Abstract
The Barbegal watermill complex, a unique cluster of 16 waterwheels in southern France, was the first known attempt in Europe to set up an industrial-scale complex of machines during the ...culmination of Roman Civilization in the second century CE. Little is known about the state of technological advance in this period, especially in hydraulics and the contemporary diffusion of knowledge. Since the upper part of the Barbegal mill complex has been destroyed and no traces of the wooden machinery survived, the mode of operation of these mills has long remained elusive. Carbonate incrustations that formed on the woodwork of the mills were used to reconstruct its structure and function, revealing a sophisticated hydraulic setup unique in the history of water mills. The lower mills used an elbow shaped flume to bring water onto overshot millwheels. This flume was specially adapted to the small water basins and serial arrangement of the mills on the slope. Carbonate deposits from ancient water systems are therefore a powerful tool in archaeological reconstructions and provide tantalizing insights into the skills of Roman engineers during a period of history that is the direct predecessor of our modern civilization.
Hydroelectricity was born in the last decades of the nineteenth century, benefiting from the pre-existing achievements of hydraulic technologies, and taking advantage of new developments in electric ...generators. It has experienced a very rapid development under the pressure of growing industrial energy demand, and needs related to the development of cities. Some regions such as the Alps or the Great Lakes basin in North America have experienced rapid development since the last decade of the nineteenth century. For a long time, city–hydroelectric plant couples allowed the development of local electricity systems, until the development of interconnected networks made it possible to efficiently share the hydroelectric resource, and to guarantee its security of supply. Gradually, large rivers became the object of chain development of low-chute plants, while the middle course of these rivers were the site for large and very large dams. Many environmental, political and human problems must be taken into account in the analysis of the past and future development of hydroelectricity, which is the most abundant source of renewable electrical energy.
In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the ...results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.
Since its appearance in the first century BC, the water wheel has developed with increasing pre-industrial activities, and has been at the origin of the industrial revolution for metallurgy, textile ...mills, and paper mills. Since the nineteenth century, the water wheel has become highly efficient. The reaction turbine appeared by 1825, and continued to undergo technological development. The impulsion turbine appeared for high chutes, by 1880. Other turbines for low-head chutes were further designed. Turbine development was associated, after 1890, with the use of hydropower to generate electricity, both for industrial activities, and for the benefits of cities. A model “one city + one plant” was followed in the twentieth century by more complex and efficient schemes when electrical interconnection developed, together with pumped plants for energy storage.
To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy.
Using a combined genetic approach including ...whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy.
We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects.
Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family.
Abstract The Roman mill complex of Barbegal in France is the largest preindustrial structure in Europe. Carbonate incrustations that formed from water flowing through basins, over flumes and ...waterwheels of the mill complex are partly preserved. The largest carbonate fragments are derived from three wooden flumes that once served the wheels of three mills in a train of eight. The deposits formed from the same water as it moved down from mill to mill. The shape, microstratigraphy and stable isotope patterns of the deposits of each flume reveal a unique history of use for each mill during the last 8 years of operation until their final abandonment. The sidewall carbonate deposits of the flumes vary in shape due to differences in the slope of the flumes during operation, associated with different‐size millwheels in different basins. At least one of the flumes must have been mobile and was uplifted to fit a millwheel of a different size. During 8 years, two millwheels were exchanged and one flume was taken out of action. Carbonate deposits from two flumes were subsequently reused for some unknown industrial purpose in a water basin, and one was later embedded as spolia in a building during late antiquity.
Spinal muscular atrophy (SMA) is a common fatal autosomal recessive disorder characterized by degeneration of lower motor neurons, leading to progressive paralysis with muscular atrophy. The gene for ...SMA has been mapped to chromosome 5q13, where large-scale deletions have been reported. We describe here the inverted duplication of a 500 kb element in normal chromosomes and narrow the critical region to 140 kb within the telomeric region. This interval contains a 20 kb gene encoding a novel protein of 294 amino acids. An highly homologous gene is present in the centromeric element of 95% of controls. The telomeric gene is either lacking or interrupted in 226 of 229 patients, and patients retaining this gene (3 of 229) carry either a point mutation (Y272C) or short deletions in the consensus splice sites of introns 6 and 7. These data suggest that this gene, termed the survival motor neuron (SMN) gene, is an SMA-determining gene.
Introduction: FKRP mutations cause a muscular dystrophy which may present in the neonatal period (MDC1C) or later in life (LGMD2I). Intelligence and brain imaging have been previously reported as ...being normal in FKRP-associated muscular dystrophy, except in rare cases presenting with mental retardation associated with structural brain abnormalities.
Patients and methods: We studied cerebral MRIs in twelve patients with FKRP-associated muscular dystrophy presenting in infancy or early childhood, at ages between 14 months and 43 years. Two patients had severe cognitive deficits, four had mild-moderate mental retardation and the rest were considered to have normal intelligence. All, but one were wheelchair-bound and 7 were mechanically ventilated.
Results: Brain MRI was abnormal in 9 of 12 patients. Brain atrophy was seen in 8 patients. One child had isolated ventricular enlargement at 4 years. Cortical atrophy involved predominantly temporal and frontal lobes and was most important at later ages. In two cases with serial images this atrophy seemed progressive. Three patients, two with severe and one with moderate mental retardation, showed structural abnormalities of the posterior fossa with hypoplasia of the vermis and pons, and cerebellar hemispheric cysts. These abnormalities were stable with time. Two of these three patients also showed diffuse white matter abnormalities in early childhood, which regressed with time.
Conclusions: MRI abnormalities are common in patients with FKRP-associated muscular dystrophy presenting at birth or in early childhood. Progressive brain atrophy is the most frequent finding. Posterior fossa malformations and transient white matter changes may be seen in patients with associated mental retardation.
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