Pkd2 dosage influences cellular repair responses following ischemia-reperfusion injury

Autosomal dominant polycystic kidney disease (ADPKD) results from mutations in either PKD1 or PKD2 and accounts for 10% of all patients on renal replacement therapy. The kidney disease phenotype is primarily characterized by cyst formation, but there are also prominent interstitial changes (inflammation, apoptosis, proliferation, and fibrosis). Using a model of unilateral ischemia-reperfusion injury, we tested the hypothesis that Pkd2 heterozygous kidneys are more sensitive to injury and that this could lead to interstitial inflammation and fibrosis. Baseline tubular proliferation in heterozygous kidneys was twofold higher than in wild-type kidneys. The magnitude and duration of tubular and interstitial proliferative responses was consistently greater in injured heterozygous compared with wild-type kidneys at all time points. Conversely, tubular p21 expression in heterozygotes was lower at baseline and following injury at all time points. Significantly more neutrophils and macrophages were detected in injured Pkd2 heterozygous kidneys at 2 days, correlating with increased expression of the cytokines interleukin (IL)-1 beta and keratinocyte-derived chemokine and resulting in interstitial fibrosis at 28 days. We conclude that Pkd2 dosage influences both susceptibility and nature of the repair responses following injury. Polycystin-2 is therefore likely to play multiple roles in regulating tubular cell viability, repair, and remodeling in the mature kidney

Characterization and observation of animals responsible for rabies post-exposure treatment in Phnom Penh, Cambodia

In order to provide relevant therapeutic answers to human patients exposed to risk of rabies infection who visit the lnstitut Pasteur du Cambodge for post-exposure treatment and to improve control of rabies in Cambodia, a pilot study was carried out in Phnom Penh Province in November and December 1997 with three objectives: characterization of the population of animals responsible for the exposure to rabies, observation of the animals concerned, and confirmation of the presence of rabies virus in the province. Between 18 November 1997 and 19 December 1997, 409 of the 741 patients treated at the lnstitut Pasteur du Cambodge because of an exposure to a known rabies vector were included in the study. The animals concerned were: 401 dogs (98 %), six monkeys (1 ,5 %) and two cats (0,5%). Three-hundred-and-seventy of the animals (90,5%) were owned, 4 (1 %) were unowned but were available for characterization and observation, and 35 (8,6 %) had an unknown ownership status and were not available for further study. The exposures occurred on private property in 84% of the cases, and 80 of the 370 owned animals (22 %) lived in the same home as had the patient. The 374 animals with known ownership status were examined. Five were already dead and two of these five dogs had presented clinical signs typical of those of rabies. The male:female sex ratio of the dogs was 2,1: 1. The 369 live animals were placed under observation for 10 d immediately after exposure of the humans had taken place. At the end of the period none of the animals had developed clinical signs of rabies, three had died of diseases other than rabies, and one was lost. Tests for the rabies nucleocapsid antigen were positive in two cases (the two suspected rabid dogs), confirming the presence of rabies in Phnom Penh Province. Consequently, we recommend measures to improve the control of rabies in Cambodia.The articles have been scanned in colour with a HP Scanjet 5590; 600dpi. Adobe Acrobat v.9 was used to OCR the text and also for the merging and conversion to the final presentation PDF-format.mn201

Spin density wave dislocation in chromium probed by coherent x-ray diffraction

We report on the study of a magnetic dislocation in pure chromium. Coherent x-ray diffraction profiles obtained on the incommensurate Spin Density Wave (SDW) reflection are consistent with the presence of a dislocation of the magnetic order, embedded at a few micrometers from the surface of the sample. Beyond the specific case of magnetic dislocations in chromium, this work may open up a new method for the study of magnetic defects embedded in the bulk.Comment: 8 pages, 7 figure

Global Phase Diagram of the Kondo Lattice: From Heavy Fermion Metals to Kondo Insulators

We discuss the general theoretical arguments advanced earlier for the T=0 global phase diagram of antiferromagnetic Kondo lattice systems, distinguishing between the established and the conjectured. In addition to the well-known phase of a paramagnetic metal with a "large" Fermi surface (P_L), there is also an antiferromagnetic phase with a "small" Fermi surface (AF_S). We provide the details of the derivation of a quantum non-linear sigma-model (QNLsM) representation of the Kondo lattice Hamiltonian, which leads to an effective field theory containing both low-energy fermions in the vicinity of a Fermi surface and low-energy bosons near zero momentum. An asymptotically exact analysis of this effective field theory is made possible through the development of a renormalization group procedure for mixed fermion-boson systems. Considerations on how to connect the AF_S and P_L phases lead to a global phase diagram, which not only puts into perspective the theory of local quantum criticality for antiferromagnetic heavy fermion metals, but also provides the basis to understand the surprising recent experiments in chemically-doped as well as pressurized YbRh2Si2. We point out that the AF_S phase still occurs for the case of an equal number of spin-1/2 local moments and conduction electrons. This observation raises the prospect for a global phase diagram of heavy fermion systems in the Kondo-insulator regime. Finally, we discuss the connection between the Kondo breakdown physics discussed here for the Kondo lattice systems and the non-Fermi liquid behavior recently studied from a holographic perspective.Comment: (v3) leftover typos corrected. (v2) Published version. 32 pages, 4 figures. Section 7, on the connection between the Kondo lattice systems and the holographic models of non-Fermi liquid, is expanded. (v1) special issue of JLTP on quantum criticalit

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology

Spin-Charge Separation in the t−Jt-J Model: Magnetic and Transport Anomalies

A real spin-charge separation scheme is found based on a saddle-point state of the $t-J$ model. In the one-dimensional (1D) case, such a saddle-point reproduces the correct asymptotic correlations at the strong-coupling fixed-point of the model. In the two-dimensional (2D) case, the transverse gauge field confining spinon and holon is shown to be gapped at {\em finite doping} so that a spin-charge deconfinement is obtained for its first time in 2D. The gap in the gauge fluctuation disappears at half-filling limit, where a long-range antiferromagnetic order is recovered at zero temperature and spinons become confined. The most interesting features of spin dynamics and transport are exhibited at finite doping where exotic {\em residual} couplings between spin and charge degrees of freedom lead to systematic anomalies with regard to a Fermi-liquid system. In spin dynamics, a commensurate antiferromagnetic fluctuation with a small, doping-dependent energy scale is found, which is characterized in momentum space by a Gaussian peak at ($\pi/a$, $\pi/a$) with a doping-dependent width ($\propto \sqrt{\delta}$, $\delta$ is the doping concentration). This commensurate magnetic fluctuation contributes a non-Korringa behavior for the NMR spin-lattice relaxation rate. There also exits a characteristic temperature scale below which a pseudogap behavior appears in the spin dynamics. Furthermore, an incommensurate magnetic fluctuation is also obtained at a {\em finite} energy regime. In transport, a strong short-range phase interference leads to an effective holon Lagrangian which can give rise to a series of interesting phenomena including linear-$T$ resistivity and $T^2$ Hall-angle. We discuss the striking similarities of these theoretical features with those found in the high-$T_c$ cuprates and give aComment: 70 pages, RevTex, hard copies of 7 figures available upon request; minor revisions in the text and references have been made; To be published in July 1 issue of Phys. Rev. B52, (1995