Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

In the present study we demonstrated that neurotoxin MPP⁺-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP⁺-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G₀/G₁ cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP⁺ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP⁺ and cell-cycle re-entry through retinoblastoma protein phosphorylation.     

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.     

Circular proteoglycans from sponges: first members of the spongican family

Species-specific cell adhesion in marine sponges is mediated by a new family of modular proteoglycans whose general supramolecular structure resembles that of hyalectans. However, neither their protein nor their glycan moieties have significant sequence homology to other proteoglycans, despite having protein subunits equivalent to link proteins and to proteoglycan monomer core proteins, and glycan subunits equivalent to hyaluronan and to the glycosaminoglycans of hyalectans. In some species, these molecular components are assembled into a structure with a circular core formed by the link protein- and hyaluronan-like subunits. Besides their involvement in cell adhesion, these sponge proteoglycans, for which we propose the term spongicans, participate in signal transduction processes and are suspected to play a role in sponge self-nonself recognition. Their in vivo roles and the mild methods used to purify large amounts of functionally active spongicans make them ideal models to study the functions and possible new applications of proteoglycans in biomedical research. Received 21 May 2002; received after revision 5 July 2002; accepted 10 July 2002 RID="*" ID="*"Corresponding author.     

The ubiquitin-specific protease USP25 interacts with three sarcomeric proteins

The biological functions of the more than one hundred genes coding for deubiquitinating enzymes in the human genome remain mostly unknown. The USP25 gene, located at 21q11.2, encodes three protein isoforms produced by alternative splicing. While two of the isoforms are expressed nearly ubiquituously, the expression of the longer USP25 isoform (USP25m) is restricted to muscular tissues and is upregulated during myogenesis. USP25m interacts with three sarcomeric proteins: actin alpha-1 (ACTA1), filamin C (FLNC), and myosin binding protein C1 (MyBPC1), which are critically involved in muscle differentiation and maintenance, and have been implicated in the pathogenesis of severe myopathies. Biochemical analyses demonstrated that MyBPC1 is a short-lived proteasomal substrate, and its degradation is prevented by over-expression of USP25m but not by other USP25 isoforms. In contrast, ACTA1 and FLNC appear to be stable proteins, indicating that their interaction with USP25m is not related to their turnover rate. Received 7 November 2005; received after revision 7 January 2006; accepted 13 January 2006     

The v-myc oncogene is sufficient to induce growth transformation of chick neuroretina cells

A number of studies have shown that full transformation of non-established rodent fibroblasts can be efficiently achieved in vitro by the concerted action of two oncogenes belonging to different complementation groups. Extension of the two-genes carcinogenesis model to other differentiated cell types, presumably endowed with different controls of growth, is desirable for a better understanding of questions such as the host cell selectivity of oncogene action. A recent report claimed that cooperation between two oncogenes, v-myc and v-mil, is required to achieve transformation of chicken embryo neuroretina cells, which are characterized by a limited growth capacity in monolayer culture. Here we present evidence that the v-myc oncogene alone is sufficient to induce growth transformation of glial and neuronal precursor cell types from chick neuroretina. We also report that induction of transformation by v-myc is accompanied by faithful preservation of some of the differentiated functions of the chick cells.     

Geschwindigkeit der selektiven Akkumulation von Mercurascan-203 im geschädigten Muskel und im ischämischen Myokard

Summary The authors demonstrate that a hydroxy derivative of fluorescein — Mercurascan 203 — very rapidly and selectively accumulates in the injured muscle and in the ischaemic myocardium and is cleared rapidly from the blood and other tissues. In vivo, scanning is positive soon after Mercurascan-203 administration.     

Inhibition of rat liver adenyl cyclase by adenosine and adenine nucleotides

Riassunto L'attività adenilciclasica delle frazioni subcellulari di fegato di ratto fu inibita dall'adenosina, dall'AMP e dall'ADP (1 mM) del 60, 50 e 40%. Alla concentrazione di 0.08 mM, l'adenosina e l'AMP inibirono l'attività ciclasica del 40 e del 30%. L'IMP, l'inosina, l'adenina e l'ipoxantina furono senza effetto.

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This work was aided by Grants No. AM06034 and No. FR05641 from the National Institutes of Health, U.S. Public Health Service.     

Ultrasound effects on zinc recovery from EAF dust by sulfuric acid leaching

In this work, an ultrasound-assisted leaching process was studied for the recovery of zinc from electric arc furnace (EAF) dust, in which zinc was mainly present in the form of franklinite (60%). Hydrometallurgy is emerging as a preferred process for the recovery of a variety of metals, and the use of ultrasound could offer advantages over the conventional leaching process, especially for the dissolution of franklinite. Franklinite is a refractory phase that is difficult to leach and represents the main obstacle in conventional hydrometallurgy processing. Atmospheric leaching with different sulfuric acid concentrations (0.2-2.0 M) at two temperatures (323 and 353 K) was performed. The tests were conducted using both conventional and ultrasound-assisted leaching. After the leaching tests, the solid residues were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques, whereas the leach liquor was analyzed by inductively coupled plasma spectroscopy (ICP). The use of ultrasound facilitated the dissolution of franklinite at low acid concentrations and resulted in a greater zinc recovery under all of the investigated operating conditions.