Is a spice missing from the recipe? The intra-cellular localization of vanillin biosynthesis needs further investigations.

Vanillin is the most popular flavor compound in the world. Substantial effort were made in the last decades to completely elucidate the metabolic pathway that leads to vanillin in plants, with some controversy reported. In V. planifolia, vanillin biosynthesis occurs in plastids or in redifferentiated-plastids termed ''phenyloplasts''. More recently, it was shown that all enzymes required for the conversion of [14 C]-phenylalanine to [14 C]-vanillin-glucoside are confined within that organelle. However, knowing that some of these enzymes are cytosolic or ER-membrane bound in most plant species, it raises questions on the interpretation of data obtained from the technique used and on the true localization of the biosynthetic enzymes in V.planifolia. In addition, intense debate has emerged about the real participation of last enzyme of the pathway involving vanillin synthase (VpVAN) in the direct conversion of ferulic acid to vanillin. With the discovery of another enzyme capable of this conversion and the lack of activity of VpVAN in vitro, further disagreement emerged. One additional challenge to VpVAN being necessary and sufficient is that the transcript for this protein is abundant invarious non-vanillin-producing tissues of the vanilla plant. In this viewpoint, we discuss the findings surrounding the cellular-localization and activity of enzymes of vanillin biosynthesis. This will help to further understand the pathway and urge for additional research study to resolve the debate.

Therapeutic Inhibition of Staphylococcus aureus ArlRS Two-Component Regulatory System Blocks Virulence.

Staphylococcus aureus is a common cause of severe infections, and its widespread antibiotic resistance necessitates search for alternative therapies, such as inhibition of virulence. As S. aureus produces multiple individual virulence factors, inhibition of an entire regulatory system might provide better effects than targeting each virulence factor separately. Herein, we describe two novel inhibitors of S. aureus two-component regulatory system ArlRS: 3,4'-dimethoxyflavone and homopterocarpin. Unlike other putative ArlRS inhibitors previously identified, these two compounds were effective and specific. In vitro kinase assays indicated that 3,4'-dimethoxyflavone directly inhibits ArlS autophosphorylation, while homopterocarpin did not exhibit such effect, suggesting that two inhibitors work through distinct mechanisms. Application of the inhibitors to methicillin-resistant S. aureus (MRSA) in vitro blocked ArlRS signaling, inducing an abnormal gene expression pattern that was reflected in changes at the protein level, enhanced sensitivity to oxacillin, and led to the loss of numerous cellular virulence traits, including the ability to clump, adhere to host ligands, and evade innate immunity. The pleiotropic antivirulence effect of inhibiting a single regulatory system resulted in a marked therapeutic potential, demonstrated by the ability of inhibitors to decrease severity of MRSA infection in mice. Altogether, this study demonstrated the feasibility of ArlRS inhibition as anti-S. aureus treatment, and identified new lead compounds for therapeutic development.

Classifying continuous, real-time e-nose sensor data using a bio-inspired spiking network modelled on the insect olfactory system.

In many application domains, conventional e-noses are frequently outperformed in both speed and accuracy by their biological counterparts. Exploring potential bio-inspired improvements, we note a number of neuronal network models have demonstrated some success in classifying static datasets by abstracting the insect olfactory system. However, these designs remain largely unproven in practical settings, where sensor data is real-time, continuous, potentially noisy, lacks a precise onset signal and accurate classification requires the inclusion of temporal aspects into the feature set. This investigation therefore seeks to inform and develop the potential and suitability of biomimetic classifiers for use with typical real-world sensor data. Taking a generic classifier design inspired by the inhibition and competition in the insect antennal lobe, we apply it to identifying 20 individual chemical odours from the timeseries of responses of metal oxide sensors. We show that four out of twelve available sensors and the first 30 s (10%) of the sensors' continuous response are sufficient to deliver 92% accurate classification without access to an odour onset signal. In contrast to previous approaches, once training is complete, sensor signals can be fed continuously into the classifier without requiring discretization. We conclude that for continuous data there may be a conceptual advantage in using spiking networks, in particular where time is an essential component of computation. Classification was achieved in real time using a GPU-accelerated spiking neural network simulator developed in our group.

