Landscape evolution of the Apurimac river drainage basin, southern Peru

The northernmost part of the Altiplano in Southern Peru is drained by the river Apurimac and its tributaries. The Altiplano is a region that covers most of the eastern part of the Cordillera Occidental and is bounded in the East by the Cordillera Oriental. The Apurirnac River Drainage Basin (ARDB) extends roughly between 13 °S and l5°S over 50000 km 2. It mainly occupies the northeastern flank of the Cordillera Occidental and a negligible part of the southwestern flank of the Cordillera Oriental. At the latitude of the Abancay deflection, i.e. 13.5 S; 72.7 W, the Apurirnac River abandons the Cordillera Occidental. On its way to the Amazon Basin in the North the Apurimac River drains the Cordillera Oriental and the Sub-Andean Zone (SAZ). The incision by the rivers of the ARDB has created differences in relief of more than 2000 m that contributed to the denudation and exhumation, hence the evolution ofthe landscape. The Altiplano sedimentary basin contains an 8 kilometers thick succession of Cenozoic sediments, which it received from the surrounding highs in the West and the Easl Its structural framework has been formed by the various tectonic events that struck the Andes and the various pulses of magmatic activity that took place during the Cenozoic. In the western part of the Altiplano Miocene volcanics domínate, whereas in the northeastern part, in the Cusco region, clastic deposits do so. In the region of Abancay, a batholite got emplaced during the mid Tertiary, that extends over few 1000 km2

Steady-state exhumation pattern in the Central Andes – SE Peru

The Western Cordillera of SE Peru is part of the Central Andes and is situated to the west of the Eastern Andes from which it is separated by the northern termination of the Altiplano – the Inter-Andean Valley. It is a volcanic–volcano-detrital chain that developed in the Palaeogene, and is characterized by a 4000 m-high mean altitude whose origin is poorly constrained. We selected a vertical profile in the region of Abancay to trace the record the evolving uplift and erosion history of the Andean orogen. Fission-track data on both apatite and zircon crystals were completed on plutonic rocks of the Tertiary Andahuaylas–Yauri batholith. Ages ranged between 24 and 14 Ma, and 38 and 30 Ma, respectively. Thermal modelling was completed for the whole profile and does not, like age–altitude relationships, show evidence of any clear disruption of the exhumation paths since 38 Ma either by sedimentary burial and/or rapid exhumation. One of the noteworthy aspects of the data is that exhumation was steady at a rate of 0.17 km Ma-1 from the late Eocene until at least the middle Miocene (38–14 Ma). The uplift of the Western Cordillera was thus probably steady for this period with sedimentary deposition restricted to the present-day Altiplano and Inter-Andean Valley regions

The Effects of Low Levels of Dystrophin on Mouse Muscle Function and Pathology

Duchenne muscular dystrophy (DMD) is a severe progressive muscular disorder caused by reading frame disrupting mutations in the DMD gene, preventing the synthesis of functional dystrophin. As dystrophin provides muscle fiber stability during contractions, dystrophin negative fibers are prone to exercise-induced damage. Upon exhaustion of the regenerative capacity, fibers will be replaced by fibrotic and fat tissue resulting in a progressive loss of function eventually leading to death in the early thirties. With several promising approaches for the treatment of DMD aiming at dystrophin restoration in clinical trials, there is an increasing need to determine more precisely which dystrophin levels are sufficient to restore muscle fiber integrity, protect against muscle damage and improve muscle function. To address this we generated a new mouse model (mdx-Xist Dhs) with varying, low dystrophin levels (3–47%, mean 22.7%, stdev 12.1, n = 24) due to skewed X-inactivation. Longitudinal sections revealed that within individual fibers, some nuclei did and some did not express dystrophin, resulting in a random, mosaic pattern of dystrophin expression within fibers. Mdx-Xist Dhs, mdx and wild type females underwent a 12 week functional test regime consisting of different tests to assess muscle function at base line, or after chronic treadmill running exercise. Overall, mdx-Xist Dhs mice with 3–14 % dystrophin outperformed mdx mice in the functional tests. Improved histopathology was observed in mice with 15–29 % dystrophin and these levels also resulted in normalized expression of pro-inflammatory biomarker genes, while for other parameters.30 % of dystrophin was needed

<i>Mdx-Xist</i>^Δhs mice.

