Insights into the mitochondrial signaling pathway: what lessons for chemotherapy?

Mitochondria are potent integrators/coordinators of apoptosis signaling pathways. Indeed, under physiological conditions, the initiation of apoptosis leads to the accumulation of second messengers that converge on mitochondria. In response, these organelles undergo a membrane permeabilization, presumably due to the opening of protein channels, culminating in the release of proapoptotic proteins into the cytosol.

Computed tomography of acute small bowel obstruction: pictorial essay.

In many patients, the diagnosis of SBO can often be made by a combination of clinical history, physical examination and plain radiographs. However, in many cases, the diagnosis of SBO may be difficult. Abdominal radiographs are limited in their ability to diagnose SBO and, more particularly, to identify a specific underlying cause.

Quantification of human ooplasmic mitochondria.

It is likely that there is an association between the fitness of mitochondria and their ability to support normal cellular function. Oocytes are greatly enriched in the number of mitochondria as they support essential developmental processes such as oocyte maturation and embryonic development, while their replication is deferred until gastrulation. The mitochondrial DNA (mtDNA) copy number in 87 human oocytes from 29 patients was evaluated after DNA extraction and real-time quantitative polymerase chain reaction (PCR).

Issues and strategies in the DNA identification of World Trade Center victims.

Identification of the nearly 3000 victims of the World Trade Center attack, represented by about 15,000 body parts, rests heavily on DNA. Reference DNA profiles are often from relatives rather than from the deceased themselves. With so large a set of victims, coincidental similarities between non-relatives abound.

Psychometrically matched visual-processing tasks in schizophrenia spectrum disorders.

Patients with schizophrenia show deficits in visual perception and working memory, but the relationship between these deficits has not been characterized with psychometrically matched tasks. The authors administered 2 visual discrimination and 6 recognition tasks to 43 schizophrenia spectrum patients and 22 nonpsychiatric subjects. When performing difficulty-matched tasks, spectrum subjects showed more severe impairments for motion compared with form processing.

Feminizing chicks: a model for avian sex determination based on titration of Hint enzyme activity and the predicted structure of an Asw-Hint heterodimer.

Background: In birds and some lizards, females are heterogametic with a ZW karyotype, while males are ZZ homogametes. The molecular basis for sexual differentiation in birds is unknown: arguments exist for doses of Z masculinizing chicks and for W information feminizing. ASW was identified as a tandemly repeated gene conserved on avian W chromosomes that is expressed in early female development and appears to be an inactive form of avian Z-encoded HINT.

Artificial-infection protocols allow immunodetection of novel Borrelia burgdorferi antigens suitable as vaccine candidates against Lyme disease.

Vaccination with recombinant outer surface protein A (OspA) from Borrelia burgdorferi provides excellent antibody-mediated protection against challenge with the pathogen in animal models and in humans. However, the bactericidal antibodies are ineffective in the reservoir host, since OspA is expressed by spirochetes only in the vector, but rarely, if at all, in mammals. Using an artificially generated immune serum (anti-10(8) spirochetes) with high protective potential for prophylactic and therapeutic treatment, we have now isolated from an expression library of B.

Factors associated with development of speech production skills in children implanted by age five.

Objective: This study investigated speech production outcomes and the factors influencing the outcomes in children who had 4 to 6 yr of experience with a multichannel cochlear implant. Production variables examined included speech intelligibility, accuracy of consonant and vowel production, percentage of plosives and fricatives produced, duration of sentences, percentage of time involved in communication breakdowns during a communication sample, and responses to a speech usage questionnaire.

Design: 181 children between the ages of 8 and 9 yr who received a multichannel cochlear implant before age 5 yr participated as subjects.

Factors associated with development of speech perception skills in children implanted by age five.

Objective: This study investigated factors contributing to speech perception outcomes in children with prelingual deafness after 4 to 7 yr of multichannel cochlear implant use. The analysis controlled for the effects of child, family and implant characteristics so that educational factors most conducive to maximum implant benefit could be identified.

Design: One hundred eighty-one 8- and 9-yr-old children from across the US and Canada who received a cochlear implant by age 5 were administered a battery of speech perception tests.

Background and educational characteristics of prelingually deaf children implanted by five years of age.

Purpose: This study documents child, family and educational characteristics of a large representative sample of 8- to 9-yr-old prelingually deaf children who received a cochlear implant by 5 yr of age. Because pre-existing factors such as the child's gender, family characteristics, additional handicaps, age at onset of deafness and at implant, may affect postimplant outcomes, these variables must be accounted for before the impact of educational factors on performance with an implant can be adequately determined. Classroom variables that may affect postimplant outcomes include placement in public or private, mainstream or special education, oral or total communication environments.

Personality dimensions in schizophrenia: associations with symptoms and coping.

While individual differences in personality exist among persons with schizophrenia and predate the onset of illness, less is known about their relationship to outcome. This study examined whether levels of three personality dimensions-neuroticism, extraversion, and agreeableness-are associated with symptomatology and coping in persons with schizophrenia. Symptom, personality, and coping measures were obtained for 59 participants with schizophrenia.

Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding.

The FHIT gene is inactivated early in the development of many human tumors, and Fhit-deficient mice have increased cancer incidence. Viral reexpression of Fhit kills Fhit-deficient cells by induction of apoptosis. Fhit, a member of branch 2 of the histidine-triad superfamily of nucleoside monophosphate hydrolases and transferases, is a diadenosine polyphosphate hydrolase, the active-site histidine of which is not required for tumor suppression.

Bcl-2 and Bax modulate adenine nucleotide translocase activity.

