Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions.

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.

Differential presentation of hypersensitivity reactions to carboplatin and oxaliplatin: Phenotypes, endotypes, and management with desensitization.

BACKGROUND: Drug hypersensitivity reactions (DHRs) to platinum-based drugs are heterogenous and restrict their access, and drug desensitization (DD) has provided a ground-breaking procedure for their re-introduction, although the response is heterogeneous. We aimed to identify the phenotypes, endotypes, and biomarkers of reactions to carboplatin and oxaliplatin and their response to DD. METHODS: Seventy-nine patients presenting with DHRs to oxaliplatin (N = 46) and carboplatin (N = 33) were evaluated at the Allergy Departments of two tertiary care hospitals in Spain. Patient symptoms, skin testing, biomarkers, and outcomes of 267 DDs were retrospectively analyzed. RESULTS: Oxaliplatin-reactive patients presented with type I (74%), cytokine release reaction (CRR) (11%), and mixed (Mx) (15%) phenotypes. In contrast, carboplatin reactive patients presented with predominantly type I (85%) and Mx (15%) but no CRRs. Out of 267 DDs, breakthrough reactions (BTRs) to oxaliplatin occurred twice as frequently as carboplatin (32% vs. 15%; p < .05). Phenotype switching from type I to another phenotype was observed in 46% of oxaliplatin DDs compared to 21% of carboplatin DDs. Tryptase was elevated in type I and Mx reactions, and IL-6 in CRR and Mx, indicating different mechanisms and endotypes. CONCLUSION: Carboplatin and oxaliplatin induced three different types of reactions with defined phenotypes and endotypes amendable to DD. Although most of the initial reactions for both were type I, oxaliplatin presented with unique CRR reactions. During DD, carboplatin reactive patients presented mostly type I BTR, while oxaliplatin-reactive patients frequently switched from type I to CRR, providing a critical difference and the need for personalized DD protocols.

A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.

Metamorphism in TDP-43 prion-like domain determines chaperone recognition.

The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease.

Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the absence of a functional copy of the Survival of Motor Neuron 1 gene (SMN1). The nearly identical paralog, SMN2, cannot compensate for the loss of SMN1 because exon 7 is aberrantly skipped from most SMN2 transcripts, a process mediated by synergistic activities of Src-associated during mitosis, 68 kDa (Sam68/KHDRBS1) and heterogeneous nuclear ribonucleoprotein (hnRNP) A1. This results in the production of a truncated, nonfunctional protein that is rapidly degraded. Here, we present several crystal structures of Sam68 RNA-binding domain (RBD). Sam68-RBD forms stable symmetric homodimers by antiparallel association of helices α3 from two monomers. However, the details of domain organization and the dimerization interface differ significantly from previously characterized homologs. We demonstrate that Sam68 and hnRNP A1 can simultaneously bind proximal motifs within the central region of SMN2 (ex7). Furthermore, we show that the RNA-binding pockets of the two proteins are close to each other in their heterodimeric complex and identify contact residues using crosslinking-mass spectrometry. We present a model of the ternary Sam68·SMN2 (ex7)·hnRNP A1 complex that reconciles all available information on SMN1/2 splicing. Our findings have important implications for the etiology of SMA and open new avenues for the design of novel therapeutics to treat splicing diseases.

Manifestaciones psicopatológicas en una adolescente debido al impacto de la COVID-19

Introducción: La adolescencia es una de las etapas más trascendentales de la vida; en ella el cerebro experimenta una serie de cambios y conexiones que suponen un antes y un después para la persona. Cada adolescente vive esta experiencia de una manera diferente. Muchos estudios muestran las devastadoras consecuencias que ha dejado el confinamiento generado por la pandemia de COVID-19 en este segmento poblacional y la importancia de aplicar un tratamiento adecuado. Objetivo: Identificar las manifestaciones psicopatológicas frente al impacto de la COVID-19. Presentación del caso: Adolescente femenina, de 13 años, de procedencia urbana, con antecedentes de salud mental previa, que convive con ambos padres y una hermana menor, en un ambiente familiar armónico. Acudió al cuerpo de guardia en compañía de su madre, por presentar manifestaciones depresivas y ansiosas dadas por miedo a contagiarse, a la muerte, a estar sola, a la oscuridad, a perder a sus familiares, deambulaba de un lado a otro sin ningún propósito y se negaba a ingerir alimentos. Todo comenzó al inicio de la pandemia por la COVID-19. Se decidió su ingreso en la sala de psiquiatría del Hospital Pediátrico Docente Sur "Dr. Antonio María Béguez César" Santiago de Cuba en abril de 2020. Conclusiones: La intervención psicoterapéutica y el tratamiento psicofarmacológico, resultaron efectivos para disminuir la ansiedad, el miedo a la muerte, la fobia y los elementos obsesivos, la depresión y el insomnio, generados por el confinamiento debido a la pandemia por COVID-19.

