Glutathione peroxidase 4: a new player in neurodegeneration?

Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippocampal and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity.

The mitochondrial RNA granule modulates manganese-dependent cell toxicity.

Prolonged manganese exposure causes manganism, a neurodegenerative movement disorder. The identity of adaptive and nonadaptive cellular processes targeted by manganese remains mostly unexplored. Here we study mechanisms engaged by manganese in genetic cellular models known to increase susceptibility to manganese exposure, the plasma membrane manganese efflux transporter SLC30A10 and the mitochondrial Parkinson's gene PARK2. We found that SLC30A10 and PARK2 mutations as well as manganese exposure compromised the mitochondrial RNA granule composition and function, resulting in disruption of mitochondrial transcript processing. These RNA granule defects led to impaired assembly and function of the mitochondrial respiratory chain. Notably, cells that survived a cytotoxic manganese challenge had impaired RNA granule function, thus suggesting that this granule phenotype was adaptive. CRISPR gene editing of subunits of the mitochondrial RNA granule, FASTKD2 or DHX30, as well as pharmacological inhibition of mitochondrial transcription-translation, were protective rather than deleterious for survival of cells acutely exposed to manganese. Similarly, adult Drosophila mutants with defects in the mitochondrial RNA granule component scully were safeguarded from manganese-induced mortality. We conclude that impairment of the mitochondrial RNA granule function is a protective mechanism for acute manganese toxicity.

Building bridges between natural and social science disciplines: a standardized methodology to combine data on ecosystem quality trends.

Despite a growing interest in interdisciplinary research, systematic ways of how to integrate data from different disciplines are still scarce. We argue that successful resource management relies on two key data sources: natural science data, which represents ecosystem structure and processes, and social science data, which describes people's perceptions and understanding. Both are vital, mutually complementing information sources that can underpin the development of feasible and effective policies and management interventions. To harvest the added value of combined knowledge, a uniform scaling system is needed. In this paper, we propose a standardized methodology to connect and explore different types of quantitative data from the natural and social sciences reflecting temporal trends in ecosystem quality. We demonstrate this methodology with different types of data such as fisheries stocks and mangrove cover on the one hand and community's perceptions on the other. The example data are collected from three United Nations Educational Scientific and Cultural Organization (UNESCO) Biosphere reserves and one marine park in Southeast Asia. To easily identify patterns of convergence or divergence among the datasets, we propose heat maps using colour codes and icons for language- and education-independent understandability. Finally, we discuss the limitations as well as potential implications for resource management and the accompanying communication strategies. This article is part of the theme issue 'Nurturing resilient marine ecosystems'.

UT-A urea transporter protein in heart: increased abundance during uremia, hypertension, and heart failure.

Urea transporters have been cloned from kidney medulla (UT-A) and erythrocytes (UT-B). We determined whether UT-A proteins could be detected in heart and whether their abundance was altered by uremia or hypertension or in human heart failure. In normal rat heart, bands were detected at 56, 51, and 39 kDa. In uremic rats, the abundance of the 56-kDa protein increased 1.9-fold compared with pair-fed, sham-operated rats, whereas the 51- and 39-kDa proteins were unchanged. We also detected UT-A2 mRNA in hearts from control and uremic rats. Because uremia is accompanied by hypertension, the effects of hypertension per se were studied in uninephrectomized deoxycorticosterone acetate salt-treated rats, where the abundance of the 56-kDa protein increased 2-fold versus controls, and in angiotensin II-infused rats, where the abundance of the 56 kDa protein increased 1.8-fold versus controls. The 51- and 39-kDa proteins were unchanged in both hypertensive models. In human left ventricle myocardium, UT-A proteins were detected at 97, 56, and 51 kDa. In failing left ventricle (taken at transplant, New York Heart Association class IV), the abundance of the 56-kDa protein increased 1.4-fold, and the 51-kDa protein increased 4.3-fold versus nonfailing left ventricle (donor hearts). We conclude that (1) multiple UT-A proteins are detected in rat and human heart; (2) the 56-kDa protein is upregulated in rat heart in uremia or models of hypertension; and (3) the rat results can be extended to human heart, where 56- and 51-kDa proteins are increased during heart failure.

Diesel exhaust particles suppress macrophage function and slow the pulmonary clearance of Listeria monocytogenes in rats.

