Distribution of human beta-defensin polymorphisms in various control and cystic fibrosis populations.

Abstract Human beta defensins contribute to the first line of defense against infection of the lung. Polymorphisms in these genes are therefore potential modifiers of the severity of lung disease in cystic fibrosis. Polymorphisms were sought in the human beta-defensin genes DEFB1, DEFB4, DEFB103A, and DEFB104 in healthy individuals and cystic fibrosis (CF) patients living in various European countries. DEFB1, DEFB4, and DEFB104 were very polymorphic, but DEFB103A was not. Within Europe, differences between control populations were found for some of the frequent polymorphisms in DEFB1, with significant differences between South-Italian and Czech populations. Moreover, frequent polymorphisms located in DEFB4 and DEFB104 were not in Hardy Weinberg equilibrium in all populations studied, while those in DEFB1 were in Hardy Weinberg equilibrium. Sequencing of a monochromosomal chromosome 8 mouse-human hybrid cell line revealed signals for multiple alleles for some loci in DEFB4 and DEFB104, but not for DEFB1. This indicated that more than one DEFB4 and DEFB104 gene was present on this chromosome 8, in agreement with recent findings that DEFB4 and DEFB104 are part of a repeat region. Individual DEFB4 and DEFB104 PCR amplification products of various samples were cloned and sequenced. The results showed that one DNA sample could contain more than two haplotypes, indicating that the various repeats on one chromosome were not identical. Given the higher complexity found in the genomic organization of the DEFB4 and DEFB104 genes, association studies with CF lung disease severity were performed only for frequent polymorphisms located in DEFB1. No association with the age of first infection by Pseudomonas aeruginosa or with the FEV1 percentage at the age of 11-13 years could be found

The protein phosphatase 1 regulator NIPP1 is essential for mammalian spermatogenesis

NIPP1 is one of the major nuclear interactors of protein phosphatase PP1. The deletion of NIPP1 in mice is early embryonic lethal, which has precluded functional studies in adult tissues. Hence, we have generated an inducible NIPP1 knockout model using a tamoxifen-inducible Cre recombinase transgene. The inactivation of the NIPP1 encoding alleles (Ppp1r8) in adult mice occurred very efficiently in testis and resulted in a gradual loss of germ cells, culminating in a Sertoli-cell only phenotype. Before the overt development of this phenotype Ppp1r8 -/- testis showed a decreased proliferation and survival capacity of cells of the spermatogenic lineage. A reduced proliferation was also detected after the tamoxifen-induced removal of NIPP1 from cultured testis slices and isolated germ cells enriched for undifferentiated spermatogonia, hinting at a testis-intrinsic defect. Consistent with the observed phenotype, RNA sequencing identified changes in the transcript levels of cell-cycle and apoptosis regulating genes in NIPP1-depleted testis. We conclude that NIPP1 is essential for mammalian spermatogenesis because it is indispensable for the proliferation and survival of progenitor germ cells, including (un)differentiated spermatogonia.publishe

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal fring as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family signifcantly linked to 7q36. We identifed and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identifed signifcantly more rare variants—nonsense, frameshift, and missense—in early-onset Alzheimer’s disease (EOAD, p value=0.03, OR=2.21 95% CI 1.05–4.82) and frontotemporal dementia (FTD, p=0.006, OR=2.59, 95% CI 1.28–5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p<0.001 and p<0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to caus

Development of psoriasiform skin lesions under anti-TNF therapy: a genetic link?

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Accidental and experimental salinomycin poisoning in rabbits Intoxicações natural e experimental por salinomicina em coelhos

An outbreak of salinomycin poisoning in rabbits is described. At least 27 out of 2,000 rabbits reared on a farm died after the coccidiostatic drug sulfaquinoxaline was substituted by salinomycin in the feed. An average of 26.9ppm salinomycin was detected in the ration given to the rabbits. Clinical signs included anorexia, apathy and bradykinesia, which progressed to incoordination and recumbency. Gross lesions consisted of pale areas in the skeletal muscles. The histopathological findings showed severe necrotic degenerative myopathy in association with infiltration of neutrophils and macrophages. One rabbit exhibited similar alterations in the myocardium. Mineralization was observed in the affected skeletal muscles in some cases. In order to verify if the poisoning was due to salinomycin, 20 rabbits were divided into five groups and a ration containing the drug at doses of 10, 25, 50, 75 and 100ppm was given. The administration of doses higher than 50ppm resulted in manifestation of the clinical signs seen in the outbreak of poisoning. It was concluded, that probably an error related to the mixture of salinomycin in the feed was the cause of deaths in the spontaneous outbreak of poisoning on the rabbit farm.<br>Relata-se, pela primeira vez, um surto de intoxicação por salinomicina em coelhos. De 2000 animais, no mínimo 27 morreram após troca do coccidiostático sulfaquinoxalina pela salinomicina. A análise de parte da ração detectou 26,9ppm de salinomicina. Os sinais clínicos observados foram anorexia, apatia e lentidão com evolução para incoordenação dos movimentos e decúbito. As lesões macroscópicas consistiram de áreas pálidas na musculatura esquelética. O exame histopatológico evidenciou miopatia degenerativo-necrótica. Adicionalmente, verificou-se reação inflamatória constituída por neutrófilos e macrófagos. Um coelho apresentou lesões similares no miocárdio. Em alguns casos, mineralização estava presente nos músculos esqueléticos afetados. Vinte coelhos experimentais foram divididos em 5 grupos que receberam 10, 25, 50, 75 e 100ppm de salinomicina por via oral, com a finalidade de reproduzir a intoxicação. Os animais que receberam a partir de 50ppm de salinomicina apresentaram sinais clínicos semelhantes aos observados no surto espontâneo. Nossos resultados indicam que, provavelmente, erro na mistura da substância à ração causou a morte dos coelhos