Reaching control of a full-torso, modelled musculoskeletal robot using muscle synergies emergent under reinforcement learning.

'Anthropomimetic' robots mimic both human morphology and internal structure-skeleton, muscles, compliance and high redundancy--thus presenting a formidable challenge to conventional control. Here we derive a novel controller for this class of robot which learns effective reaching actions through the sustained activation of weighted muscle synergies, an approach which draws upon compelling, recent evidence from animal and human studies, but is almost unexplored to date in the musculoskeletal robot literature. Since the effective synergy patterns for a given robot will be unknown, we derive a reinforcement-learning approach intended to allow their emergence, in particular those patterns aiding linearization of control. Using an extensive physics-based model of the anthropomimetic ECCERobot, we find that effective reaching actions can be learned comprising only two sequential motor co-activation patterns, each controlled by just a single common driving signal. Factor analysis shows the emergent muscle co-activations can be largely reconstructed using weighted combinations of only 13 common fragments. Testing these 'candidate' synergies as drivable units, the same controller now learns the reaching task both faster and better.

A comparative study of the neuropsychiatric and neurocognitive phenotype in two microdeletion syndromes: velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes.

PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS. METHODS: Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions. RESULTS: We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders. CONCLUSION: These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS.

The effects of selenium and the GPx-1 selenoprotein on the phosphorylation of H2AX.

BACKGROUND: Significant data supports the health benefits of selenium although supplementation trials have yielded mixed results. GPx-1, whose levels are responsive to selenium availability, is implicated in cancer etiology by human genetic data. Selenium's ability to alter the phosphorylation of the H2AX, a histone protein that functions in the reduction of DNA damage by recruiting repair proteins to the damage site, following exposure to ionizing radiation and bleomycin was investigated. METHODS: Human cell lines that were either exposed to selenium or were transfected with a GPx-1 expression construct were exposed to ionizing radiation or bleomycin. Phosphorylation of histone H2AX was quantified by flow cytometry and survival by the MTT assay. Phosphorylation of the Chk1 and Chk2 checkpoint proteins was quantified by western blotting. RESULTS: In colon-derived cells, selenium increases GPx-1 and attenuated H2AX phosphorylation following genotoxic exposures while the viability of these cells was unaffected. MCF-7 cells and transfectants that express high GPx-1 levels were exposed to ionizing radiation and bleomycin, and H2AX phosphorylation and cell viability were assessed. GPx-1 increased H2AX phosphorylation and viability following the induction of DNA damage while enhancing the levels of activated Chk1 and Chk2. CONCLUSIONS: Exposure of mammalian cells to selenium can alter the DNA damage response and do so by mechanisms that are dependent and independent of its effect on GPx-1. GENERAL SIGNIFICANCE: Selenium and GPx-1 may stimulate the repair of genotoxic DNA damage and this may account for some of the benefits attributed to selenium intake and elevated GPx-1 activity.

Negative effects of habitat loss on survival of migrant Warblers in a forest mosaic.

Habitat loss and fragmentation in forested landscapes often negatively affect animal abundance; however, whether these factors also affect fitness is not well known. We hypothesized that observed decreases in bird occurrence and abundance in landscapes with harvested forests are associated with reduced apparent survival of adults. We defined apparent survival as an estimate of survival that accounts for an imperfect resighting probability, but not permanent emigration (i.e., dispersal). We examined the association between spatially extensive habitat loss and apparent survival of males of 2 Neotropical migrant species, Blackburnian Warbler (Dendroica fusca) and Black-Throated Green Warbler (D. virens), over 7 years in the Greater Fundy Ecosystem, New Brunswick, Canada. We estimated apparent survival among and within breeding seasons. We quantified amount of habitat in the context of individual species. In this landscape, boundaries between land-cover types are gradual rather than clearly identifiable and abrupt. Estimated apparent within-season survival of both species decreased as a function of amount of habitat within a 2000-m radius; survival was approximately 12 times (95% CI 3.43-14) greater in landscapes with 85% habitat than in landscapes with 10% habitat. Apparent annual survival also decreased as a function of amount of habitat within a 100-m radius. Over the range of habitat amount, apparent annual survival decreased 15% (95% CI 7-29%) as the amount of habitat decreased. Our results suggest that reduced species occurrence in landscapes with low proportions of habitat is due partly to lower apparent survival at these sites. This mechanism operates both directly (i.e., via effects on mortality or dispersal during breeding) and possibly through indirect effects during the nonbreeding season. Habitat loss was associated not only with a lower number of individuals, but also with lower survival of those individuals.

