Serum adrenal androgens (AAs), including androstenedione (Δ4A) and dehydroepiandrosterone sulfate (DHEAS), have been reported to be lower in female rheumatoid arthritis (RA) patients with early disease. Few data are available on hormonal status of women before the onset of clinical rheumatoid arthritis (pre-RA). A broad baseline panel of serum adrenal and sex steroids was compared in 36 female pre-RA to 144 matched cohort control (CN) subjects to determine differences in their mean values and in patterns of hormonal correlations. Study subjects having lower versus higher baseline serum cortisol levels than the total group's mean value were also analyzed separately to investigate differences in their hormonal levels and correlational patterns. In total subjects, mean (±SE) Δ4A level (nmol/L) was lower (P = 0.018) in 28 pre-RA cases (6.4 ± 0.40) versus 108 CN (7.8 ± 0.28). The significant (P = 0.013) difference was restricted to 9 pre-RA versus 53 CN subjects having lower cortisol levels (5.6 ± 0.73 versus 8.0 ± 0.42 nmol/L, resp.). In total subjects, no significant difference was found between study subjects in their bivariate correlations of the hormonal panel variables, unlike results found in the subgroups stratified by lower versus higher cortisol levels. A subgroup of pre-RA females may have relative adrenal cortical insufficiency, as reflected by lower Δ4A, especially observed among those subjects with lower cortisol levels.

Mitochondria have their own translational machineries for the synthesis of thirteen polypeptide chains that are components of the complexes that participate in the process of oxidative phosphorylation (or ATP generation). Translation initiation in mammalian mitochondria requires two initiation factors, IF2 mt and IF3 mt , instead of the three that are present in eubacteria. The mammalian IF2 mt possesses a unique 37 amino acid insertion domain, which is known to be important for the formation of the translation initiation complex. We have obtained a three-dimensional cryoelectron microscopic map of the mammalian IF2 mt in complex with initiator fMet-tRNA i Met and the eubacterial ribosome. We find that the 37 amino acid insertion domain interacts with the same binding site on the ribosome that would be occupied by the eubacterial initiation factor IF1, which is absent in mitochondria. Our finding suggests that the insertion domain of IF2 mt mimics the function of eubacterial IF1, by blocking the ribosomal aminoacyl-tRNA binding site (A site) at the initiation step.protein synthesis | ribosome-IF2mt complex | cryo-EM structure | molecular modeling P rotein synthesis entails a complex series of events in which the ribosome interacts with a number of ligands and translation factors so as to conduct an efficient, accurate, and well-regulated process (1). The first event in translation is the initiation step, which requires the formation of an initiation complex, composed of the small ribosomal subunit (30S, in eubacteria), mRNA, initiator tRNA (fMet-tRNA i Met ) and three initiation factors (IF1, IF2, and IF3) (2). IF3 helps in preparation of the 30S initiation complex by preventing premature docking of the large subunit (50S, in eubacteria) (3, 4). IF2 promotes the binding of the initiator tRNA to the peptidyl (P) site of the 30S subunit and facilitates the association of the 50S subunit to form the 70S initiation complex (5). Initiation factor IF1, together with IF2, stabilizes the 30S initiation complex (6). IF1 also plays a role in translation initiation fidelity in conjunction with IF3 (7-9). The binding site of IF1 overlaps with that of the aminoacyl-tRNA on the 30S subunit (the A site), thereby making this site unavailable for the initiator tRNA during translation initiation (10-13). However, no equivalent of eubacterial IF1 has been detected in mammalian mitochondria (14); mitochondrial protein synthesis requires only two initiation factors, IF2 mt and IF3 mt .There is a lack of consensus in the nomenclature used to describe the domains of IF2 by biochemists (15-18) and structural biologists (12,19). A uniform nomenclature that addresses both structural and functional considerations was used in our previous study (20). According to this nomenclature the approximately 98 kDa Escherichia coli IF2 is composed of six domains (Fig. 1A). Domains I and II are not present in all of the eubacterial factors, are not highly conserved, and are also absent in the mammalian IF2 mt . Domain VI is divided into two structura...

In humans the mitochondrial inner membrane protein Oxa1L is involved in the biogenesis of membrane proteins and facilitates the insertion of both mitochondrial-and nuclear-encoded proteins from the mitochondrial matrix into the inner membrane. The C-terminal ϳ100-amino acid tail of Oxa1L (Oxa1L-CTT) binds to mitochondrial ribosomes and plays a role in the co-translational insertion of mitochondria-synthesized proteins into the inner membrane. Contrary to suggestions made for yeast Oxa1p, our results indicate that the C-terminal tail of human Oxa1L does not form a coiled-coil helical structure in solution. The Oxa1L-CTT exists primarily as a monomer in solution but forms dimers and tetramers at high salt concentrations. The binding of Oxa1L-CTT to mitochondrial ribosomes is an enthalpy-driven process with a K d of 0.3-0.8 M and a stoichiometry of 2. Oxa1L-CTT cross-links to mammalian mitochondrial homologs of the bacterial ribosomal proteins L13, L20, and L28 and to mammalian mitochondrial specific ribosomal proteins MRPL48, MRPL49, and MRPL51. Oxa1L-CTT does not cross-link to proteins decorating the conventional exit tunnel of the bacterial large ribosomal subunit (L22, L23, L24, and L29).