Introduction: Adolescence is one of the most transcendental stages of life. In it the brain undergoes a series of changes and connections that represent a before and after for the person. Every teenager lives this experience in a different way. Many studies show the devastating consequences left by the confinement generated by the COVID-19 pandemic in this population segment, and the importance of applying adequate treatment. Objective: To identify the psycho-pathological manifestations against the impact of COVID-19. Case presentation: Female adolescent, 13 years old, of urban origin, with a previous mental health history, who lives with both parents and a younger sister, in a harmonious family environment. She went to the emergency service in the company of her mother, after presenting depressive and anxious manifestations given by fears of being infected, of death, of being alone, of darkness, of losing her relatives; she wandered back and forth without any purpose and refused to eat food. It all started at the beginning of the COVID-19 pandemic. It was decided to admit her to the psychiatric service of "Dr. Antonio María Béguez César" South Teaching Pediatric Hospital, in Santiago de Cuba province in April 2020. Conclusions: Psychotherapeutic intervention and psycho-pharmacological treatment were effective in reducing anxiety, fear of death, phobia and obsessive elements, and depression and insomnia generated by the confinement due to the COVID-19 pandemic.

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities.

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug design.

Encopresis en niños atendidos en consulta externa de psiquiatria infantil

RESUMEN La encopresis, también llamada incontinencia fecal o evacuación involuntaria de los intestinos, es el paso repetido de heces (por lo general involuntario) hacia la ropa. Suele suceder cuando las heces retenidas se acumulan en el colon y el recto; el colon se llena demasiado y las heces líquidas se filtran alrededor de las heces retenidas, lo que termina manchando la ropa interior. Apreciamos lo poco que se ha investigado este trastorno, que es abordado de forma breve y generalmente asociado a otros síntomas como la enuresis en los textos de psiquiatría y pediatría. Brindar información acerca de aspectos epidemiológicos, fisiopatològicos, causas, síntomas y opciones terapéuticas, entre otros, es el objetivo de esta publicación Los niños encopréticos son objetos de burlas, rechazo y manifestaciones agresivas de quienes lo rodean, pues consideran que este síntoma es producto de malacrianza o falta de vergüenza. La consulta de psiquiatría es importante ya que casi la mitad de los niños presentan problemas psicológicos que pueden ser la causa de la incontinencia o parte de las repercusiones. Se concluye que es pertinente implementar y promover medidas de prevención por parte de los médicos de atención primaria, que involucren no solo a los pacientes y sus familiares, sino también al personal responsable de los niños en las escuelas, círculos infantiles y lograr una adecuada adherencia al tratamiento multimodal. La mayor parte de los factores asociados son modificables como los malos hábitos para la defecación y los dietéticos.

ABSTRACT Encopresis, also called fecal incontinence or involuntary bowel movement is the repeated passage of stool (usually involuntary) into clothing. It usually happens when retained stool accumulates in the colon and rectum; the colon becomes too full and liquid stools seep around the retained stool, which ends up staining the underwear. We noticed how little research has been done on this disorder, which is addressed briefly and generally associated with other symptoms such as enuresis in psychiatry and pediatrics texts. Providing information about epidemiological aspects, pathophysiological aspects, causes, symptoms and therapeutic options, among others, is the objective of this publication. Encopretic children are objects of ridicule, rejection and aggressive manifestations of those around them, because they consider that this symptom is the product of churlishness or lack of shame. The psychiatry consultation is important since almost half of the children have psychological problems that can be the cause of incontinence or part of the repercussions. It is concluded that it is pertinent to implement and promote prevention measures by primary care physicians, involving not only patients and their families, but also the staff responsible for children in schools, kindergartens and achieving adequate adherence to multimodal treatment. Most of the associated factors are modifiable such as bad habits for defecation and dietetics.