Resolution of severe obsessive--compulsive disorder after a small unilateral nondominant frontoparietal infarct.

Obsessive--compulsive disorder (OCD) is a disabling neuropsychiatric disorder, which rarely spontaneously remits. We present a case of a patient suffering with severe OCD whose symptoms disappeared immediately following a small right posterior frontoparietal infarct. We speculate that the lesion modulated the cortical-subcortical circuits, likely through a change in input into in the dorsolateral prefrontal cortex. This could have implications regarding surgical targeting in OCD.

Aminoglycoside-induced vestibular injury: maintaining a sense of balance.

OBJECTIVE: To describe the mechanism and risk factors for the development of aminoglycoside-induced vestibular injury and discuss their implications for therapeutic monitoring of aminoglycoside antibiotics. DATA SOURCES: A MEDLINE search (1975-January 2008) was performed to identify literature on aminoglycoside-induced vestibular injury and risk factors associated with this outcome and their impact on therapeutic drug monitoring. Additional references were identified through review of bibliographies of identified articles. STUDY SELECTION AND DATA EXTRACTION: Data on the mechanisms of vestibular toxicity and its development in association with aminoglycoside exposure were extracted from identified references. DATA SYNTHESIS: The mechanism leading to the development of irreversible vestibular injury from exposure to aminoglycosides appears to be through the excessive production of oxidative free radicals. This production and subsequent toxicity appears to be a time-dependent process and is unrelated to dose or serum concentration. For similarly designed studies, the pooled incidence of vestibular toxicity is 10.9% for gentamicin, 7.4% for amikacin, 3.5% for tobramycin, and 1.1% for netilmicin. Current evidence suggests that this form of drug toxicity is not restricted to traditionally dosed systemic therapy, since intraperitoneal administration, high-dose once-daily administration, topical inhalation, and eardrop administration have all been associated with the development of this adverse outcome. CONCLUSIONS: Given the lack of association between serum concentrations and vestibulotoxicity, it is imperative for the pharmacist to interview the patient and not focus solely on maintaining target range drug concentrations. Minimizing the duration of exposure to aminoglycosides is recommended to reduce the risk from this form of drug toxicity.

Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer.

Studies of families who segregate BRCA2 mutations have found that men who carry disease-associated mutations have an increased risk of prostate cancer, particularly early-onset disease. A study of sporadic prostate cancer in the UK reported a prevalence of 2.3% for protein-truncating BRCA2 mutations among patients diagnosed at ages < or =55 years, highlighting the potential importance of this gene in prostate cancer susceptibility. To examine the role of protein-truncating BRCA2 mutations in relation to early-onset prostate cancer in a US population, 290 population-based patients from King County, Washington, diagnosed at ages <55 years were screened for germline BRCA2 mutations. The coding regions, intron-exon boundaries, and potential regulatory elements of the BRCA2 gene were sequenced. Two distinct protein-truncating BRCA2 mutations were identified in exon 11 in two patients. Both cases were Caucasian, yielding a mutation prevalence of 0.78% (95% confidence interval (95%CI) 0.09-2.81%) and a relative risk (RR) of 7.8 (95%CI 1.8-9.4) for early-onset prostate cancer in white men carrying a protein-truncating BRCA2 mutation. Results suggest that protein-truncating BRCA2 mutations confer an elevated RR of early-onset prostate cancer. However, we estimate that <1% of early-onset prostate cancers in the general US Caucasian population can be attributed to these rare disease-associated BRCA2 mutations.

Islet allograft rejection by contact-dependent CD8+ T cells: perforin and FasL play alternate but obligatory roles.