Serum concentrations of acute phase proteins, inflammatory cytokines, and other immunological components were individually assayed using high-sensitivity ELISA in a com-munity-based cohort of preclinical rheumatoid arthritis (pre-RA) and matched non-RA control (CN) subjects. Bivariate correlations of the biomarker panel concentrations were compared in pre-RA versus CN and female versus male subjects. Clinically elevated CRP levels (8+ mg/l) occurred in a higher (p = 0.010) frequency in 46 pre-RA (n = 8, 17.4%) subjects than in 179 CN (n = 9, 5.0%), and were independent of age, gender, smoking behaviors, and serum rheumatoid factor. Selected age and gender differences were found in levels of the immunological network factors. In each study group, the ratio of sTNF-RI to IL-2sRα mean concentrations was 2-fold higher in men than in women. Aging correlated positively with CRP, ASAA, and TNF-α levels, but negatively with IL-1β. Bivariate correlations were similar in pre-RA subjects versus CN and by gender, with few exceptions. Factor loadings in principal component analysis of the total subjects indicated that age- and gender-related variables constituted the two main components. Using multiple regression analyses, an integrative working model of all variable interrelations was generated. The tentative, directional model supports a concept of gender dimorphism of the ratio of sTNF-RI to IL-2sRα serum concentrations and displays differing effects of age on TNF-α versus IL-1β levels. These findings indicate complex age, gender, and cytokine interrelations in control of the immune systems network. Future research in testing such inflammatory pathways promises a better understanding of predisposition to diseases, like RA.

Glioblastoma is both the most common and most lethal primary CNS malignancy in adults, accounting for 45.6% of all malignant CNS tumors, with a 5-year survival rate of only 5.0%, despite the utilization of multimodal therapy including resection, chemotherapy, and radiation. Currently available treatment options for glioblastoma often remain limited, offering brief periods of improved survival, but with substantial side effects. As such, improvements in current treatment strategies or, more likely, the implementation of novel strategies altogether are warranted. In this topic review, the authors provide a comprehensive review on the potential of alternating electric fields (AEFs) in the treatment of glioblastoma. Alternating electric fields—also known as tumor-treating fields (TTFs)—represent an entirely original therapeutic modality with preliminary studies suggesting comparable, and at times improved, efficacy to standard chemotherapeutic agents in the treatment of recurrent glioblastoma. A recent multicenter, Phase III, randomized clinical trial comparing NovoTTF-100A monotherapy to physician's best choice chemotherapy in patients with recurrent glioblastoma revealed that AEFs have similar efficacy to standard chemotherapeutic agents with a more favorable side-effects profile and improved quality of life. In particular, AEFs were shown to have limited systemic adverse effects, with the most common side effect being contact dermatitis on the scalp at the sites of transducer placement. This study prompted FDA approval of the NovoTTF-100A system in April 2011 as a standalone therapy for treatment of recurrent glioblastoma refractory to surgical and radiation treatment. In addition to discussing the available clinical evidence regarding the utilization of AEFs in glioblastoma, this article provides essential information regarding the supposed therapeutic mechanism as well as modes of potential tumor resistance to such novel therapy, delineating future perspectives regarding basic science research on the issue.

Serum testosterone levels are generally reported to be lower in male rheumatoid arthritis (RA) patients, but it is not determined if a deficiency may occur before clinical onset of disease (pre-RA). Lower testosterone levels were recently reported in males many years before RA onset but were predictive only of rheumatoid factor (RF)—negative disease. A preceding prospective study did not reveal androgenic-anabolic hormone association with risk of RA in men or women. This cohort study of males analyzed baseline serum levels of gonadal and adrenocortical steroids, luteinizing hormone, and prolactin in 18 pre-RA versus 72 matched non-RA control (CN) subjects. Findings in males were compared to those in female pre-RA and CN subjects in the same cohort, and sex differences were analyzed. Steroidal and hormonal levels, including total testosterone, were similar between male study groups. In females, mean (±SE) serum androstenedione (nmol/L) was slightly (P = 0.048) lower in 36 pre-RA (6.7 ± 0.36) than 144 CN (7.6 ± 0.22). With the exception of 3 partial correlations of hormonal variables observed to differ between pre-RA versus CN subjects, the patterns were similar overall. However, partial correlations of hormonal variables differed frequently by sex, both within and between study groups.

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Neurocutaneous melanocytosis (NCM) is a rare disease characterized by excessive proliferation of melanocytes in the leptomeninges and brain parenchyma, primarily occurring in children with large or giant congenital melanocytic nevi (LCMN) or multiple congenital melanocytic nevi. [1][2][3] LCMN is diagnosed in an estimated 1/20 000-1/50 000 births with NCM identified in up to 30% of these individuals. 1,3 On magnetic resonance imaging (MRI), NCM can be identified as multifocal T1 shortening involving the brain or spine or diffuse leptomeningeal thickening. 4,5 Clinical manifestations of NCM are variable, ranging from asymptomatic melanocytosis to multiple cranial neuropathies, seizures, and symptomatic hydrocephalus. [1][2][3][4][5] Large or giant congenital melanocytic nevi or multiple congenital melanocytic nevi and NCM are associated with risk of cutaneous and central nervous system (CNS) melanoma. 1,6,7 In patients with LCMN or multiple congenital melanocytic nevi, an abnormal MRI represents the most significant predictor for development of melanoma. 7