Bcl-2 is a prosurvival factor that reportedly prevents the nonspecific permeabilization of mitochondrial membranes, yet enhances specific ADP/ATP exchange by these organelles. Here, we show that Bcl-2 enhances the ADP/ATP exchange in proteoliposomes containing the purified adenine nucleotide translocase (ANT) in isolated mitochondria and mitoplasts, as well as in intact cells in which mitochondrial matrix ATP was monitored continuously using a specific luciferase-based assay system. Conversely, Bax, which displaces Bcl-2 from ANT in apoptotic cells, inhibits ADP/ATP exchange through a direct action on ANT.

Catalysis in the nitrilase superfamily.

Recently, we defined the nitrilase superfamily as consisting of 12 families of amidases, N-acyltransferases and presumptive amidases, in addition to the family of plant and bacterial nitrilases for which the superfamily was named. A novel Glu-Lys-Cys catalytic triad, found at the crystallographically defined Nit active site of worm NitFhit, was postulated to constitute the catalytic residues for all members of the superfamily. Recent experimental results confirm the essentiality of the catalytic triad residues and specify the biochemical functions of additional branches and sub-branches of the nitrilase superfamily.

Genotyping: the HLA system and embryo development.

The human major histocompatibility complex (MHC), in addition to its role in the regulation of cell-cell interactions in the immune response, also influences reproductive success. Human leukocyte antigen-G (HLA-G) is an MHC class I gene of particular interest in reproductive biology because of its specific expression on fetal cytotrophoblast cells, and its reported involvement both in protection of the developing fetus from destruction by the maternal immune response and in the prevention of maternal pre-eclampsia. HLA-G has 15 known alleles at the DNA level, and allelic frequency varies among ethnic groups.

Visual processing and neuropsychological function in schizophrenia and schizoaffective disorder.

Persons with schizophrenia and schizoaffective disorder exhibit deficits in both visual processing and neuropsychological tasks. Little is known, however, about whether these deficits are related to one another. We administered psychophysical tests of visual discrimination and recognition, and neuropsychological tests of abstract flexibility, verbal learning, visual memory, working memory and attention to 42 outpatients with stable but chronic schizophrenia or schizoaffective disorder.

Mitochondrial permeability transition as a novel principle of hepatorenal toxicity in vivo.

Atractyloside (Atr) binds to the adenine nucleotide translocator (ANT) and inhibits ANT-mediated ATP/ADP exchange on the inner mitochondrial membrane. In addition, Atr can trigger opening of a non-specific ion channel, within the ANT-containing permeability transition pore complex (PTPC), which is subject to redox regulation and inhibited by cyclosporin A (CsA). Here we show that the cytotoxic effects of Atr, both in vivo and in vitro, are determined by its capacity to induce PTPC opening and consequent mitochondrial membrane permeabilization (MMP).

Dnmt3L is a transcriptional repressor that recruits histone deacetylase.

The Dnmt3L protein belongs to the Dnmt3 family of DNA methyltransferases by virtue of its sequence homology in the plant homeodomain (PHD)-like motif. Dnmt3L is essential for the establishment of maternal genomic imprints and, given its lack of key methyltransferase motifs, is more likely to act as a regulator of methylation rather than as an enzyme that methylates DNA. Here, we show that Dnmt3L, like Dnmt3a and Dnmt3b, interacts both in vitro and in vivo with the histone deacetylase HDAC1.

Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.

HIT (histidine triad) proteins, named for a motif related to the sequence HphiHphiHphiphi (phi, a hydrophobic amino acid), are a superfamily of nucleotide hydrolases and transferases, which act on the alpha-phosphate of ribonucleotides, and contain a approximately 30 kDa domain that is typically either a homodimer of approximately 15 kDa polypeptides with two active-sites or an internally, imperfectly repeated polypeptide that retains a single HIT active site. On the basis of sequence, substrate specificity, structure, evolution, and mechanism, HIT proteins can be classified into the Hint branch, which consists of adenosine 5'-monophosphoramide hydrolases, the Fhit branch, which consists of diadenosine polyphosphate hydrolases, and the GalT branch, which consists of specific nucleoside monophosphate transferases, including galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylyl sulfate:phosphate adenylytransferase. At least one human representative of each branch is lost in human diseases.

Conflict, compromise formation, and structural theory.

Evidence is put forth to support the previously presented view (Brenner 1994, 1998) that present knowledge of mental conflict and compromise formation renders invalid the widely accepted theory of mind as functionally separable structures called id, ego, and superego. The nature, origins, and timing of conflict and compromise formation in mental development are discussed, as well as their relation to psychic trauma.

Control of dinucleoside polyphosphates by the FHIT-homologous HNT2 gene, adenine biosynthesis and heat shock in Saccharomyces cerevisiae.

Background: The FHIT gene is lost early in the development of many tumors. Fhit possesses intrinsic ApppA hydrolase activity though ApppA cleavage is not required for tumor suppression. Because a mutant form of Fhit that is functional in tumor suppression and defective in catalysis binds ApppA well, it was hypothesized that Fhit-substrate complexes are the active, signaling form of Fhit.

The adenine nucleotide translocator in apoptosis.

Alteration of mitochondrial membrane permeability is a central mechanism leading invariably to cell death, which results, at least in part, from the opening of the permeability transition pore complex (PTPC). Indeed, extended PTPC opening is sufficient to trigger an increase in mitochondrial membrane permeability and apoptosis. Among the various PTPC components, the adenine nucleotide translocator (ANT) appears to act as a bi-functional protein which, on the one hand, contributes to a crucial step of aerobic energy metabolism, the ADP/ATP translocation, and on the other hand, can be converted into a pro-apoptotic pore under the control of onco- and anti-oncoproteins from the Bax/Bcl-2 family.