Though CD8(+) T lymphocytes are important cellular mediators of islet allograft rejection, their molecular mechanism of rejection remains unidentified. Surprisingly, while it is generally assumed that CD8(+) T cells require classic cytotoxic mechanisms to kill grafts in vivo, neither perforin nor FasL (CD95L) are required for acute islet allograft rejection. Thus, it is unclear whether such contact-dependent cytotoxic pathways play an essential role in islet rejection. Moreover, both perforin and CD95L have been implicated in playing roles in peripheral tolerance, further obscuring the role of these effector pathways in rejection. Therefore, we determined whether perforin and/or FasL (CD95L) were required by donor MHC-restricted ('direct') CD8(+) T cells to reject islet allografts in vivo. Islet allograft rejection by primed, alloreactive CD8(+) T cells was examined independently of other lymphocyte subpopulations via adoptive transfer studies. Individual disruption of T-cell-derived perforin or allograft Fas expression had limited impact on graft rejection. However, simultaneous disruption of both pathways prevented allograft rejection in most recipients despite the chronic persistence of transferred T cells at the graft site. Thus, while there are clearly multiple cellular pathways of allograft rejection, perforin and FasL comprise alternate and necessary routes of acute CD8(+) T-cell-mediated islet allograft rejection.

Angioplasty for intracranial artery stenosis.

BACKGROUND: Intracranial artery stenosis causes up to 10% of all ischaemic strokes. The rate of recurrent vascular ischaemic events is very high. Angioplasty with or without stent placement is a feasible procedure to dilate the vessel affected. However, its safety and efficacy have not been systematically studied. OBJECTIVES: To determine the efficacy and safety of angioplasty combined with best medical treatment compared with best medical treatment alone in patients with acute ischaemic stroke or transient ischaemic attack (TIA) resulting from intracranial artery stenosis for preventing recurrent ischaemic strokes, death, and vascular events. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched March 2006). In addition we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to March 2006), EMBASE (1980 to February 2006) and Science Citation Index (1945 to March 2006). To identify further published, unpublished and ongoing trials we searched reference lists of relevant articles and contacted authors and experts in the field. SELECTION CRITERIA: Randomised or otherwise controlled studies comparing best medical care plus angioplasty of the intracranial cerebral arteries, with or without stent placement, with best medical care alone. Studies were only included if data for clinical significant endpoints such as recurrent ischaemic stroke, haemorrhagic stroke and death were available. DATA COLLECTION AND ANALYSIS: Two review authors selected trials for inclusion, and independently assessed trial quality and extracted data. Calculation of relative treatment effects with subgroup analysis was done if possible. MAIN RESULTS: No randomised controlled trials were found. There were 79 articles of interest consisting of open-label case series with three or more cases. The safety profile of the procedure showed an overall perioperative rate of stroke of 7.9% (95% confidence intervals (CI) 5.5% to 10.4%), perioperative death of 3.4% (95% CI 2.0% to 4.8%), and perioperative stroke or death of 9.5% (95% CI 7.0% to 12.0%). No comments can be made on the effectiveness of the procedure. AUTHORS' CONCLUSIONS: At present there is insufficient evidence to recommend angioplasty with or without stent placement in routine practice for the prevention of stroke in patients with intracranial artery stenosis. The descriptive studies show that the procedure is feasible although carries a significant morbidity and mortality risk. Evidence from randomised controlled trials is needed to assess the safety of angioplasty and its effectiveness in preventing recurrent stroke.

Parathyroid hormone hormone-related protein and the PTH receptor regulate angiogenesis of the skin.