In this study, we tested the hypothesis that exposure to diesel exhaust particles (DEP) may increase susceptibility of the host to pulmonary infection. Male Sprague-Dawley rats received a single dose of DEP (5 mg/kg), carbon black (CB, 5 mg/kg), or saline intratracheally. Three days later, the rats were inoculated intratracheally with approximately 5,000 Listeria monocytogenes and sacrificed at 3, 5, and 7 days postinfection, and we determined the number of viable Listeria in the left lobe of lungs. The remaining lungs underwent bronchoalveolar lavage (BAL) and the retrieved BAL cells were identified and counted. Luminol-dependent chemiluminescence, a measure of reactive oxygen species (ROS) formation, generated by BAL cells was monitored and the levels of nitric oxide and tumor necrosis factor (TNF)-[alpha] produced by macrophages in culture were determined. At 7 days postinfection, we excised the lung-draining lymph nodes and phenotyped the lymphocyte subpopulations. Exposure of rats to DEP, but not to CB, decreased the clearance of Listeria from the lungs. Listeria-induced generation of luminol-dependent chemiluminescence by pulmonary phagocytes decreased by exposure to DEP but not CB. Similarly, Listeria-induced production of NO by alveolar macrophages was negated at 3, 5, and 7 days after inoculation in DEP-exposed rats. In contrast, CB exposure had no effect on Listeria-induced NO production at 3 days after infection and had a substantially smaller effect than DEP at later days. Exposure to DEP or CB resulted in enlarged lung-draining lymph nodes and increased the number and percentage of CD4(+) and CD8(+) T cells. These results showed that exposure to DEP decreased the ability of macrophages to produce antimicrobial oxidants in response to Listeria, which may play a role in the increased susceptibility of rats to pulmonary infection. This DEP-induced suppression is caused partially by chemicals adsorbed onto the carbon core of DEP, because impaired macrophage function and decreased Listeria clearance were not observed following exposure to CB.

A time course analysis of Stroop interference and facilitation: comparing normal individuals and individuals with schizophrenia.

Using randomized stimulus onset asynchrony (SOAs), the authors traced the time course of Stroop interference and facilitation in normal participants and participants with schizophrenia. Unlike earlier findings using blocked SOAs, singular peaks in interference, facilitation, or both occurred at particular SOAs. The peaks of normal participants and participants with schizophrenia differed. Findings are congruent with a model of Stroop performance that posits individual differences in processing speeds of target and nontarget stimulus dimensions, coupled with critical points in response selection. Participants with schizophrenia also showed more overall interference than normal control participants. A second experiment that added a temporal gap between the distractor word and target color obliterated Stroop effects only for individuals with schizophrenia. These findings provide a new empirical basis for models of Stroop effects. They are also consistent with hypotheses about the importance of the prefrontal cortex for working memory and prefrontal dysfunction in schizophrenia.

Stroop theory, memory, and prefrontal cortical functioning: reply to Cohen et al. (1997)

In this article, the authors respond to J. D. Cohen, K. O. Dunbar, D. M. Barch and T. S. Braver's (1997) comment on their target article. The present article (a) takes issue with the characterization given by Cohen et al. of the authors' approach as a classical speed-of-processing account of Stroop effects, (b) discusses the value and relevance of other theoretical concepts, such as traditional accounts of working memory and parallel distributed processing (PDP) approaches to Stroop effects, (c) further examines the possibility that the differences the authors observed in Experiment 2 between normal participants' performance and that of participants with schizophrenia may have been due to distractor stimulus degradation, particularly for participants with schizophrenia, and (d) argues for the relevance of the prefrontal cortex, as well as other brain areas, in accounting for their results. The authors conclude with a final theoretical question.

Manual and saccadic reaction time with constant and variable preparatory intervals in schizophrenia.

Saccadic reaction time (RT) has been shown to be unimpaired in schizophrenia. Could this be due to its not requiring controlled information processing? The authors gave 49 schizophrenia patients and 34 controls manual and saccadic RT tasks with preparatory intervals of 1, 3, and 5 s given in regular and irregular sequences. If saccades require mainly automatic processes, they should not be affected by variations in the preparatory interval that are mediated by controlled processing. The manual task showed typical slower RT and larger preparatory interval effects in patients than in controls. Although the saccadic task showed significant effects of both the preparatory interval and the preparatory interval on the preceding trial similar in kind to those in manual RT, there were no group differences in these or in RT. The results are attributed to greater stimulus-response compatibility in the saccadic task, which puts fewer demands on working memory.

Continued inhibitory capacity throughout adulthood: conceptual negative priming in younger and older adults.

Two negative priming experiments in older and younger adults are reported. Participants in Experiment 1, involving both positive and negative priming conditions, showed both types of priming. There were no significant differences between age groups. If anything, older participants showed more negative priming. In Experiment 2, involving only negative priming conditions, similar results were obtained. Our findings rule out possible effects of experimental conditions that episodic retrieval theorists have suggested might account for negative priming in older adults. Although our results may be consistent with an explanation of negative priming in older adults by an expansively specified theory of episodic retrieval, they are at least as consistent with the view that inhibitory processes are intact in older adults. In light of these findings, conflicting empirical results and alternative views of negative priming in older adults are examined.

Bilateral synchronous mixed tumors of the parotid glands.

Bilateral synchronous mixed tumors of the parotid glands are uncommon. In this case, they occurred in association with multiple benign tumors elsewhere in the body. The larger of the two parotid neoplasms was asymptomatic and undetected on physical examination, even after its presence had been established by computed tomographic scan.

Giant cholesterol cysts of the petrous apex.

