Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas

Transforming growth factor beta (TGF-) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor- binding proteins (LTBPs) are known to modulate TGF- functions. The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3, and TGF-1, TGF-2, TGF-3, and SMAD2, SMAD3 and SMAD4 in human and murine (WAP-TNP8) DCIS compared to invasive mammary tumors. Additionally mammary malignant (MCF7, Hs578T, MDA-MB361) and non malignant cell lines (Hs578BsT) were analysed. Microarray, q-PCR, immunoblot, immunohistochemistry and immunofluorescence were used. In comparison to non-malignant tissues (n = 5), LTBP4 was downregulated in all human and mouse DCIS (n = 9) and invasive mammary adenocarcinomas (n = 5) that were investigated. We also found decreased expression of bone morphogenic protein 4 (BMP4) and increased expression of its inhibitor gremlin (GREM1). Treatment of the mammary tumor cell line (Hs578T) with recombinant TGF-1 rescued BMP4 and GREM1 expression. We conclude that the lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-1 and BMP bioavailability and function

Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule

Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy

Summary Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems

Physical Principles of Retroviral Integration in the Human Genome

Some retroviruses, including HIV, insert their DNA in a non-random manner in the host genome through a poorly understood selection mechanism. Here the authors develop a biophysical model of retroviral integration, identifying previously unnoticed universal principles that regulate this phenomenon

Population structure, growth and production of the yellow clam Mesodesma mactroides (Bivalvia: Mesodesmatidae) from a high-energy, temperate beach in northern Argentina

The yellow clam Mesodesma mactroides (Bivalvia: Mesodesmatidae) was once the most abundant intertidal species on the Atlantic coast of northern Argentina and an important commercial resource in South America. This study of a population inhabiting the intertidal zone of the sheltered-dissipative sandy beach Santa Teresita documents the species' population biology, including demographic structure, growth and production during December 2004 and December 2006, and adumbrates the critical state of M. mactroides at present. A total of 3,015 M. mactroides were collected and measured, whereas individuals were found with an anterior-posterior shell length between 2 and 64 mm. A von Bertalanffy growth function with an asymptotic length (L∞) of 85 mm and a growth constant (K) of 0.47 year-1 was established from length-frequency distributions. The longevity of the species is estimated at approximately 6 years, and instantaneous mortality rate was about three times higher than 40 years ago. Besides, this study confirmed that the overall growth performance index (OGP) is habitat-specific and can be used to group M. mactroides and M. donacium from different areas into temperate and upwelling species. Furthermore, OGP is inversely correlated with the latitudinal distribution of Mesodesma populations. The intertidal biomass ranged between 0.06 and 0.07 g AFDM m-2 year-1. Individual production was observed to be highest at 47 mm length (0.35 g AFDM m-2 year-1), and annual production ranged between 0.12 and 0.19 g AFDM m-2 year-1, resulting in productivity values (P/B) between 1.84 and 2.93. The comparison of the results of the present study with those of growth studies conducted on M. mactroides 40 years ago revealed the following considerable differences in the population structure of M. mactroides, indicating the conservation status of this intertidal bivalve as endangered: (1) present growth rates are faster, but that the maximum length attained has decreased, (2) the numbers of individuals per square metre were many times higher in the past than in the present, (3) bivalves from the present work never reached the 'commercial size' of 60 mm and (4) 40 years ago, the population of M. mactroides was composed of up to three cohorts, whereas in this study, there was only one single cohort visible.Fil: Herrmann, Marko. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; Argentina. Johann Heinrich von Thünen Institute; AlemaniaFil: Fernandez Alfaya, Jose Elias. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; ArgentinaFil: Lepore, Mauro L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; ArgentinaFil: Penchaszadeh, Pablo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; ArgentinaFil: Arntz, Wolf E.. Institute for Polar and Marine Research; Alemani