In developing organs, parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PPR) signaling inhibits proliferation and differentiation of mesenchyme-derived cell types resulting in control of morphogenic events. Previous studies using PPR agonists and antagonists as well as transgenic overexpression of the PPR ligand PTHrP have suggested that this ligand receptor combination might regulate the anagen to catagen transition of the hair cycle. To further understand the precise role of PTHrP and the PPR in the hair cycle, we have evaluated hair growth in the traditional K14-PTHrP (KrP) and an inducible bitransgenic PTHrP mice. High levels of PTHrP trangene expression limited to the adult hair cycle resulted in the production of shorter hair shafts. Morphometric analysis indicated that reduced proliferation in the matrix preceded the appearance of thinner hair follicles and shafts during late anagen. CD31 staining revealed that the late anagen hair follicles of the KrP mice were surrounded by reduced numbers of smaller diameter capillaries as compared to controls. Moreover, the fetal skins of the PTHrP and PPR knockouts (KOs) had reciprocal increases in the length, diameter, and density of capillaries. Finally, crossing the KrP transgene onto a thrombospondin-1 KO background reversed the vascular changes as well as the delayed catagen exhibited by these mice. Taken together, these findings suggest that PTHrP's influence on the hair cycle is mediated in part by its effects on angiogenesis.

The effect of deep brain stimulation on quality of life in movement disorders.

Deep brain stimulation (DBS) is a viable treatment alternative for patients with Parkinson's disease (PD), essential tremor (ET), dystonia, and cerebellar outflow tremors. When poorly controlled, these disorders have detrimental effects on the patient's health related quality of life (HRQoL). Instruments that measure HRQoL are useful tools to assess burden of disease and the impact of therapeutic interventions on activities of daily living, employment, and other functions. We systematically and critically reviewed the literature on the effects of DBS on HRQoL in PD, ET, dystonia, and cerebellar outflow tremor related to multiple sclerosis.

Seabirds as indicators of changes in marine ecosystems: ecological monitoring on Machias Seal Island.

Changes in marine ecosystems can be manifested in many different ways, on different temporal and spatial scales. Seabirds are top consumers in marine foodwebs and offer opportunities to detect and assess the biological effects of changes in physical parameters (sea-surface temperature [SST], salinity, depth of thermocline etc.) of the marine ecosystem. We compare six-eight years' of data on the biology (diet, and breeding success) of four species of seabird (arctic tern Sterna paradisaea and common tern S. hirundo, which feed at the sea surface; and Atlantic puffin Fratercula antica and razorbill Alca torda, which dive 30-60 m for their prey) breeding on Machias Seal Island (MSI) in the Bay of Fundy with both our own meteorological and oceanographic measurements, and with standard measurements from conventional sources. These are compared with fisheries data on changes in the main prey of all the seabirds concerned (juvenile or '0-group' herring Clupea harengus) which are the most direct link between the seabirds and the physical properties of the marine system. We explore relationships between seabird productivity and diet, and other aspects of both herring biology (larval surveys, and fat content) and oceanography (SST data from the island, and remotely sensed data from the entrance to the Bay of Fundy). Timing of laying by puffins followed SST variation at neither the local (MSI) nor regional scales, but at the scale of the North Atlantic, following the trend of populations breeding off northern Norway. The proportion of herring in the diet of terns over 6 years varied inversely with herring larval abundance the previous fall; this relationship was not statistically significant in the puffin and razorbill. A major new finding is the considerable (approximately 50%) inter-annual variation in the energy density (fat content) of juvenile herring that are the main seabird prey; breeding success of both species of tern varied in parallel with the energy density of juvenile herring in the diet until the last two years of the study, when sandlance (Ammodytes sp.) and euphausid shrimp predominated in the diet. Our long-term research approach combines traditional population monitoring (of numbers of breeding birds) with demographic, behavioural and environmental monitoring, to provide new understanding of the marine ecosystem as well as of seabirds.

General surgery in a district hospital in Tajikistan: clinical impact of a partnership between visiting volunteers and host specialists.

After the collapse of the Soviet Union and 5 years of civil war, health care services in Tajikistan are in disarray. Nongovernmental organizations are playing a key role in recovery programs. A group of volunteer physicians from the West went to Khorog General Hospital in the Pamiri mountains to establish a dialogue with their physician counterparts, recommend evidence-based best practice appropriate for local conditions, and reintroduce a culture of continuing medical education. The arrangements included a group visit to Khorog for 3 weeks annually over 3 years. In this article we describe the experiences of the 2 general surgeons attached to the group in the second year and the status of the partnership 1 year later.