Converter Phenotype: A New Profile That Is Not Exclusive to Taxanes.

Introduction: Phenotype I hypersensitivity reactions are the most commonly reported drug reactions; however, precision medicine has made it possible to characterize new phenotypes. A recent communication proposed the existence of a "converter phenotype," which would affect patients who present non-immediate hypersensitivity reactions and in subsequent exposures develop immediate hypersensitivity reactions. This study aimed to describe the clinical characteristics of converter phenotype reactions and their evolution during desensitization to chemotherapeutic drugs and monoclonal antibodies. Methods: We retrospectively reviewed our database of patients undergoing desensitization to chemotherapy or biological agents and selected those with a converter phenotype. Demographic and clinical characteristics of the patients, the results of skin tests, tryptase and IL-6 levels, and desensitization outcomes were assessed. Results: Of 116 patients evaluated, 12 (10.3%) were identified as having a converter phenotype. The median interval between drug exposure and reaction was 90.6 h (range 8-288 h). After the conversion, phenotype I was the most frequent (58.3%), followed by cytokine release reactions (33.3%). Fifty-one desensitizations were undertaken and all treatments completed, with 10 (19.6%) breakthrough reactions. No new changes in the phenotype were detected. Conclusions: The symptoms of non-immediate drug hypersensitivity reactions may indicate the need for an early allergological evaluation to assess the risk of future immediate drug reactions. Clinical characteristics, skin test results, and biomarkers can help predict responses to rapid drug desensitization, guiding clinicians on how to optimize therapy delivery while maintaining patient safety.

A predictive model for serious adverse events in adults with acute poisoning in prehospital and hospital care.

OBJECTIVE: The objective of this study was to design a risk model with variables determined before hospital arrival to predict the risk of serious adverse events in patients with acute poisoning. METHODS: A preliminary prospective, multicentre cohort study of adults with prehospital diagnosis of acute intoxication was conducted. The study was carried out in the Public Health System of the Community of Castilla-Leon (Spain), including seven advanced life support units and five hospitals, between April 1, 2018, and June 30, 2019. People aged >18 years with a main prehospital diagnosis of acute poisoning admitted to a referral hospital on advanced life support were included. The main outcome measure was prehospital and hospital serious adverse events in patients with acute poisoning. RESULTS: We included 221 patients, with a median age of 47 years (interquartile range: 33-61). The most frequent cause of poisoning was psychopharmaceuticals (111 cases, 49.8%): 38 (17.2%) patients had a serious adverse event, with a hospital mortality of 4.1% (nine cases) in the 30 days after the index event. The final model included age ≥65 years (odds ratio [OR]: 9.59, 95% confidence interval [CI]: 3.48-26.45; p < 0.001), oxygen saturation/fraction of inspired oxygen index ≤300 (OR: 15.03, 95% CI: 5.74-39.33; p < 0.001), and point-of-care lactate ≥4 mmol/L (OR: 7.68, 95% CI: 2.88-20.45; p < 0.001). The poisoning Early Warning Score was constructed from these three variables, and 1 point was assigned to each variable. The area under the curve of the score was 0.896 (95% CI: 0.82-0.96; p < 0.001). CONCLUSIONS: The poisoning Early Warning Score may help in decision-making and promote early identification of high-risk patients with acute poisoning in the prehospital context.

TET2 missense variants in human neoplasia. A proposal of structural and functional classification.