<p>A. To breed mice with low dystrophin levels, female <i>Xist</i>^Δhs mice, carrying a mutation in the <i>Xist</i> promoter which coordinates X-inactivation, were crossed with dystrophin negative <i>mdx</i> males. During embryogenesis, the maternal X-chromosome encoding a functional dystrophin gene will be preferentially (60–90%) inactivated as a result of the mutated <i>Xist</i> promoter. The <i>Xist</i>^Δhs mice were a kind gift from N. Brockdorff (MRC Clinical Sciences Center, London, UK, current affiliation Department of Biochemistry, University of Oxford, UK). B. Picture of a representative Western blot. The percentage of dystrophin was determined for the quadriceps of all <i>mdx-Xist</i>^Δhs mice by Western blot (2–9 technical replicates per mouse). The percentage of individual mice was determined using a concentration curve made from wild type samples. Myosin was used as a loading control. C. Skewed X-inactivation resulted in dystrophin levels of 3–47% (mean 22.7, stdev 12.1, <i>n</i> = 24) (as determined by Western blot) in the female <i>mdx-Xist</i>^Δhs offspring. Each bar represents the dystrophin level of an individual mouse. The dystrophin levels of the individual mice belonging to the three dystrophin groups can be appreciated from this graph. D. Dystrophin levels determined by Western blot and manual counting of dystrophin positive fibers demonstrate a strong correlation (R = 0.97). E. Longitudinal sections of a quadriceps stained with dystrophin (green) and spectrin (red). From the pictures it can be appreciated that dystrophin expression is not homogeneously expressed across the fiber but rather confined to certain nuclear domains.</p

Exercise induced histopathology and biomarker gene expression.

<p>A. Wild type mice were less severely affected than <i>mdx</i> and <i>mdx-Xist</i>^Δhs mice. Due to high variation between individual <i>mdx</i> mice, the difference between <i>mdx</i> and wild type mice was not significant. <i>Mdx-Xist</i>^Δhs mice had slightly less fibrotic tissue than <i>mdx</i> mice. B. No difference in expression of genes involved in disease pathology was found between <i>mdx</i> and <i>mdx-Xist</i>^Δhs mice. Both mouse strains did differ significantly from wild type mice, of which the expression levels were low. Single and double asterisks indicate a <i>P</i><0.05 and <i>P</i><0.01, respectively. # Indicates a significant difference from all other groups, average dystrophin levels of <i>mdx-Xist</i>^Δhs mice was 21% (2%–45% median 25.8).</p

Functional performance measured directly after treadmill exercise.

<p>A. Longest hanging time with the two limb hanging test was achieved by wild type and <i>mdx-Xist</i>^Δhs mice which both performed significantly (<i>P</i><0.001) better than <i>mdx</i> mice. B. Fore limb grip strength of <i>mdx-Xist</i>^Δhs mice was significantly (<i>P</i><0.001) better than that of <i>mdx</i> mice. C. Wild type mice outperformed <i>mdx</i> and <i>mdx-Xist</i>^Δhs mice on the rotarod, while no significant difference was observed between <i>mdx</i> and <i>mdx-Xist</i>^Δhs mice. Average dystrophin level of <i>mdx-Xist</i>^Δhs mice was 21% (2%–45% median 25.8).</p

Muscle fiber size, degree of central nucleation and percentage of fibrotic/necrotic tissue.

<p>A. Regenerating and hypertrophic fibers were mainly observed in the <i>mdx</i> mice. A dystrophin level depend trend towards wild type distribution was observed for <i>mdx-Xist</i>^Δhs mice where <15% dystrophin already resulted in improvement. B. Dystrophin levels between 15–30% and >30% resulted in a reduction of the percentage of centralized nuclei of 40% and 60% respectively. C. The quadriceps of all mice was significantly more severely affected compared to <i>Xist</i>^Δhs mice. D. The diaphragm was the most severely affected muscle with on average 20% fibrotic/necrotic tissue in <i>mdx</i> mice. All mice were significantly more severely affected compared to <i>Xist</i>^Δhs mice. <i>Mdx-Xist</i>^Δhs mice with >30% dystrophin had less fibrotic/necrotic tissue than <i>mdx</i> and <i>mdx-Xist</i>^Δhs mice with <15% dystrophin, but this difference was only significant between both <i>mdx-Xist</i>^Δhs groups. # indicates a significant difference of that bar with all the other groups. Single asterisks indicate a <i>P</i><0.05 and double asterisks indicate a <i>P</i><0.01.</p

Expression of several genes involved in disease pathology.

<p>A and B. For most biomarkers a clear dystrophin level dependent restoration of gene expression levels was observed in the <i>mdx-Xist</i>^Δhs mice, where intermediate dystrophin levels resulted in low expression of genes involved in disease pathology. For some genes, dystrophin levels <15% were enough to reduce gene expression while for other genes >30% was necessary. C. In the heart, even dystrophin levels of <15% decreased expression of fibrotic biomarkers like <i>Timp-1</i>. Since the mice were young, no difference in expression levels in heart function was observed, except for <i>Nppa</i>. Double asterisks indicate a <i>P</i><0.01.</p