The giant cholesterol cyst is a clinical entity distinct from cholesterol granulomas and other destructive lesions of the petrous bone. Preoperative assessment by computed tomographic scan and magnetic resonance imaging is extremely helpful. Attempts at total resection of the lesion are not necessary. Adequate surgical drainage may be established through the mastoid or middle fossa.

Autoradiographic studies of ethylenediurea distribution in woody plants.

Carbon-14-labelled ethylenediurea (EDU), synthesised from diethylenetriamine and (14)C-urea, was stem-injected into 2-year-old seedlings of sugar maple, white ash, flowering dogwood and flowering crabapple. At time intervals ranging from 1 h to 42 days after treatment, macroautoradiographs of leaf, stem and root tissue were made to determine relative distribution patterns of labelled chemical. Translocation of (14)C-EDU was very rapid and predominantly acropetal, especially after the first few hours. Maximum quantities of (14)C were found in leaf tissue approximately 7-10 days following injection, after which the intensity of the labelled chemical declined over the remainder of the study (42 days). Distribution patterns of (14)C-EDU were correlated with observed levels of protection afforded most plants when the chemical is injected 7 days before fumigation with ozone.

Antinociceptive effects of intrathecal 5-HT agonists in sheep.

OBJECTIVES: To examine the role of spinal 5-hydroxytryptamine (5-HT) binding sites in nociceptive processing in conscious sheep and to study the role of 5-HT agonists in mediating analgesia. STUDY DESIGN: Prospective controlled study. ANIMALS: Nine adult healthy female sheep (Swaledale, Swaledale-cross or Clun Forest) weighing 45-65 kg. METHODS: Intrathecal (IT) catheters were implanted at the cervical (n = 5) or lumbar (n = 4) level of the spinal cord under general anaesthesia. At least 1 week later, and at 1 week intervals thereafter, the effects of intrathecal Ringer's solution (control), xylazine (100 µg), 5-HT creatinine sulphate (200, 400 and 800 µg), RU24969 (200 µg), α-Methyl-5-HT and 1-(3-Chlorophenyl)-biguanide (CPBG) on the mechanical nociceptive threshold (MT) were studied. Results were plotted as mean variable versus time curves. Areas under portions of the curves (0-30 and 0-60 minutes) were measured and expressed as mean ± standard error. Differences between values for control and drug trials were examined using the two-tailed Student's t-test. RESULTS: Baseline values of MT were lower on the hind limbs than on the forelimbs. Intrathecal Ringer's solution did not alter MT in the cervical or lumbar region. Xylazine (100 µg) produced a characteristic elevation in MT between 5 and 60 + minutes. Lumbar IT injection of 5-HT (800 µg) raised the MT more than cervical injection, while cervical injection of RU24969 (200 µg) raised the MT more than lumbar administration. Cervical IT injection of α-Me-5-HT (500 µg) produced a marked and significant increase in MT while lumbar application had no effect. CPBG (500 µg) injection caused no significant effect on MT with either cervical or lumbar applications. CONCLUSIONS: The activation of 5-HT1 and 5-HT2 receptors particularly at the cervical level appears to be involved in spinal nociceptive processing in the sheep. CLINICAL RELEVANCE: These effects, which lasted about 60 minutes, may have an implication in the development of new analgesic strategies for animals.

Total temporal bone resection. A radical but life-saving procedure.

Traditional therapeutic approaches for malignancies of the temporal bone have produced unacceptably low survival figures. The morbidity and mortality associated with temporal bone cancer justify extensive surgery. Total temporal bone resection can be performed successfully in the hands of an experienced skull-base surgical team. By circumscribing the tumor rather than transgressing it, this procedure follows generally accepted principles of oncologic surgery. This procedure also shows promise in resection of extensive, carefully selected, recurrent benign tumors. We believe this approach offers hope for improved survival in patients with malignancy of the temporal bone. Further refinements in technique are suggested by each new case. Additional experience and long-term follow-up are needed to assess the efficacy of this procedure. The interest, expertise, and active participation of the operating room nursing team are critical to the success of this surgery. Ideally, not only intraoperative participation but also preoperative assessment and postoperative support should be routine. Close cooperation and extensive communication among the surgeons and nurses are essential.

Preservation of otologic homografts.

Techniques for preservation of homografts for replacement of tympanic membranes, ossicles, closure of the oval window, and canalplasty remain controversial. Review of 300 articles reveals no evidence opposing the harvesting of grafts from living patients or cadavers, or the prolonged storage of these materials in antibacterial solutions. It appears to be important to store the grafting material long enough to reduce antigenicity. Numerous techniques and materials are being used with success. Additional research on antigens, histologic fate of grafts, long-term success, and complications is essential to determine ideal grafting materials, preservatives, and techniques.

Urbanization, sectoral transformation, and the utilization of labor in Latin America.

PIP: The authors examine the relationships among economic imperialism, economic development, and urbanization in Latin America. In particular, they contrast the effects of nineteenth-century British capitalism and those of modern U.S. capitalism. The consequent development of urbanization patterns similar to those that occurred in Northern America is considered.^ieng