BACKGROUND: The human TET2 gene plays a pivotal role in the epigenetic regulation of normal and malignant hematopoiesis. Somatic TET2 mutations have been repeatedly identified in age-related clonal hematopoiesis and in myeloid neoplasms ranging from acute myeloid leukemia (AML) to myeloproliferative neoplasms. However, there have been no attempts to systematically explore the structural and functional consequences of the hundreds of TET2 missense variants reported to date. METHODS: We have sequenced the TET2 gene in 189 Spanish AML patients using Sanger sequencing and NGS protocols. Next, we performed a thorough bioinformatics analysis of TET2 protein and of the expected impact of all reported TET2 missense variants on protein structure and function, exploiting available structure-and-function information as well as 3D structure prediction tools. RESULTS: We have identified 38 TET2 allelic variants in the studied patients, including two frequent SNPs: p.G355D (10 cases) and p.I1762V (28 cases). Four of the detected mutations are reported here for the first time: c.122C>T (p.P41L), c.4535C>G (p.A1512G), c.4760A>G (p.D1587G), and c.5087A>T (p.Y1696F). We predict a complex multidomain architecture for the noncatalytic regions of TET2, and in particular the presence of well-conserved α+ß globular domains immediately preceding and following the actual catalytic unit. Further, we provide a rigorous interpretation of over 430 missense SNVs that affect the TET2 catalytic domain, and we hypothesize explanations for ~700 additional variants found within the regulatory regions of the protein. Finally, we propose a systematic classification of all missense mutants and SNPs reported to date into three major categories (severe, moderate, and mild), based on their predicted structural and functional impact. CONCLUSIONS: The proposed classification of missense TET2 variants would help to assess their clinical impact on human neoplasia and may guide future structure-and-function investigations of TET family members.

Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants.

Inflammation and immune-mediated processes are pivotal to the pathogenic progression of age-related macular degeneration (AMD). Although plasma levels of C-reactive protein (CRP) have been shown to be associated with an increased risk for AMD, the pathophysiological importance of the prototypical acute-phase reactant in the etiology of the disease is unknown, and data regarding the exact role of CRP in ocular inflammation are limited. In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the "risk" His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained.

Cadmium-induced oxidative stress and histological damage in the myocardium. Effects of a soy-based diet.

Cd exposure has been associated to an augmented risk for cardiovascular disease. We investigated the effects of 15 and 100 ppm of Cd on redox status as well as histological changes in the rat heart and the putative protective effect of a soy-based diet. Male Wistar rats were separated into 6 groups and treated during 60 days as follows: groups (1), (2) and (3) were fed a casein-based diet; groups (4), (5) and (6), a soy-based diet; (1) and (4) were given tap water; (2) and (5) tap water containing 15 ppm of Cd²âº; and (3) and (6) tap water containing 100 ppm of Cd²âº. Serum lipid peroxides increased and PON-1 activity decreased in group (3). Lipoperoxidation also increased in the heart of all intoxicated groups; however protein oxidation only augmented in (3) and reduced glutathione levels diminished in (2) and (3). Catalase activity increased in groups (3) and (6) while superoxide dismutase activity increased only in (6). Glutathione peroxidase activity decreased in groups (3) and (6). Nrf2 expression was higher in groups (3) and (6), and MTI expression augmented in (3). Histological examination of the heart tissue showed the development of hypertrophic and fusion of cardiomyocytes along with foci of myocardial fiber necrosis. The transmission electron microscopy analysis showed profound ultra-structural damages. No protection against tissue degeneration was observed in animals fed the soy-based diet. Our findings indicate that even though the intake of a soy-based diet is capable of ameliorating Cd induced oxidative stress, it failed in preventing cardiac damage.

Interaction between head and neck squamous cell carcinoma cells and fibroblasts in the biosynthesis of PGE2.

Prostaglandin (PG)E(2) is relevant in tumor biology, and interactions between tumor and stroma cells dramatically influence tumor progression. We tested the hypothesis that cross-talk between head and neck squamous cell carcinoma (HNSCC) cells and fibroblasts could substantially enhance PGE(2) biosynthesis. We observed an enhanced production of PGE(2) in cocultures of HNSCC cell lines and fibroblasts, which was consistent with an upregulation of COX-2 and microsomal PGE-synthase-1 (mPGES-1) in fibroblasts. In cultured endothelial cells, medium from fibroblasts treated with tumor cell-conditioned medium induced in vitro angiogenesis, and in tumor cell induced migration and proliferation, these effects were sensitive to PGs inhibition. Proteomic analysis shows that tumor cells released IL-1, and tumor cell-induced COX-2 and mPGES-1 were suppressed by the IL-1-receptor antagonist. IL-1α levels were higher than those of IL-1ß in the tumor cell-conditioning medium and in the secretion from samples obtained from 20 patients with HNSCC. Fractionation of tumor cell-conditioning media indicated that tumor cells secreted mature and unprocessed forms of IL-1. Our results support the concept that tumor-associated fibroblasts are a relevant source of PGE(2) in the tumor mass. Because mPGES-1 seems to be essential for a substantial biosynthesis of PGE(2), these findings also strengthen the concept that mPGES-1 may be \a target for therapeutic intervention in patients with HNSCC.

