A polycystin-centric view of cyst formation and disease: the polycystins revisited

It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs have led in turn to a period of intense investigation into the function of the two proteins encoded, polycystin-1 and polycystin-2, and how defects in either protein lead to cyst formation and nonrenal phenotypes. In this review, we summarize the major findings in this area and present a current model of how the polycystin proteins function in health and disease

Dry season foraging preferences of cattle and sheep in a communal area of South Africa.

We examined landscape and habitat (vegetation) scale foraging of cattle and sheep at two communal villages in the Eastern Cape, South Africa, to determine the key resources utilised during the dry season. At the landscape scale, cattle at both sites displayed overall preference for the arable lands at this time, although this diminished steadily as the dry season progressed. In contrast, sheep made considerably less use of these areas, showing only sporadic preference. At the vegetation scale, cattle demonstrated greatest preference for crop residues and uncultivated ‘commonage' areas, although foraging in grassland increased considerably in the latter stages of the dry season. Sheep utilised a much smaller range of vegetation types, preferring crop residues and fields that had been recently fallow and avoiding all other vegetation categories. We suggest that given the spatial limitations in planned, communal villages, the arable lands function as key resource areas for livestock during the dry season. It is recommended that management of these areas emphasise greater integration of sheep and cattle grazing and focus on maintaining vegetation heterogeneity in order to facilitate opportunistic ‘switching' in foraging patterns at different stages of the dry season.African Journal of Range & Forage Science 2007, 24(3): 109–12

Letter to the Editor: 1H, 15N, and 13C chemical shift assignments of the resuscitation promoting factor domain of Rv1009 from Mycobacterium tuberculosis

International audienceNo abstract availabl

Insulin-like growth factor-1 induces hyperproliferation of PKD1 cystic cells via a Ras/Raf dependent signalling pathway

Autosomal dominant polycystic kidney disease (ADPKD) largely results from mutations in the PKD1 gene leading to hyperproliferation of renal tubular epithelial cells and consequent cyst formation. Rodent models of PKD suggest that the multifunctional hormone insulin-like growth factor-1 (IGF-1) could play a pathogenic role in renal cyst formation. In order to test this possibility, conditionally immortalized renal epithelial cells were prepared from normal individuals and from ADPKD patients with known germline mutations in PKD1. All patient cell lines had a decreased or absence of polycystin-1 but not polycystin-2. These cells had an increased sensitivity to IGF-1 and to cyclic AMP, which required phosphatidylinositol-3 (PI3)-kinase and the mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) for enhanced growth. Inhibition of Ras or Raf abolished the stimulated cell proliferation. Our results suggest that haploinsufficiency of polycystin-1 lowers the activation threshold of the Ras/Raf signalling system leading to growth factor-induced hyperproliferation. Inhibition of Ras or Raf activity may be a therapeutic option for decreasing tubular cell proliferation in ADPKD

Outer Regions of the Milky Way

With the start of the Gaia era, the time has come to address the major challenge of deriving the star formation history and evolution of the disk of our MilkyWay. Here we review our present knowledge of the outer regions of the Milky Way disk population. Its stellar content, its structure and its dynamical and chemical evolution are summarized, focussing on our lack of understanding both from an observational and a theoretical viewpoint. We describe the unprecedented data that Gaia and the upcoming ground-based spectroscopic surveys will provide in the next decade. More in detail, we quantify the expect accuracy in position, velocity and astrophysical parameters of some of the key tracers of the stellar populations in the outer Galactic disk. Some insights on the future capability of these surveys to answer crucial and fundamental issues are discussed, such as the mechanisms driving the spiral arms and the warp formation. Our Galaxy, theMilkyWay, is our cosmological laboratory for understanding the process of formation and evolution of disk galaxies. What we learn in the next decades will be naturally transferred to the extragalactic domain.Comment: 22 pages, 10 figures, Invited review, Book chapter in "Outskirts of Galaxies", Eds. J. H. Knapen, J. C. Lee and A. Gil de Paz, Astrophysics and Space Science Library, Springer, in pres

Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients

Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles

Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Purpose To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020). Methods All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing. Results Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%). Conclusion We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance

Effective Field Theory for Layered Quantum Antiferromagnets with Non-Magnetic Impurities

We propose an effective two-dimensional quantum non-linear sigma model combined with classical percolation theory to study the magnetic properties of site diluted layered quantum antiferromagnets like La$_{2}$Cu$_{1-x}$M$_x$O$_{4}$ (M$=$Zn, Mg). We calculate the staggered magnetization at zero temperature, $M_s(x)$, the magnetic correlation length, $\xi(x,T)$, the NMR relaxation rate, $1/T_1(x,T)$, and the N\'eel temperature, $T_N(x)$, in the renormalized classical regime. Due to quantum fluctuations we find a quantum critical point (QCP) at $x_c \approx 0.305$ at lower doping than the two-dimensional percolation threshold $x_p \approx 0.41$. We compare our results with the available experimental data.Comment: Final version accepted for publication as a Rapid Communication on Physical Review B. A new discussion on the effect of disorder in layered quantum antiferromagnets is include

Critical Hysteresis from Random Anisotropy

Critical hysteresis in ferromagnets is investigated through a $N$-component spin model with random anisotropies, more prevalent experimentally than the random fields used in most theoretical studies. Metastability, and the tensorial nature of anisotropy, dictate its physics. Generically, random field Ising criticality occurs, but other universality classes exist. In particular, proximity to $\mathcal{O}(N)$ criticality may explain the discrepancy between experiment and earlier theories. The uniaxial anisotropy constant, which can be controlled in magnetostrictive materials by an applied stress, emerges as a natural tuning parameter.Comment: four pages, revtex4; minor corrections in the text and typos corrected (published version