National level promotion of physical activity: results from England's ACTIVE for LIFE campaign.

STUDY OBJECTIVE: To assess the impact of a national campaign on awareness of the campaign, change in knowledge of physical activity recommendations and self reported physical activity. DESIGN: three year prospective longitudinal survey using a multi-stage, cluster random probability design to select participants. SETTING: England. PARTICIPANTS: A nationally representative sample of 3189 adults aged 16-74 years. MAIN OUTCOME MEASURES: Awareness of the advertising element of the campaign, changes in knowledge of physical activity recommendations for health and self reported physical activity. RESULTS: 38% of participants were aware of the main advertising images, assessed six to eight months after the main television advertisement. The proportion of participants knowledgeable about moderate physical activity recommendations increased by 3.0% (95% CI: 1.4%, 4.5%) between waves 1 and 2 and 3.7% (95% CI: 2.1%, 5.3%) between waves 1 and 3. The change in proportion of active people between baseline and waves 1 and 2 was -0.02 (95% CI: -2.0 to +1.7) and between waves 1 and 3 was -9.8 (-7.9 to -11.7). CONCLUSION: The proportion of participants who were knowledgeable about the new recommendations, increased significantly after the campaign. There was however, no significant difference in knowledge by awareness of the main campaign advertisement. There is no evidence that ACTIVE for LIFE improved physical activity, either overall or in any subgroup.

Glutathione peroxidase and viral replication: implications for viral evolution and chemoprevention.

It is likely that several of the biological effects of selenium are due to its effects on selenoprotein activity. While the effects of the anti-oxidant selenoprotein glutathione peroxidase (GPx) on inhibiting HIV activation have been well documented, it is clear that increased expression of this enzyme can stimulate the replication and subsequent appearance of cytopathic effects associated with an acutely spreading HIV infection. The effects of GPx on both phases of the viral life cycle are likely mediated via its influence on signaling molecules that use reactive oxygen species, and similar influences on signaling pathways may account for some of the anti-cancer effects of selenium. Similarly, selenium can alter mutagenesis rates in both viral genomes and the DNA of mammalian cells exposed to carcinogens. Comparisons between the effects of selenium and selenoproteins on viral infections and carcinogenesis may yield new insights into the mechanisms of action of this element.

Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA.

Selenocysteine (Sec) tRNA (tRNA([Ser]Sec)) serves as both the site of Sec biosynthesis and the adapter molecule for donation of this amino acid to protein. The consequences on selenoprotein biosynthesis of overexpressing either the wild type or a mutant tRNA([Ser]Sec) lacking the modified base, isopentenyladenosine, in its anticodon loop were examined by introducing multiple copies of the corresponding tRNA([Ser]Sec) genes into the mouse genome. Overexpression of wild-type tRNA([Ser]Sec) did not affect selenoprotein synthesis. In contrast, the levels of numerous selenoproteins decreased in mice expressing isopentenyladenosine-deficient (i(6)A(-)) tRNA([Ser]Sec) in a protein- and tissue-specific manner. Cytosolic glutathione peroxidase and mitochondrial thioredoxin reductase 3 were the most and least affected selenoproteins, while selenoprotein expression was most and least affected in the liver and testes, respectively. The defect in selenoprotein expression occurred at translation, since selenoprotein mRNA levels were largely unaffected. Analysis of the tRNA([Ser]Sec) population showed that expression of i(6)A(-) tRNA([Ser]Sec) altered the distribution of the two major isoforms, whereby the maturation of tRNA([Ser]Sec) by methylation of the nucleoside in the wobble position was repressed. The data suggest that the levels of i(6)A(-) tRNA([Ser]Sec) and wild-type tRNA([Ser]Sec) are regulated independently and that the amount of wild-type tRNA([Ser]Sec) is determined, at least in part, by a feedback mechanism governed by the level of the tRNA([Ser]Sec) population. This study marks the first example of transgenic mice engineered to contain functional tRNA transgenes and suggests that i(6)A(-) tRNA([Ser]Sec) transgenic mice will be useful in assessing the biological roles of selenoproteins.