Modelling spatial and temporal variations in the water quality of an artificial water reservoir in the semiarid midwest of Argentina.

Temporal and spatial patterns of water quality of an important artificial water reservoir located in the semiarid Midwest of Argentina were investigated using chemometric techniques. Surface water samples were collected at 38 points of the water reservoir during eleven sampling campaigns between October 1998 and June 2000, covering the warm wet season and the cold dry season, and analyzed for dissolved oxygen (DO), conductivity, pH, ammonium, nitrate, nitrite, total dissolved solids (TDS), alkalinity, hardness, bicarbonate, chloride, sulfate, calcium, magnesium, fluoride, sodium, potassium, iron, aluminum, silica, phosphate, sulfide, arsenic, chromium, lead, cadmium, chemical oxygen demand (COD), biochemical oxygen demand (BOD), viable aerobic bacteria (VAB) and total coliform bacteria (TC). Concentrations of lead, ammonium, nitrite and coliforms were higher than the maximum allowable limits for drinking water in a large proportion of the water samples. To obtain a general representation of the spatial and temporal trends of the water quality parameters at the reservoir, the three-dimensional dataset (sampling sites×parameters×sampling campaigns) has been analyzed by matrix augmentation principal component analysis (MA-PCA) and N-way principal component analysis (N-PCA) using Tucker3 and PARAFAC (Parallel Factor Analysis) models. MA-PCA produced a component accounting for the general behavior of parameters associated with organic pollution. The Tucker3 models were not appropriate for modelling the water quality dataset. The two-factor PARAFAC model provided the best picture to understand the spatial and temporal variation of the water quality parameters of the reservoir. The first PARAFAC factor contains useful information regarding the relation of organic pollution with seasonality, whereas the second factor also encloses information concerning lead pollution. The most polluted areas in the reservoir and the polluting sources were identified by plotting PARAFAC loadings as a function of the UTM (Universal Transverse Mercator) coordinates.

Myocardial oxidative stress following sub-chronic and chronic oral cadmium exposure in rats.

We investigated the effect of oral cadmium intoxication on the antioxidant/prooxidant status in serum and heart. Wistar rats, separated into four groups, that received: (1) tap water for 60 days (control); (2), (3) and (4) Cd(2+) (15 ppm)-containing water, during 15, 30 and 60 days, respectively. Lipoperoxidation increased in serum and heart of group 4. Circulating paraoxonase-1 activity was higher in groups 2 and 3. Protein carbonyl-groups increased while total and reduced glutathione levels decreased in the heart after 15 days of cadmium intoxication. Cardiac catalase activity was higher in groups 3 and 4 but glutathione peroxidase activity diminished in the heart of all poisoned groups. Superoxide dismutase transcript levels as well as Nrf2 expression also increased in the heart of groups 2 and 3, while gp91phox and p47phox mRNA levels rose only in group 3. We suggest cadmium intoxication modifies antioxidant/prooxidant ratio in serum and heart in a time-of-exposure-dependent way.

Lead and cadmium accumulation in anuran amphibians of a permanent water body in arid Midwestern Argentina.

