesis of muscle weakness in caveolin-3 deficient muscle.

William Hayes, physician, microbiologist and geneticist, made his own special contribution to modem genetics and molecular biology in a manner unlike those of any of his contemporaries. Bill, as he was universally known, was an unlikely candidate for such distinction. It is interesting to speculate on the events which transformed someone likely to have had a distinguished but still traditional medical career into a world renowned scientist who influenced a whole generation of microbiologists and geneticists. He did not come from a family with a history of scientific or academic activities. Nor did he study at the centres of biological research. Moreover, at the beginning of his meteoric rise to eminence, he did not have the support of the scientific elite or access to research resources. It is likely that had he been born 20 years later the originality that he brought to microbial genetics would have been lost to us. Perhaps the situation he found in India during the war and the relative freedom of the research system operating in the United Kingdom in the 1950s ideally suited the talents of Bill Hayes. He was a dedicated experimentalist with a talent for improvisation, and his major contributions were experiments that he did himself, rather than through an assistant or graduate student. He would not have described himself as a leader, although his associates willingly gave him their loyalty and support. Nor would he have thought of himself as having charisma; indeed he was unusually self-effacing. When he gave up experimental work to write his outstanding and extraordinarily influential book, The genetics of bacteria and their viruses (13), he typed the first draft himself. Administration and the power it can provoke were anathema to Bill. Nevertheless, he created, first at Hammersmith Hospital in London and then at the University of Edinburgh, research groups that were the envy of his peers in terms of their productivity and innovation.

Genetics provides an approach to the analysis of the complex function of lignin biodegradation, through the isolation of mutants and the creation of gene libraries for the identification of genes and their products. However, white-rot fungi (for example, Phanerochaete chrysosporium) have not so far been analysed from this point of view, and there is the challenge of establishing such genetics. P. chrysosporium is convenient experimentally because relatively few genes are switched on at the onset of ligninolytic activity. We describe the isolation of clones carrying genes expressed specifically in the ligninolytic phase, the development of a general strategy for mapping such clones, and the elucidation of the mating system of this organism. Another objective is the development of methods for transforming DNA into P. chrysosporium. This would allow the use of site-directed mutagenesis to analyse the functioning of ligninases, and the control of expression of the corresponding genes. The use of genetic crosses for strain improvement and the identification of components of the system are also discussed.

The thesis is concerned with the sex factor ofEscherichia coli K12. The sex factor, which confers upon itshost cell the ability to transfer genetic materiel, can existeither as an autonomous particle (in F cells) or integratedwith the chromosome (Hfr cells). In this introduction anaccount is given of present knowledge on its structure,functioning and relation to its host cell. Special attentionis paid to ideas and experimental results concerned with themechanism by which the sex factor becomes integrated with thechromosome.In the first experimental section an account isgiven of studies with a series of newly isolated hfr strains.The results obtained are consistent with a scheme forintegration involving genetic recombination between the sexfactor and the-chromosome. In the second motion the isolationof a new type of F prime factor (= variant sex factor carrying chromosomal genes) i . described A mechanism for its origin isproposed (=clavicle= supporting this model is presented. Thisparticular type of P-prime factor was found to differ from thetypes previously described in that it gives rise to Hfr-strainsof a single type. This effect was-analysed and an explanation is proposed. The third. section is concerned with the genetic analysisof the property Of some strains of E-coli of allowing phage T3 toform plaques only with low efficiency It is shown that thisheritable property is carried on the sex factor. In this contexta structure formed by recombination between an F-prime factor and a mutant sex factor is described.

The functionality of cellular membranes relies on the molecular order imparted by lipids. In eukaryotes, sterols such as cholesterol modulate membrane order, yet they are not typically found in prokaryotes. The structurally similar bacterial hopanoids exhibit similar ordering properties as sterols in vitro, but their exact physiological role in living bacteria is relatively uncharted. We present evidence that hopanoids interact with glycolipids in bacterial outer membranes to form a highly ordered bilayer in a manner analogous to the interaction of sterols with sphingolipids in eukaryotic plasma membranes. Furthermore, multidrug transport is impaired in a hopanoid-deficient mutant of the gram-negativeMethylobacterium extorquens, which introduces a link between membrane order and an energy-dependent, membrane-associated function in prokaryotes. Thus, we reveal a convergence in the architecture of bacterial and eukaryotic membranes and implicate the biosynthetic pathways of hopanoids and other order-modulating lipids as potential targets to fight pathogenic multidrug resistance.