PURPOSE: Heavy metals have been detected in water and sediments from the Embalse La Florida, an artificial lake in the arid region of San Luis province, Argentina, representing one of the few sources of permanent water for reproduction of native anuran species. This study assesses lead (Pb) and cadmium (Cd) concentrations in the anuran species found in this water reservoir as well as differences between compounds, species and sites of collection. METHODS: Adult anuran amphibians were collected on the north and south shores of the Embalse La Florida and Pb and Cd concentrations were measured in whole body homogenates digested using wet ashing techniques. RESULTS: All individuals of the six species assayed had detectable levels of Pb and Cd that ranged from 1.19 to 5.57 µg/g dry mass and from 1.09 to 6.86 µg/g dry mass, respectively. Anuran amphibians collected in the more contaminated south shore accumulated 21% more Cd and 40% more Pb than individuals from the less altered north shore. Cd and Pb accumulation was not significantly correlated with the concentration in water at the site of collection. CONCLUSIONS: Amphibians of the Embalse La Florida accumulate Cd and Pb. Between and within species, differences were detected in Cd and Pb concentrations. Differences in metal concentrations between species, metals, and individuals collected on shores of the Embalse La Florida with different contamination, were detected. Therefore, it is crucial to implement adequate policies to protect amphibians from the accelerated urban development experienced in this location.

Plasticity in food assimilation, retention time and coprophagy allow herbivorous cavies (Microcavia australis) to cope with low food quality in the Monte desert.

Energy balance depends on the efficiency with which organisms make use of their trophic resources, and has direct impact on their fitness. There are environmental variations that affect the availability as well as the quality of such resources; energy extraction also depends on the design of the digestive tract. It is expected that features associated with food utilization will be subjected to selective pressures and show some adjustment to the variability of the environment. Since energetic constraints challenge animals to display digestive compensatory mechanisms, the objective of this study is to determine the physiological and behavioral responses to spatial and seasonal heterogeneity in food quality. We investigated digestive strategies (digestive efficiency and coprophagy) in cavies inhabiting two different populations, and hence naturally experiencing different levels of diet quality. Cavies under experimentally different quality diets showed changes in dry matter digestibility and intake, digesta retention time and coprophagy. Our results partially support the expectations from theory and also reveal interpopulation differences in the ability to cope with changes in food quality, and may explain the capability of Microcavia australis to colonize extreme habitats.

Heritability of thromboxane A2 and prostaglandin E2 biosynthetic machinery in a Spanish population.

OBJECTIVE: Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated. METHODS AND RESULTS: The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found. CONCLUSIONS: These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.

Contamination of heavy metals in birds from Embalse La Florida (San Luis, Argentina).

Embalse La Florida is an artificial lake located in midwestern Argentina's San Luis province. It provides drinking water to approximately 70% of the province's human population and approximately 20% of the province is irrigated with water from the reservoir. The presence of heavy metals in Embalse La Florida's water has previously been reported. Nevertheless, no information about the levels of these contaminants in birds is available for this region. The aim of this study, therefore, is to (1) establish baseline data on lead (Pb) and cadmium (Cd) levels in birds from Embalse La Florida, (2) assess metal accumulation patterns between organs and bird species, and (3) evaluate the potential risk that these heavy metals pose for the local avifauna. We measured Pb and Cd in bone, pectoralis muscle, liver, gonad, and brain of three bird species representative of the Embalse La Florida ecosystem: Podiceps major (Great Grebe), Phalacrocorax brasilianus (Neotropic Cormorant), both of which are piscivorous, and Pitangus sulphuratus (Great Kiskadee), which is omnivorous. We also measured both heavy metals in Great Grebe eggs. Pb and Cd were detected in all of the tissues we assayed, and Pb concentrations were significantly higher than those for Cd in all tissues. The patterns of Pb and Cd accumulation differed between tissues, however. In general, gonads had the highest concentrations of Pb while Cd tended to accumulate in the liver. An interspecific analysis revealed that the omnivorous species had higher levels of both metals in bone, liver, and brain compared to both piscivorous species. There were no differences in Pb and Cd concentrations between males and females. The highest liver level of Pb (4.69 ppm wet weight) detected in Great Kiskadee, was comparable to those associated with toxic effects in birds, and Pb concentrations found in the liver of two females and two males (2.07 to 2.32 ppm wet weight) were also similar to those that could be physiologically detrimental in other species. In all birds assayed, Cd levels in liver tissue were lower than those typically shown to be harmful. Our results indicate that Great Kiskadees are highly polluted by Pb and their exposure to this contaminant exceeds the level reported to trigger adverse effects. This is the first study to assay heavy metals in birds from midwest Argentina and provides a starting point for studies examining the impact that these metals have on both wildlife and humans in the region.